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Entry
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- *300017 - FILAMIN A; FLNA
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- OMIM
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<div class="container hidden-print">
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<div id="mimAlertBanner">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300017</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/300017">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000196924;t=ENST00000369850" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=2316" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=300017" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000196924;t=ENST00000369850" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001110556,NM_001456" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001110556" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=300017" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=02060&isoform_id=02060_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/FLNA" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/28243,1203969,1335065,1657316,15779184,18676444,27552849,45595637,53791219,53791221,116063573,116241365,119593150,119593151,119593152,119593153,119593154,145207313,160420317,190192178,190192180,190192182,190192184,190192186,190192188,194385488,194390356,308219538,317040158,326205158,384368273,384368275,667630687,929654832" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P21333" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=2316" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000196924;t=ENST00000369850" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=FLNA" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=FLNA" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+2316" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/FLNA" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:2316" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/2316" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chrX&hgg_gene=ENST00000369850.10&hgg_start=154348531&hgg_end=154374634&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3754" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3754" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/flna" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300017[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/c213e412-f88e-4b2a-882c-b376efd92d46/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=300017[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/FLNA/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000196924" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=FLNA" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=FLNA" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=FLNA" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/FLNA" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FLNA&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA28172" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
|
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</a>
|
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</span>
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</span>
|
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</div>
|
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:3754" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0014141.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:95556" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/FLNA#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:95556" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/2316/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2316" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00022048;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-2145" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2316" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=FLNA&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1186709006, 13449007, 42432003, 448227009, 54036001, 784010006<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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300017
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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FILAMIN A; FLNA
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</span>
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</h3>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
FILAMIN, ALPHA<br />
|
|
FILAMIN 1; FLN1<br />
|
|
FLN<br />
|
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ACTIN-BINDING PROTEIN 280; ABP280
|
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</span>
|
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</h4>
|
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</div>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FLNA" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FLNA</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/X/857?start=-3&limit=10&highlight=857">Xq28</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:154348531-154374634&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">X:154,348,531-154,374,634</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
</span>
|
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</p>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=300321,314400,300048,305620,300049,300048,309350,311300,304120,300244" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="10">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/857?start=-3&limit=10&highlight=857">
|
|
Xq28
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?FG syndrome 2
|
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
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<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
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</span>
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<span class="mim-font">
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<a href="/entry/300321"> 300321 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="X-linked">XL</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Cardiac valvular dysplasia, X-linked
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<td>
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<span class="mim-font">
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<a href="/entry/314400"> 314400 </a>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="X-linked">XL</abbr>
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</span>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Congenital short bowel syndrome
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<span class="mim-font">
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<a href="/entry/300048"> 300048 </a>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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<tr>
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<td>
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<span class="mim-font">
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Frontometaphyseal dysplasia 1
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<td>
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<span class="mim-font">
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<a href="/entry/305620"> 305620 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<td>
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<span class="mim-font">
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Heterotopia, periventricular, 1
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</span>
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<span class="mim-font">
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<a href="/entry/300049"> 300049 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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<tr>
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<span class="mim-font">
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Intestinal pseudoobstruction, neuronal
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/300048"> 300048 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Melnick-Needles syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/309350"> 309350 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Otopalatodigital syndrome, type I
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/311300"> 311300 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Otopalatodigital syndrome, type II
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/304120"> 304120 </a>
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
|
Terminal osseous dysplasia
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
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<a href="/entry/300244"> 300244 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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|
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<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/300017" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/300017" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>The FLNA gene encodes filamin A, a widely expressed 280-kD actin-binding protein that regulates reorganization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes, and second messengers. Filamins crosslink actin filaments into orthogonal networks in the cytoplasm and participate in the anchoring of membrane proteins to the actin cytoskeleton. Remodeling of the cytoskeleton is central to the modulation of cell shape and migration (<a href="#42" class="mim-tip-reference" title="Maestrini, E., Patrosso, C., Mancini, M., Rivella, S., Rocchi, M., Repetto, M., Villa, A., Frattini, A., Zoppe, M., Vezzoni, P., Toniolo, D. <strong>Mapping of two genes encoding isoforms of the actin binding protein ABP-280, a dystrophin like protein, to Xq28 and to chromosome 7.</strong> Hum. Molec. Genet. 2: 761-766, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7689010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7689010</a>] [<a href="https://doi.org/10.1093/hmg/2.6.761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7689010">Maestrini et al., 1993</a>; <a href="#19" class="mim-tip-reference" title="Fox, J. W., Lamperti, E. D., Eksioglu, Y. Z., Hong, S. E., Feng, Y., Graham, D. A., Scheffer, I. E., Dobyns, W. B., Hirsch, B. A., Radtke, R. A., Berkovic, S. F., Huttenlocher, P. R., Walsh, C. A. <strong>Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.</strong> Neuron 21: 1315-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9883725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9883725</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80651-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9883725">Fox et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9883725+7689010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>By analysis of the native ABP280 protein and cloning of the human endothelial ABP280 cDNA, <a href="#25" class="mim-tip-reference" title="Gorlin, J. B., Yamin, R., Egan, S., Stewart, M., Stossel, T. P., Kwiatkowski, D. J., Hartwig, J. H. <strong>Human endothelial actin-binding protein (ABP-280, nonmuscle filamin): a molecular leaf spring.</strong> J. Cell Biol. 111: 1089-1105, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2391361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2391361</a>] [<a href="https://doi.org/10.1083/jcb.111.3.1089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2391361">Gorlin et al. (1990)</a> demonstrated that ABP280 is a 2,647-amino acid protein with 3 functional domains: an N-terminal filamentous actin-binding domain, a C-terminal self-association domain, and a membrane glycoprotein-binding domain. The N-terminal actin-binding domain of ABP280 displays strong structural and functional similarity to the N-terminal domains of dystrophin (<a href="/entry/300377">300377</a>), alpha-actinin (<a href="/entry/102575">102575</a>), and beta-spectrin (<a href="/entry/182870">182870</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2391361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a search for muscle- and heart-specific isoforms that might be involved in Emery muscular dystrophy (EDMD; <a href="/entry/310300">310300</a>), <a href="#42" class="mim-tip-reference" title="Maestrini, E., Patrosso, C., Mancini, M., Rivella, S., Rocchi, M., Repetto, M., Villa, A., Frattini, A., Zoppe, M., Vezzoni, P., Toniolo, D. <strong>Mapping of two genes encoding isoforms of the actin binding protein ABP-280, a dystrophin like protein, to Xq28 and to chromosome 7.</strong> Hum. Molec. Genet. 2: 761-766, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7689010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7689010</a>] [<a href="https://doi.org/10.1093/hmg/2.6.761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7689010">Maestrini et al. (1993)</a> identified several different ABP280 mRNAs. Two were X-linked and were produced by alternative splicing of a small exon of 24 nucleotides. Both of these were ubiquitous in distribution. At least 1 additional gene encoding an RNA more than 70% identical to ABP280 was found and was shown to map to chromosome 7 by study of human/hamster somatic cell hybrids (FLNC; <a href="/entry/102565">102565</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7689010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<br />
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<div>
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<a id="geneStructure" class="mim-anchor"></a>
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<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimGeneStructureToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<div id="mimGeneStructureFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#49" class="mim-tip-reference" title="Patrosso, M. C., Repetto, M., Villa, A., Milanesi, L., Frattini, A., Faranda, S., Mancini, M., Maestrini, E., Toniolo, D., Vezzoni, P. <strong>The exon-intron organization of the human X-linked gene (FLN1) encoding actin-binding protein 280.</strong> Genomics 21: 71-76, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8088819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8088819</a>] [<a href="https://doi.org/10.1006/geno.1994.1226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8088819">Patrosso et al. (1994)</a> found that the FLN1 gene is composed of 47 exons spanning approximately 26 kb. The first and part of the second exon are untranslated. The actin-binding domain at the N terminus is encoded by exons 2 to 5. The 96-amino acid repeats corresponding to the elongated backbone of the protein are encoded by the remaining 42 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8088819" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Fox, J. W., Lamperti, E. D., Eksioglu, Y. Z., Hong, S. E., Feng, Y., Graham, D. A., Scheffer, I. E., Dobyns, W. B., Hirsch, B. A., Radtke, R. A., Berkovic, S. F., Huttenlocher, P. R., Walsh, C. A. <strong>Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.</strong> Neuron 21: 1315-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9883725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9883725</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80651-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9883725">Fox et al. (1998)</a> stated that FLN1 consists of 48 exons covering 26 kb of genomic sequence, with a 7.9-kb open reading frame. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9883725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Chakarova, C., Wehnert, M. S., Uhl, K., Sakthivel, S., Vosberg, H.-P., van der Ven, P. F. M., Furst, D. O. <strong>Genomic structure and fine mapping of the two human filamin gene paralogues FLNB and FLNC and comparative analysis of the filamin gene family.</strong> Hum. Genet. 107: 597-611, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11153914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11153914</a>] [<a href="https://doi.org/10.1007/s004390000414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11153914">Chakarova et al. (2000)</a> compared the genomic structure of the filamin gene family. A previously unknown intron was found in FLNA. The comparison of FLNA with the 2 paralogs, FLNB (<a href="/entry/603381">603381</a>) and FLNC, demonstrated a highly conserved exon/intron structure with significant differences in exon 32 of all paralogs encoding the hinge I region, as well as the insertion of a novel exon 40A in FLNC only. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11153914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>When sequences from CpG islands in the Xq28 region (<a href="#43" class="mim-tip-reference" title="Maestrini, E., Rivella, S., Tribioli, C., Purtilo, D., Rocchi, M., Archidiacono, N., Toniolo, D. <strong>Probes for CpG islands on the distal long arm of the human X chromosome are clustered in Xq24 and Xq28.</strong> Genomics 8: 664-670, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2177445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2177445</a>] [<a href="https://doi.org/10.1016/0888-7543(90)90253-q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2177445">Maestrini et al., 1990</a>) were compared to sequences in databases, the gene for ABP280 was found. It is located in the distal part of Xq28, 50-60 kb downstream of the colorblindness genes. A similar localization was reported by <a href="#38" class="mim-tip-reference" title="Kunst, C. B., Henske, E., Hartwig, J. H., Kwiatkowski, D. J., D'Urso, M., Bruns, G., Warren, S. T., Gorlin, J. B. <strong>The dystrophin-like actin binding protein 280 gene maps between DXS52 and G6PD overlapping the Emery-Dreifuss muscular dystrophy locus. (Abstract)</strong> Am. J. Hum. Genet. 51: A21, 1992."None>Kunst et al. (1992)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2177445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Kunst, C. B., Henske, E., Hartwig, J. H., Kwiatkowski, D. J., D'Urso, M., Bruns, G., Warren, S. T., Gorlin, J. B. <strong>The dystrophin-like actin binding protein 280 gene maps between DXS52 and G6PD overlapping the Emery-Dreifuss muscular dystrophy locus. (Abstract)</strong> Am. J. Hum. Genet. 51: A21, 1992."None>Kunst et al. (1992)</a> mapped the ABP280 cDNA to Xq28 by somatic hybrid cell panel analysis and fluorescence in situ hybridization (FISH).</p><p><a href="#24" class="mim-tip-reference" title="Gorlin, J. B., Henske, E., Warren, S. T., Kunst, C. B., D'Urso, M., Palmieri, G., Hartwig, J. H., Bruns, G., Kwiatkowski, D. J. <strong>Actin-binding protein (ABP-280) filamin gene (FLN) maps telomeric to the color vision locus (R/GCP) and centromeric to G6PD in Xq28.</strong> Genomics 17: 496-498, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8406501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8406501</a>] [<a href="https://doi.org/10.1006/geno.1993.1354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8406501">Gorlin et al. (1993)</a> mapped the FLN gene to Xq28 by Southern blot analysis of somatic cell hybrid lines, by FISH, and by identification of portions of the FLN gene within cosmids and YACs mapped to Xq28. Specifically, the FLN gene was located within a 200-kb region between the G6PD locus at the telomeric end and the colorblindness loci and the DXS52 marker at the proximal end. Because of its similarities to dystrophin, <a href="#24" class="mim-tip-reference" title="Gorlin, J. B., Henske, E., Warren, S. T., Kunst, C. B., D'Urso, M., Palmieri, G., Hartwig, J. H., Bruns, G., Kwiatkowski, D. J. <strong>Actin-binding protein (ABP-280) filamin gene (FLN) maps telomeric to the color vision locus (R/GCP) and centromeric to G6PD in Xq28.</strong> Genomics 17: 496-498, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8406501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8406501</a>] [<a href="https://doi.org/10.1006/geno.1993.1354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8406501">Gorlin et al. (1993)</a> suggested FLN as a candidate gene for 2 myopathies that map to Xq28: EDMD and Barth syndrome (<a href="/entry/302060">302060</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8406501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Fox, J. W., Lamperti, E. D., Eksioglu, Y. Z., Hong, S. E., Feng, Y., Graham, D. A., Scheffer, I. E., Dobyns, W. B., Hirsch, B. A., Radtke, R. A., Berkovic, S. F., Huttenlocher, P. R., Walsh, C. A. <strong>Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.</strong> Neuron 21: 1315-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9883725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9883725</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80651-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9883725">Fox et al. (1998)</a> stated that the FLN1 gene is adjacent to the emerin gene (<a href="/entry/300384">300384</a>), which is mutant in EDMD, and the 2 genes are flanked by inverted repeats, causing the genomic segment containing these 2 genes to be present in 2 orientations in the population at large (<a href="#59" class="mim-tip-reference" title="Small, K., Wagener, M., Warren, S. T. <strong>Isolation and characterization of the complete mouse emerin gene.</strong> Mammalian Genome 8: 337-341, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9107678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9107678</a>] [<a href="https://doi.org/10.1007/s003359900435" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9107678">Small et al., 1997</a>). Notably, all large-scale rearrangements of emerin associated with EDMD failed to include FLN1, suggesting that loss of FLN1 function might be embryonically lethal. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9107678+9883725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Gariboldi, M., Maestrini, E., Canzian, F., Manenti, G., De Gregorio, L., Rivella, S., Chatterjee, A., Herman, G. E., Archidiacono, N., Antonacci, R., Pierotti, M. A., Dragani, T. A., Toniolo, D. <strong>Comparative mapping of the actin-binding protein 280 genes in human and mouse.</strong> Genomics 21: 428-430, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8088838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8088838</a>] [<a href="https://doi.org/10.1006/geno.1994.1288" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8088838">Gariboldi et al. (1994)</a> mapped the mouse homolog to the X chromosome in a region of syntenic homology with Xq28. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8088838" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#9" class="mim-tip-reference" title="Clark, A. R., Sawyer, G. M., Robertson, S. P., Sutherland-Smith, A. J. <strong>Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders.</strong> Hum. Molec. Genet. 18: 4791-4800, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19773341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19773341</a>] [<a href="https://doi.org/10.1093/hmg/ddp442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19773341">Clark et al. (2009)</a> determined the crystal structures of wildtype and E254K (<a href="#0010">300017.0010</a>)-mutant FLNA actin-binding domains (ABDs) at 2.3-angstrom resolution, revealing that they adopt similar closed conformations. The E254K mutation removes a conserved salt bridge but does not disrupt the ABD structure. The solution structures are also equivalent as determined by circular dichroism spectroscopy, but differential scanning fluorimetry denaturation showed reduced thermal stability for E254K. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19773341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#64" class="mim-tip-reference" title="Vadlamudi, R. K., Li, F., Adam, L., Nguyen, D., Ohta, Y., Stossel, T. P., Kumar, R. <strong>Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1.</strong> Nature Cell Biol. 4: 681-690, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198493</a>] [<a href="https://doi.org/10.1038/ncb838" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12198493">Vadlamudi et al. (2002)</a> identified FLNA as a binding partner of PAK1 (<a href="/entry/602590">602590</a>) in a yeast 2-hybrid screen of a mammary gland cDNA library. By mutation analysis, they localized the PAK1-binding region in FLNA to tandem repeat 23 in the C terminus, and the FLNA-binding region in PAK1 between amino acids 52 and 132 in the conserved CDC42 (<a href="/entry/116952">116952</a>)/RAC (<a href="/entry/602048">602048</a>)-interacting domain. Endogenous FLNA was phosphorylated by PAK1 on ser2152 following stimulation with physiologic signaling molecules. Following stimulation, FLNA colocalized with PAK1 in membrane ruffles. The ruffle-forming activity of PAK1 was found in FLNA-expressing cells, but not in cells deficient in FLNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12198493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Androgen receptor (AR; <a href="/entry/313700">313700</a>), a nuclear transcription factor, mediates male sexual differentiation. <a href="#41" class="mim-tip-reference" title="Loy, C. J., Sim, K. S., Yong, E. L. <strong>Filamin-A fragment localizes to the nucleus to regulate androgen receptor and coactivator functions.</strong> Proc. Nat. Acad. Sci. 100: 4562-4567, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12682292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12682292</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12682292[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0736237100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12682292">Loy et al. (2003)</a> characterized a negative regulatory domain in the AR hinge region that interacts with filamin A. Filamin A interferes with AR interdomain interactions and competes with the coactivator transcriptional intermediary factor-2 (TIF2; <a href="/entry/601993">601993</a>) to downregulate AR function specifically. Although full-length filamin A is predominantly cytoplasmic, a C-terminal 100-kD fragment colocalized with AR to the nucleus. This naturally occurring filamin A fragment repressed AR transactivation and disrupted AR interdomain interactions and TIF2-activated AR function in a manner reminiscent of full-length filamin A, raising the possibility that the inhibitory effects of cytoplasmic filamin A may be transduced through this fragment, which can localize to the nucleus and form part of the preinitiation complex. This unanticipated role of filamin A added to the evidence for the involvement of cytoskeletal proteins in transcription regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12682292" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Mutation in the X-linked FLNA gene can cause the neurologic disorder periventricular heterotopia (<a href="/entry/300049">300049</a>). Although periventricular heterotopia is characterized by a failure in neuronal migration into the cerebral cortex with consequent formation of nodules in the ventricular and subventricular zones, many neurons appear to migrate normally, even in males, suggesting compensatory mechanisms. <a href="#56" class="mim-tip-reference" title="Sheen, V. L., Feng, Y., Graham, D., Takafuta, T., Shapiro, S. S., Walsh, C. A. <strong>Filamin A and filamin B are co-expressed within neurons during periods of neuronal migration and can physically interact.</strong> Hum. Molec. Genet. 11: 2845-2854, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12393796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12393796</a>] [<a href="https://doi.org/10.1093/hmg/11.23.2845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12393796">Sheen et al. (2002)</a> showed that, in mice, Flna mRNA was widely expressed in all brain cortical layers, whereas a homolog, Flnb (<a href="/entry/603381">603381</a>), was most highly expressed in the ventricular and subventricular zones during development. In adulthood, widespread but reduced expression of Flna and Flnb persisted throughout the cerebral cortex. Flna and Flnb proteins were highly expressed in both the leading processes and somata of migratory neurons during corticogenesis. Postnatally, Flna immunoreactivity was largely localized to the cell body, whereas Flnb was localized to the soma and neuropil during neuronal differentiation. The putative Flnb homodimerization domain strongly interacted with itself or the corresponding homologous region of Flna, as shown by yeast 2-hybrid interaction. The 2 proteins colocalized within neuronal precursors by immunocytochemistry, and the existence of Flna-Flnb heterodimers could be detected by coimmunoprecipitation. <a href="#56" class="mim-tip-reference" title="Sheen, V. L., Feng, Y., Graham, D., Takafuta, T., Shapiro, S. S., Walsh, C. A. <strong>Filamin A and filamin B are co-expressed within neurons during periods of neuronal migration and can physically interact.</strong> Hum. Molec. Genet. 11: 2845-2854, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12393796/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12393796</a>] [<a href="https://doi.org/10.1093/hmg/11.23.2845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12393796">Sheen et al. (2002)</a> suggested that FLNA and FLNB may form both homodimers and heterodimers, and that their interaction could potentially compensate for the loss of FLNA function during cortical development within patients with periventricular heterotopia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12393796" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a yeast 2-hybrid screen, <a href="#27" class="mim-tip-reference" title="Grimbert, P., Valanciute, A., Audard, V., Lang, P., Guellaen, G., Sahali, D. <strong>The filamin-A is a partner of Tc-mip, a new adapter protein involved in c-maf-dependent Th2 signaling pathway.</strong> Molec. Immun. 40: 1257-1261, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15128042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15128042</a>] [<a href="https://doi.org/10.1016/j.molimm.2003.11.035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15128042">Grimbert et al. (2004)</a> identified FLNA as a binding partner for both CMIP (<a href="/entry/610112">610112</a>) and its truncated isoform, TCMIP. Coimmunoprecipitation analysis confirmed the interactions. Immunofluorescence microscopy demonstrated homogeneous colocalization of CMIP and FLNA in the cytoplasm, but restriction of TCMIP/FLNA colocalization to points of intercellular contact. Western blot analysis showed increased FLNA expression in patients with relapse of minimal change nephrotic syndrome, a glomerular disease thought to result from abnormal T-cell activation. <a href="#27" class="mim-tip-reference" title="Grimbert, P., Valanciute, A., Audard, V., Lang, P., Guellaen, G., Sahali, D. <strong>The filamin-A is a partner of Tc-mip, a new adapter protein involved in c-maf-dependent Th2 signaling pathway.</strong> Molec. Immun. 40: 1257-1261, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15128042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15128042</a>] [<a href="https://doi.org/10.1016/j.molimm.2003.11.035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15128042">Grimbert et al. (2004)</a> proposed that FLNA and CMIP/TCMIP interact in a T-cell signaling pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15128042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using proteomic approaches, <a href="#62" class="mim-tip-reference" title="Thelin, W. R., Chen, Y., Gentzsch, M., Kreda, S. M., Sallee, J. L., Scarlett, C. O., Borchers, C. H., Jacobson, K., Stutts, M. J., Milgram, S. L. <strong>Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR.</strong> J. Clin. Invest. 117: 364-374, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235394</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17235394[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI30376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235394">Thelin et al. (2007)</a> showed that FLNA associates with the extreme CFTR (<a href="/entry/602421">602421</a>) N terminus. Cell studies revealed that filamin tethers plasma membrane CFTR to the underlying actin network, stabilizing CFTR at the cell surface and regulating the plasma membrane dynamics and confinement of the channel. In the absence of filamin binding, CFTR is rapidly internalized from the cell surface, where it accumulates prematurely in lysosomes and is ultimately degraded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17235394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid analysis and protein pull-down assays, <a href="#35" class="mim-tip-reference" title="Jimenez-Baranda, S., Gomez-Mouton, C., Rojas, A., Martinez-Prats, L., Mira, E., Lacalle, R. A., Valencia, A., Dimitrov, D. S., Viola, A., Delgado, R., Martinez-A., C., Manes, S. <strong>Filamin-A regulates actin-dependent clustering of HIV receptors.</strong> Nature Cell Biol. 9: 838-846, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17572668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17572668</a>] [<a href="https://doi.org/10.1038/ncb1610" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17572668">Jimenez-Baranda et al. (2007)</a> showed that the human immunodeficiency virus (HIV)-1 (see <a href="/entry/609423">609423</a>) receptor CD4 (<a href="/entry/186940">186940</a>) and the HIV-1 coreceptors CCR5 (<a href="/entry/601373">601373</a>) and CXCR4 (<a href="/entry/162643">162643</a>) interacted with FLNA, which regulated clustering of the HIV-1 receptors on the cell surface. Binding of HIV-1 gp120 to the receptors induced transient cofilin (see CFL1; <a href="/entry/601442">601442</a>) phosphorylation inactivation through a RHOA (<a href="/entry/165390">165390</a>)-ROCK (see <a href="/entry/601702">601702</a>)-dependent mechanism. Blockade of FLNA interaction with CD4 and/or the coreceptors inhibited gp120-induced RHOA activation and cofilin inactivation. <a href="#35" class="mim-tip-reference" title="Jimenez-Baranda, S., Gomez-Mouton, C., Rojas, A., Martinez-Prats, L., Mira, E., Lacalle, R. A., Valencia, A., Dimitrov, D. S., Viola, A., Delgado, R., Martinez-A., C., Manes, S. <strong>Filamin-A regulates actin-dependent clustering of HIV receptors.</strong> Nature Cell Biol. 9: 838-846, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17572668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17572668</a>] [<a href="https://doi.org/10.1038/ncb1610" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17572668">Jimenez-Baranda et al. (2007)</a> concluded that FLNA is an adaptor protein that links HIV-1 receptors to the actin skeleton remodeling machinery, possibly facilitating virus infection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17572668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Ehrlicher, A. J., Nakamura, F., Hartwig, J. H., Weitz, D. A., Stossel, T. P. <strong>Mechanical strain in actin networks regulates FilGAP and integrin binding to filamin A.</strong> Nature 478: 260-263, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21926999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21926999</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21926999[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21926999">Ehrlicher et al. (2011)</a> identified the actin-binding protein filamin A (FLNA) as a central mechanotransduction element of the cytoskeleton, and reconstituted a minimal system consisting of actin filaments, FLNA, and 2 FLNA-binding partners: the cytoplasmic tail of beta-integrin (<a href="/entry/135630">135630</a>) and FilGAP (<a href="/entry/610586">610586</a>). Integrins form an essential mechanical linkage between extracellular and intracellular environments, with beta-integrin tails connecting to the actin cytoskeleton by binding directly to filamin. FilGAP is an FLNA-binding GTPase-activating protein specific for RAC, which in vivo regulates cell spreading and bleb formation. Using fluorescence loss after photoconversion, <a href="#15" class="mim-tip-reference" title="Ehrlicher, A. J., Nakamura, F., Hartwig, J. H., Weitz, D. A., Stossel, T. P. <strong>Mechanical strain in actin networks regulates FilGAP and integrin binding to filamin A.</strong> Nature 478: 260-263, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21926999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21926999</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21926999[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21926999">Ehrlicher et al. (2011)</a> demonstrated that both externally imposed bulk shear and myosin-II-driven forces differentially regulate the binding of these partners to FLNA. Consistent with structural predictions, strain increases beta-integrin binding to FLNA, whereas it causes FilGAP to dissociate from FLNA, providing a direct and specific molecular basis for cellular mechanotransduction. <a href="#15" class="mim-tip-reference" title="Ehrlicher, A. J., Nakamura, F., Hartwig, J. H., Weitz, D. A., Stossel, T. P. <strong>Mechanical strain in actin networks regulates FilGAP and integrin binding to filamin A.</strong> Nature 478: 260-263, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21926999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21926999</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21926999[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21926999">Ehrlicher et al. (2011)</a> concluded that their results identified a molecular mechanotransduction element within the actin cytoskeleton, revealing that mechanical strain of key proteins regulates the binding of signaling molecules. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21926999" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By yeast 2-hybrid and immunoprecipitation analyses, <a href="#1" class="mim-tip-reference" title="Adams, M., Simms, R. J., Abdelhamed, Z., Dawe, H. R., Szymanska, K., Logan, C. V., Wheway, G., Pitt, E., Gull, K., Knowles, M. A., Blair, E., Cross, S. H., Sayer, J. A., Johnson, C. A. <strong>A meckelin-filamin A interaction mediates ciliogenesis.</strong> Hum. Molec. Genet. 21: 1272-1286, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22121117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22121117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22121117[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddr557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22121117">Adams et al. (2012)</a> found that the C-terminal cytoplasmic tail of meckelin (TMEM67; <a href="/entry/609884">609884</a>) interacted with filamin A. Loss of filamin A or meckelin in immortalized fibroblasts from patients with null mutations in the genes or by small interfering RNA in mouse IMCD3 cells resulted in similar cellular phenotypes, including abnormal basal body positioning and ciliogenesis, aberrant remodeling of the actin cytoskeleton, deregulation of RHOA (<a href="/entry/165390">165390</a>) activity, and hyperactivation of canonical Wnt (see <a href="/entry/606359">606359</a>) signaling. <a href="#1" class="mim-tip-reference" title="Adams, M., Simms, R. J., Abdelhamed, Z., Dawe, H. R., Szymanska, K., Logan, C. V., Wheway, G., Pitt, E., Gull, K., Knowles, M. A., Blair, E., Cross, S. H., Sayer, J. A., Johnson, C. A. <strong>A meckelin-filamin A interaction mediates ciliogenesis.</strong> Hum. Molec. Genet. 21: 1272-1286, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22121117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22121117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22121117[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddr557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22121117">Adams et al. (2012)</a> concluded that the meckelin-filamin A signaling axis is a key regulator of ciliogenesis and normal Wnt signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22121117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid and immunoprecipitation analyses, <a href="#31" class="mim-tip-reference" title="Hu, J., Lu, J., Lian, G., Ferland, R. J., Dettenhofer, M., Sheen, V. L. <strong>Formin 1 and filamin B physically interact to coordinate chondrocyte proliferation and differentiation in the growth plate.</strong> Hum. Molec. Genet. 23: 4663-4673, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24760772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24760772</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24760772[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddu186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24760772">Hu et al. (2014)</a> found that mouse Flna and Flnb (<a href="/entry/603381">603381</a>) interacted directly with the actin-nucleating protein Fmn1 (<a href="/entry/136535">136535</a>). The filamins and Fmn1 colocalized in cytoplasm and, to a lesser extent, nucleus, and they were coexpressed in chondrocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24760772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Periventricular Heterotopia 1</em></strong></p><p>
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X-linked dominant periventricular heterotopia (PVNH1; <a href="/entry/300049">300049</a>) is a disorder in which many neurons fail to migrate to the cerebral cortex and persist as nodules lining the ventricular surface. Heterozygous females with the disorder present with epilepsy and other signs, including patent ductus arteriosus (see <a href="/entry/607411">607411</a>) and coagulopathy, whereas hemizygous affected males die embryonically. <a href="#19" class="mim-tip-reference" title="Fox, J. W., Lamperti, E. D., Eksioglu, Y. Z., Hong, S. E., Feng, Y., Graham, D. A., Scheffer, I. E., Dobyns, W. B., Hirsch, B. A., Radtke, R. A., Berkovic, S. F., Huttenlocher, P. R., Walsh, C. A. <strong>Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.</strong> Neuron 21: 1315-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9883725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9883725</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80651-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9883725">Fox et al. (1998)</a> identified the cause as mutations in the FLN1 gene (<a href="#0001">300017.0001</a>-<a href="#0005">300017.0005</a>), which is required for locomotion of many cell types. They demonstrated a previously unrecognized high level of expression of FLN1 in the developing cortex. Their studies demonstrated that FLN1 is required for neuronal migration to the cortex and is essential for embryogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9883725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In identifying filamin-1 as the gene mutant in periventricular heterotopia, <a href="#19" class="mim-tip-reference" title="Fox, J. W., Lamperti, E. D., Eksioglu, Y. Z., Hong, S. E., Feng, Y., Graham, D. A., Scheffer, I. E., Dobyns, W. B., Hirsch, B. A., Radtke, R. A., Berkovic, S. F., Huttenlocher, P. R., Walsh, C. A. <strong>Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.</strong> Neuron 21: 1315-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9883725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9883725</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80651-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9883725">Fox et al. (1998)</a> first narrowed the map location to an interval approximately 1 cM between marker DXS15 and the pseudoautosomal region of Xq28 by the study of additional markers. Subsequent analysis of a large duplication of Xq28 in a male patient with periventricular heterotopia (<a href="#17" class="mim-tip-reference" title="Fink, J. M., Dobyns, W. B., Guerrini, R., Hirsch, B. A. <strong>Identification of a duplication of Xq28 associated with bilateral periventricular nodular heterotopia.</strong> Am. J. Hum. Genet. 61: 379-387, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9311743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9311743</a>] [<a href="https://doi.org/10.1086/514863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9311743">Fink et al., 1997</a>) with a severe, albeit nonlethal, phenotype allowed the candidate interval to be refined even further. They defined the exact centromeric boundary of the duplicated segment of Xq28 as base 3377 of 3,395 bases in intron 1 of the isocitrate dehydrogenase gene (IDH3G; <a href="/entry/300089">300089</a>), approximately 600 kb distal to DXS15. However, none of the genes identified at the breakpoints or insertion site of the duplication harbored independent mutations in other patients with periventricular heterotopia. Therefore, <a href="#19" class="mim-tip-reference" title="Fox, J. W., Lamperti, E. D., Eksioglu, Y. Z., Hong, S. E., Feng, Y., Graham, D. A., Scheffer, I. E., Dobyns, W. B., Hirsch, B. A., Radtke, R. A., Berkovic, S. F., Huttenlocher, P. R., Walsh, C. A. <strong>Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.</strong> Neuron 21: 1315-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9883725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9883725</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80651-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9883725">Fox et al. (1998)</a> concluded that the duplication of FLN1 itself was responsible for the disorder in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9883725+9311743" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Fox, J. W., Lamperti, E. D., Eksioglu, Y. Z., Hong, S. E., Feng, Y., Graham, D. A., Scheffer, I. E., Dobyns, W. B., Hirsch, B. A., Radtke, R. A., Berkovic, S. F., Huttenlocher, P. R., Walsh, C. A. <strong>Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.</strong> Neuron 21: 1315-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9883725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9883725</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80651-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9883725">Fox et al. (1998)</a> studied the pattern of X inactivation in females with FLN1 mutations in nucleated peripheral blood cells. No evidence of preferential lyonization in these cells was found, suggesting that FLN1 is not required in a cell-autonomous fashion for survival of mixed peripheral white blood cells. However, an essential cell-autonomous role for FLN1 in a subset of nucleated cells or nonnucleated cells (e.g., platelets) could not be excluded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9883725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#55" class="mim-tip-reference" title="Sheen, V. L., Dixon, P. H., Fox, J. W., Hong, S. E., Kinton, L., Sisodiya, S. M., Duncan, J. S., Dubeau, F., Scheffer, I. E., Schachter, S. C., Wilner, A., Henchy, R., and 18 others. <strong>Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females.</strong> Hum. Molec. Genet. 10: 1775-1783, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11532987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11532987</a>] [<a href="https://doi.org/10.1093/hmg/10.17.1775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11532987">Sheen et al. (2001)</a> performed SSCP analysis of FLN1 throughout its entire coding region in 6 periventricular heterotopia pedigrees, 31 sporadic female patients, and 24 sporadic male periventricular heterotopia patients. The authors detected FLN1 mutations in 83% of periventricular heterotopia pedigrees and 19% of sporadic females with periventricular heterotopia. Moreover, 0 of 7 females with periventricular heterotopia with atypical radiographic features showed FLN1 mutations, suggesting that other genes may cause atypical periventricular heterotopia. Two of 24 males analyzed with periventricular heterotopia (9%) also carried FLN1 mutations. Whereas FLN1 mutations in periventricular heterotopia pedigrees caused severe predicted loss of FLN1 protein function, both male FLN1 mutations were consistent with partial loss of function of the protein. Moreover, sporadic female FLN1 mutations associated with periventricular heterotopia appear to cause either severe or partial loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11532987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#57" class="mim-tip-reference" title="Sheen, V. L., Jansen, A., Chen, M. H., Parrini, E., Morgan, T., Ravenscroft, R., Ganesh, V., Underwood, T., Wiley, J., Leventer, R., Vaid, R. R., Ruiz, D. E., and 21 others. <strong>Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome.</strong> Neurology 64: 254-262, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15668422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15668422</a>] [<a href="https://doi.org/10.1212/01.WNL.0000149512.79621.DF" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15668422">Sheen et al. (2005)</a> reported 2 familial cases and 9 sporadic cases with what they designated an Ehlers-Danlos variant of periventricular heterotopia, characterized by nodular brain heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular periventricular heterotopia, indistinguishable from periventricular heterotopia due to FLNA mutations. Mutations in the FLNA gene were identified in 3 affected females (<a href="#0017">300017.0017</a>-<a href="#0019">300017.0019</a>); in another pedigree with no detectable exonic mutation, positive linkage to the FLNA locus on Xq28 was demonstrated, and an affected individual in this family had no detectable FLNA protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15668422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 female patients from a 3-generation Spanish family with what the authors called Ehlers-Danlos syndrome and periventricular heterotopia, <a href="#23" class="mim-tip-reference" title="Gomez-Garre, P., Seijo, M., Gutierrez-Delicado, E., Castro del Rio, M., de la Torre, C., Gomez-Abad, C., Morales-Corraliza, J., Puig, M., Serratosa, J. M. <strong>Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation.</strong> J. Med. Genet. 43: 232-237, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15994863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15994863</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15994863[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2004.029173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15994863">Gomez-Garre et al. (2006)</a> identified heterozygosity for a missense mutation in the FLNA gene (<a href="#0021">300017.0021</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15994863" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Jamuar, S. S., Lam, A. N., Kircher, M., D'Gama, A. M., Wang, J., Barry, B. J., Zhang, X., Hill, R. S., Partlow, J. N., Rozzo, A., Servattalab, S., Mehta, B. K., and 20 others. <strong>Somatic mutations in cerebral cortical malformations.</strong> New Eng. J. Med. 371: 733-743, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25140959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25140959</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25140959[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa1314432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25140959">Jamuar et al. (2014)</a> used a customized panel of known and candidate genes associated with brain malformations to apply targeted high-coverage sequencing (depth greater than or equal to 200x) to leukocyte-derived DNA samples from 158 individuals with brain malformations. They found that, of 8 patients carrying somatic mutations, 1 was a female patient with periventricular nodular heterotopia carrying a mutation in FLNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25140959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Multiple Malformation Syndromes</em></strong></p><p>
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Loss-of-function mutations of FLNA are, as indicated, embryonic lethal in males but are manifest in females as a localized neuronal migration disorder, periventricular nodular heterotopia (PVNH). <a href="#52" class="mim-tip-reference" title="Robertson, S. P., Twigg, S. R. F., Sutherland-Smith, A. J., Biancalana, V., Gorlin, R. J., Horn, D., Kenwrick, S. J., Kim, C. A., Morava, E., Newbury-Ecob, R., Orstavik, K. H., Quarrell, O. W. J., Schwartz, C. E., Shears, D. J., Suri, M., Kendrick-Jones, J., OPD-spectrum Disorders Clinical Collaborative Group, Wilkie, A. O. M. <strong>Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans.</strong> Nature Genet. 33: 487-491, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612583</a>] [<a href="https://doi.org/10.1038/ng1119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612583">Robertson et al. (2003)</a> described localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations, affecting craniofacial structures, skeleton, brain, viscera, and urogenital tract, in 4 X-linked human disorders: otopalatodigital syndrome types I (OPD1; <a href="/entry/311300">311300</a>) and II (OPD2; <a href="/entry/304120">304120</a>), frontometaphyseal dysplasia (FMD1; <a href="/entry/305620">305620</a>), and Melnick-Needles syndrome (MNS; <a href="/entry/309350">309350</a>). Several of the mutations were recurrent, and all were clustered in 4 regions of the gene: the actin-binding domain and rod domain repeats 3, 10, and 14/15. The patterns of mutation, X-chromosome inactivation, and phenotypic manifestations in this class of mutations indicated gain-of-function effects, implicating filamin A in signaling pathways that mediate organogenesis in multiple systems during embryonic development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 26-year-old Mexican female with OPD1, <a href="#29" class="mim-tip-reference" title="Hidalgo-Bravo, A., Pompa-Mera, E. N., Kofman-Alfaro, S., Gonzalez-Bonilla, C. R., Zenteno, J. C. <strong>A novel filamin A D203Y mutation in a female patient with otopalatodigital type 1 syndrome and extremely skewed X chromosome inactivation.</strong> Am. J. Med. Genet. 136A: 190-193, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15940695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15940695</a>] [<a href="https://doi.org/10.1002/ajmg.a.30792" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15940695">Hidalgo-Bravo et al. (2005)</a> identified a heterozygous missense mutation in the FLNA gene (<a href="#0020">300017.0020</a>). The patient had prominent features of OPD1, including cleft palate; an extremely skewed pattern of X inactivation toward the maternal allele was noted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15940695" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 6 affected females with cranial hyperostosis and various skeletal abnormalities from a 4-generation pedigree, <a href="#60" class="mim-tip-reference" title="Stefanova, M., Meinecke, P., Gal, A., Bolz, H. <strong>A novel 9 bp deletion in the filamin A gene causes an otopalatodigital-spectrum disorder with a variable, intermediate phenotype.</strong> Am. J. Med. Genet. 132A: 386-390, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15654694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15654694</a>] [<a href="https://doi.org/10.1002/ajmg.a.30484" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15654694">Stefanova et al. (2005)</a> identified heterozygosity for a deletion in the FLNA gene (<a href="#0016">300017.0016</a>). The disorder resulted in early lethality in male children in this family. The phenotype of the females was variable, rather mild, and bridged the phenotypes of various OPD spectrum disorders (see <a href="/entry/311300">311300</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15654694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#66" class="mim-tip-reference" title="Zenker, M., Nahrlich, L., Sticht, H., Reis, A., Horn, D. <strong>Genotype-epigenotype-phenotype correlations in females with frontometaphyseal dysplasia.</strong> Am. J. Med. Genet. 140A: 1069-1073, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16596676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16596676</a>] [<a href="https://doi.org/10.1002/ajmg.a.31213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16596676">Zenker et al. (2006)</a> reported a gly1728-to-cys mutation (<a href="#0022">300017.0022</a>) in repeat 15 of the filamin A rod domain of the FLNA gene in a girl with manifestations of frontometaphyseal dysplasia and otopalatodigital syndrome 1. In a second family with FMD, they identified a ser1186-to-leu mutation (S1186L; <a href="#0015">300017.0015</a>) in a mother and her son. In contrast to most previous reports on manifesting females or carriers of FLNA-related skeletal dysplasias, the affected females in these 2 families showed only mild to moderate skewing of X-inactivation against the mutant allele. <a href="#66" class="mim-tip-reference" title="Zenker, M., Nahrlich, L., Sticht, H., Reis, A., Horn, D. <strong>Genotype-epigenotype-phenotype correlations in females with frontometaphyseal dysplasia.</strong> Am. J. Med. Genet. 140A: 1069-1073, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16596676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16596676</a>] [<a href="https://doi.org/10.1002/ajmg.a.31213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16596676">Zenker et al. (2006)</a> suggested that the data may indicate that in females, genotype-phenotype correlation between certain FLNA mutations and OPD1 and FMD, respectively, is less strict than previously assumed. They proposed that X-inactivation is an important epigenetic modifier of the phenotype in females with the FLNA-related skeletal dysplasias. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16596676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Hehr, U., Hehr, A., Uyanik, G., Phelan, E., Winkler, J., Reardon, W. <strong>A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome. (Letter)</strong> J. Med. Genet. 43: 541-544, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16299064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16299064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16299064[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.038505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16299064">Hehr et al. (2006)</a> described a male patient with periventricular nodular heterotopia (PVNH), craniofacial features, and severe constipation. The phenotype was associated with a splice mutation in exon 13 of the FLNA gene (<a href="#0024">300017.0024</a>). <a href="#28" class="mim-tip-reference" title="Hehr, U., Hehr, A., Uyanik, G., Phelan, E., Winkler, J., Reardon, W. <strong>A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome. (Letter)</strong> J. Med. Genet. 43: 541-544, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16299064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16299064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16299064[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.038505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16299064">Hehr et al. (2006)</a> suggested that the patient retained enough FLNA function to avoid the usual lethality associated with loss-of-function mutations in FLNA in males. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16299064" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an 18-month-old German boy with FG syndrome-2 (FGS2; <a href="/entry/300321">300321</a>), <a href="#63" class="mim-tip-reference" title="Unger, S., Mainberger, A., Spitz, C., Bahr, A., Zeschnigk, C., Zabel, B., Superti-Furga, A., Morris-Rosendahl, D. J. <strong>Filamin A mutation is one cause of FG syndrome.</strong> Am. J. Med. Genet. 143A: 1876-1879, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632775</a>] [<a href="https://doi.org/10.1002/ajmg.a.31751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632775">Unger et al. (2007)</a> identified a hemizygous mutation in the FLNA gene (P1291L; <a href="#0028">300017.0028</a>). He had severe constipation, large rounded forehead, prominent ears, frontal hair upsweep, and mild delay in language acquisition. The parents declined brain MRI studies. <a href="#63" class="mim-tip-reference" title="Unger, S., Mainberger, A., Spitz, C., Bahr, A., Zeschnigk, C., Zabel, B., Superti-Furga, A., Morris-Rosendahl, D. J. <strong>Filamin A mutation is one cause of FG syndrome.</strong> Am. J. Med. Genet. 143A: 1876-1879, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632775</a>] [<a href="https://doi.org/10.1002/ajmg.a.31751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632775">Unger et al. (2007)</a> suggested that the patient reported by <a href="#28" class="mim-tip-reference" title="Hehr, U., Hehr, A., Uyanik, G., Phelan, E., Winkler, J., Reardon, W. <strong>A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome. (Letter)</strong> J. Med. Genet. 43: 541-544, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16299064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16299064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16299064[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.038505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16299064">Hehr et al. (2006)</a> actually had FGS2, due to the presence of severe constipation and dysmorphic facial features. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16299064+17632775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Dissanayake, R., Senanayake, M. P., Fernando, J., Robertson, S. P., Dissanayake, V. H. W., Sirisena, N. D. <strong>Frontometaphyseal dysplasia 1 in a patient from Sri Lanka.</strong> Am. J. Med. Genet. 185A: 1317-1320, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33372358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33372358</a>] [<a href="https://doi.org/10.1002/ajmg.a.62058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33372358">Dissanayake et al. (2021)</a> identified hemizygosity for the previously identified S1186L mutation (<a href="#0015">300017.0015</a>) in a boy from Sri Lanka with FMD1. His mother, who had prominent supraorbital ridges but was otherwise unaffected, was heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33372358" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Intestinal Pseudoobstruction/Congenital Short Bowel Syndrome</em></strong></p><p>
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In an Italian family with an X-linked recessive form of chronic idiopathic intestinal pseudoobstruction (CIIP) mapping to chromosome Xq28 (CIIPX; <a href="/entry/300048">300048</a>), <a href="#20" class="mim-tip-reference" title="Gargiulo, A., Auricchio, R., Barone, M. V., Cotugno, G., Reardon, W., Milla, P. J., Ballabio, A., Ciccodicola, A., Auricchio, A. <strong>Filamin A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement.</strong> Am. J. Hum. Genet. 80: 751-758, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357080</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357080[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357080">Gargiulo et al. (2007)</a> detected a 2-bp deletion in exon 2 of the FLNA gene that was present in heterozygous state in the carrier females of the family (<a href="#0025">300017.0025</a>). The frameshift mutation was located between 2 close methionines at the filamin N terminus and was predicted to produce a protein truncated shortly after the first predicted methionine. Because loss-of-function FLNA mutations have been associated with X-linked dominant nodular ventricular heterotopia (PVNH1; <a href="/entry/300049">300049</a>), a central nervous system migration defect that presents with seizures in females and lethality in males, it was notable that the male bearing the FLNA mutation had signs of central nervous system (CNS) involvement and possibly PVNH. To understand how the severe frameshift mutation found by <a href="#20" class="mim-tip-reference" title="Gargiulo, A., Auricchio, R., Barone, M. V., Cotugno, G., Reardon, W., Milla, P. J., Ballabio, A., Ciccodicola, A., Auricchio, A. <strong>Filamin A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement.</strong> Am. J. Hum. Genet. 80: 751-758, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357080</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357080[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357080">Gargiulo et al. (2007)</a> explained the CIIPX phenotype and its X-linked recessive inheritance, <a href="#20" class="mim-tip-reference" title="Gargiulo, A., Auricchio, R., Barone, M. V., Cotugno, G., Reardon, W., Milla, P. J., Ballabio, A., Ciccodicola, A., Auricchio, A. <strong>Filamin A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement.</strong> Am. J. Hum. Genet. 80: 751-758, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357080</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357080[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357080">Gargiulo et al. (2007)</a> transiently expressed both the wildtype and the mutant filamin in cell culture and found filamin translation to start from either of the 2 initial methionines in these conditions. Therefore, translation of a normal, shorter filamin can occur in vitro from the second methionine downstream of the 2-bp insertion. <a href="#20" class="mim-tip-reference" title="Gargiulo, A., Auricchio, R., Barone, M. V., Cotugno, G., Reardon, W., Milla, P. J., Ballabio, A., Ciccodicola, A., Auricchio, A. <strong>Filamin A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement.</strong> Am. J. Hum. Genet. 80: 751-758, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357080</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357080[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357080">Gargiulo et al. (2007)</a> confirmed this, demonstrating that the filamin protein was present in the patient's lymphoblastoid cell line that shows abnormal cytoskeletal actin organization compared with normal lymphoblasts. The authors concluded that the filamin N-terminal region between the initial 2 methionines is crucial for proper enteric neuron development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17357080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Clayton-Smith, J., Walters, S., Hobson, E., Burkitt-Wright, E., Smith, R., Toutain, A., Amiel, J., Lyonnet, S., Mansour, S., Fitzpatrick, D., Ciccone, R., Ricca, I., Zuffardi, O., Donnai, D. <strong>Xq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance.</strong> Europ. J. Hum. Genet. 17: 434-443, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18854860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18854860</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18854860[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2008.192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18854860">Clayton-Smith et al. (2009)</a> identified a duplication of the FLNA gene in affected members of 2 families with intestinal pseudoobstruction, patent ductus arteriosus, and thrombocytopenia with giant platelets (<a href="/entry/300048">300048</a>). One of the families had been reported by <a href="#18" class="mim-tip-reference" title="FitzPatrick, D. R., Strain, L., Thomas, A. E., Barr, D. G. D., Todd, A., Smith, N. M., Scobie, W. G. <strong>Neurogenic chronic idiopathic intestinal pseudo-obstruction, patent ductus arteriosus, and thrombocytopenia segregating as an X linked recessive disorder.</strong> J. Med. Genet. 34: 666-669, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9279759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9279759</a>] [<a href="https://doi.org/10.1136/jmg.34.8.666" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9279759">FitzPatrick et al. (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9279759+18854860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#65" class="mim-tip-reference" title="van der Werf, C. S., Sribudiani, Y., Verheij, J. B. G. M., Carroll, M., O'Loughlin, E., Chen, C.-H., Brooks, A. S., Liszewski, M. K., Atkinson, J. P., Hofstra, R. M. W. <strong>Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations.</strong> Genet. Med. 15: 310-313, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23037936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23037936</a>] [<a href="https://doi.org/10.1038/gim.2012.123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23037936">Van der Werf et al. (2013)</a> reported a 2-basepair deletion in exon 2 of filamin A (<a href="#0035">300017.0035</a>) in 1 family segregating X-linked congenital short bowel syndrome (see <a href="/entry/300048">300048</a>) and in an unrelated affected individual. In the family, all obligate carriers were heterozygous for the mutation; in the isolated male, the mutation had occurred as a de novo event. <a href="#65" class="mim-tip-reference" title="van der Werf, C. S., Sribudiani, Y., Verheij, J. B. G. M., Carroll, M., O'Loughlin, E., Chen, C.-H., Brooks, A. S., Liszewski, M. K., Atkinson, J. P., Hofstra, R. M. W. <strong>Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations.</strong> Genet. Med. 15: 310-313, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23037936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23037936</a>] [<a href="https://doi.org/10.1038/gim.2012.123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23037936">Van der Werf et al. (2013)</a> stated that they could not exclude involvement of the central nervous system in these patients because no magnetic resonance imaging brain scans were available. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23037936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Terminal Osseous Dysplasia</em></strong></p><p>
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In affected members of 3 families segregating terminal osseous dysplasia (TOD; <a href="/entry/300244">300244</a>), 2 of which were previously described by <a href="#7" class="mim-tip-reference" title="Breuning, M. H., Oranje, A. P., Langemeijer, R. A. T. M., Hovius, S. E. R., Diepstraten, A. F. M., den Hollander, J. C., Baumgartner, N., Dwek, J. R., Sommer, A., Toriello, H. <strong>Recurrent digital fibroma, focal dermal hypoplasia, and limb malformations.</strong> Am. J. Med. Genet. 94: 91-101, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10982965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10982965</a>] [<a href="https://doi.org/10.1002/1096-8628(20000911)94:2<91::aid-ajmg1>3.0.co;2-d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10982965">Breuning et al. (2000)</a> and <a href="#5" class="mim-tip-reference" title="Baroncini, A., Castelluccio, P., Morleo, M., Soli, F., Franco, B. <strong>Terminal osseous dysplasia with pigmentary defects: clinical description of a new family.</strong> Am. J. Med. Genet. 143A: 51-57, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17152064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17152064</a>] [<a href="https://doi.org/10.1002/ajmg.a.31557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17152064">Baroncini et al. (2007)</a>, and in 3 sporadic case individuals, who were previously described by <a href="#30" class="mim-tip-reference" title="Horii, E., Sugiura, Y., Nakamura, R. <strong>A syndrome of digital fibromas, facial pigmentary dysplasia, and metacarpal and metatarsal disorganization.</strong> Am. J. Med. Genet. 80: 1-5, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9800904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9800904</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19981102)80:1<1::aid-ajmg1>3.0.co;2-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9800904">Horii et al. (1998)</a>, <a href="#13" class="mim-tip-reference" title="Drut, R., Pedemonte, L., Rositto, A. <strong>Noninclusion-body infantile digital fibromatosis: a lesion heralding terminal osseous dysplasia and pigmentary defects syndrome.</strong> Int. J. Surg. Path. 13: 181-184, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15864382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15864382</a>] [<a href="https://doi.org/10.1177/106689690501300209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15864382">Drut et al. (2005)</a>, and <a href="#7" class="mim-tip-reference" title="Breuning, M. H., Oranje, A. P., Langemeijer, R. A. T. M., Hovius, S. E. R., Diepstraten, A. F. M., den Hollander, J. C., Baumgartner, N., Dwek, J. R., Sommer, A., Toriello, H. <strong>Recurrent digital fibroma, focal dermal hypoplasia, and limb malformations.</strong> Am. J. Med. Genet. 94: 91-101, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10982965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10982965</a>] [<a href="https://doi.org/10.1002/1096-8628(20000911)94:2<91::aid-ajmg1>3.0.co;2-d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10982965">Breuning et al. (2000)</a>, respectively, <a href="#61" class="mim-tip-reference" title="Sun, Y., Almomani, R., Aten, E., Celli, J., van der Heijden, J., Venselaar, H., Robertson, S. P., Baroncini, A., Franco, B., Basel-Vanagaite, L., Horii, E., Drut, R., Ariyurek, Y., den Dunnen, J. T., Breuning, M. H. <strong>Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene.</strong> Am. J. Hum. Genet. 87: 146-153, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20598277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20598277</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20598277[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.06.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20598277">Sun et al. (2010)</a> identified a causative mutation in the FLNA gene: a c.5217G-A transition activated a cryptic splice site, removing the last 48 nucleotides from exon 31 and resulting in a loss of 16 amino acids (<a href="#0029">300017.0029</a>). In the families, the variant segregated with the disease. <a href="#61" class="mim-tip-reference" title="Sun, Y., Almomani, R., Aten, E., Celli, J., van der Heijden, J., Venselaar, H., Robertson, S. P., Baroncini, A., Franco, B., Basel-Vanagaite, L., Horii, E., Drut, R., Ariyurek, Y., den Dunnen, J. T., Breuning, M. H. <strong>Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene.</strong> Am. J. Hum. Genet. 87: 146-153, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20598277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20598277</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20598277[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.06.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20598277">Sun et al. (2010)</a> showed that because of nonrandom X chromosome inactivation, the mutant allele was not expressed in the patient fibroblasts. RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. The mutation was not found in 400 control X chromosomes, pilot data from 1000 Genomes Project, or the FLNA gene variant database. Because the mutation was predicted to remove a sequence at the surface of filamin repeat 15, <a href="#61" class="mim-tip-reference" title="Sun, Y., Almomani, R., Aten, E., Celli, J., van der Heijden, J., Venselaar, H., Robertson, S. P., Baroncini, A., Franco, B., Basel-Vanagaite, L., Horii, E., Drut, R., Ariyurek, Y., den Dunnen, J. T., Breuning, M. H. <strong>Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene.</strong> Am. J. Hum. Genet. 87: 146-153, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20598277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20598277</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20598277[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.06.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20598277">Sun et al. (2010)</a> suggested that the missing region in the filamin A protein affects or prevents the interaction of filamin A with other proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17152064+9800904+10982965+20598277+15864382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Turkish girl with terminal osseous dysplasia with pigmentary defects, <a href="#3" class="mim-tip-reference" title="Azakli, H., Akkaya, A. D., Aygun, M. S., Demirkesen, C., Eraslan, S., Kayserili, H. <strong>Terminal osseous dysplasia with pigmentary defects (TODPD) in a Turkish girl with new skin findings.</strong> Am. J. Med. Genet. 179A: 123-129, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30561107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30561107</a>] [<a href="https://doi.org/10.1002/ajmg.a.60686" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30561107">Azakli et al. (2019)</a> identified the recurrent c.5217G-A mutation in the FLNA gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30561107" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>X-Linked Cardiac Valvular Dysplasia</em></strong></p><p>
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In a large 5-generation French pedigree with X-linked cardiac valvular dysplasia (CVDPX; <a href="/entry/314400">314400</a>) mapping to Xq28, originally reported by <a href="#6" class="mim-tip-reference" title="Benichou, B., Kyndt, F., Schott, J.-J., Trochu, J.-N., Baranger, F., Herbert, O., Scott, V., Fressinaud, E., David, A., Moisan, J.-P., Bouhour, J.-B., Le Marec, H. <strong>Mapping of X-linked valvular dysplasia to chromosome Xq28. (Abstract)</strong> Am. J. Hum. Genet. 61 (suppl.): A268 only, 1997."None>Benichou et al. (1997)</a> and <a href="#40" class="mim-tip-reference" title="Kyndt, F., Schott, J.-J., Trochu, J.-N., Baranger, F., Herbert, O., Scott, V., Fressinaud, E., David, A., Moisan, J.-P., Bouhour, J.-B., Le Marec, H., Benichou, B. <strong>Mapping of X-linked myxomatous valvular dystrophy to chromosome Xq28.</strong> Am. J. Hum. Genet. 62: 627-632, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9497244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9497244</a>] [<a href="https://doi.org/10.1086/301747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9497244">Kyndt et al. (1998)</a>, <a href="#39" class="mim-tip-reference" title="Kyndt, F., Gueffet, J.-P., Probst, V., Jaafar, P., Legendre, A., Le Bouffant, F., Toquet, C., Roy, E., McGregor, L., Lynch, S. A., Newbury-Ecob, R., Tran, V., Young, I., Trochu, J.-N., Le Marec, H., Schott, J.-J. <strong>Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy.</strong> Circulation 115: 40-49, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17190868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17190868</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.106.622621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17190868">Kyndt et al. (2007)</a> analyzed candidate genes and identified a missense mutation in the FLNA gene that segregated with disease (P637Q; <a href="#0030">300017.0030</a>). In 3 more families with cardiac valvular disease, <a href="#39" class="mim-tip-reference" title="Kyndt, F., Gueffet, J.-P., Probst, V., Jaafar, P., Legendre, A., Le Bouffant, F., Toquet, C., Roy, E., McGregor, L., Lynch, S. A., Newbury-Ecob, R., Tran, V., Young, I., Trochu, J.-N., Le Marec, H., Schott, J.-J. <strong>Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy.</strong> Circulation 115: 40-49, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17190868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17190868</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.106.622621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17190868">Kyndt et al. (2007)</a> identified 2 different missense mutations and an in-frame deletion (<a href="#0031">300017.0031</a>-<a href="#0033">300017.0033</a>, respectively). No signs of periventricular heterotopia, otopalatodigital syndrome, frontometaphyseal dysplasia, or Melnick-Needles or Ehlers-Danlos syndromes were observed in these families. The missense mutations all involve highly conserved residues within the first, fourth, and fifth repeat consensus sequences of FLNA, respectively, and the deletion results in a truncated protein lacking repeats 5 through 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9497244+17190868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 affected male cousins from a 3-generation Italian family in which 5 affected males and 1 female had died of congestive heart failure due to multivalvular disease, <a href="#50" class="mim-tip-reference" title="Ritelli, M., Morlino, S., Giacopuzzi, E., Carini, G., Cinquina, V., Chiarelli, N., Majore, S., Colombi, M., Castori, M. <strong>Ehlers-Danlos syndrome with lethal cardiac valvular dystrophy in males carrying a novel splice mutation in FLNA.</strong> Am. J. Med. Genet. 173A: 169-176, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27739212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27739212</a>] [<a href="https://doi.org/10.1002/ajmg.a.38004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27739212">Ritelli et al. (2017)</a> identified hemizygosity for a splicing mutation in the FLNA gene (<a href="#0037">300017.0037</a>). In addition to cardiac valvular disease, these patients exhibited skin hyperextensibility and joint hypermobility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27739212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 3-generation family with multivalvular dysplasia, <a href="#45" class="mim-tip-reference" title="Mercer, C. L., Andreoletti, G., Carroll, A., Salmon, A. P., Temple, I. K., Ennis, S. <strong>Familial Ebstein anomaly: whole exome sequencing identifies novel phenotype associated with FLNA.</strong> Circ. Cardiovasc. Genet. 10: e001683, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29237676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29237676</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.116.001683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29237676">Mercer et al. (2017)</a> identified a missense mutation in the FLNA gene (G1554R; <a href="#0038">300017.0038</a>) that segregated with disease. Other features in these patients included joint stiffness from early childhood and keloid scarring. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29237676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Reviews</em></strong></p><p>
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For a review of the disorders caused by mutations in the FLNA gene, see <a href="#53" class="mim-tip-reference" title="Robertson, S. P. <strong>Filamin A: phenotypic diversity.</strong> Curr. Opin. Genet. Dev. 15: 301-307, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15917206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15917206</a>] [<a href="https://doi.org/10.1016/j.gde.2005.04.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15917206">Robertson (2005)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15917206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Robert J. <a href="#26" class="mim-tip-reference" title="Gorlin, R. J. <strong>Personal Communication.</strong> Minneapolis, Minn. 4/15/2003."None>Gorlin (2003)</a> was responsible for the initial description of 3 of the conditions that had been shown to be caused by mutations in the FLNA gene: OPD1, OPD2, and frontometaphyseal dysplasia. Furthermore, he correctly interpreted the genetics of Melnick-Needles syndrome as X-linked recessive rather than autosomal recessive. His son, Jed Gorlin, sequenced the FLNA gene (<a href="#25" class="mim-tip-reference" title="Gorlin, J. B., Yamin, R., Egan, S., Stewart, M., Stossel, T. P., Kwiatkowski, D. J., Hartwig, J. H. <strong>Human endothelial actin-binding protein (ABP-280, nonmuscle filamin): a molecular leaf spring.</strong> J. Cell Biol. 111: 1089-1105, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2391361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2391361</a>] [<a href="https://doi.org/10.1083/jcb.111.3.1089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2391361">Gorlin et al., 1990</a>) and mapped it to chromosome Xq28 (<a href="#24" class="mim-tip-reference" title="Gorlin, J. B., Henske, E., Warren, S. T., Kunst, C. B., D'Urso, M., Palmieri, G., Hartwig, J. H., Bruns, G., Kwiatkowski, D. J. <strong>Actin-binding protein (ABP-280) filamin gene (FLN) maps telomeric to the color vision locus (R/GCP) and centromeric to G6PD in Xq28.</strong> Genomics 17: 496-498, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8406501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8406501</a>] [<a href="https://doi.org/10.1006/geno.1993.1354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8406501">Gorlin et al., 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2391361+8406501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#16" class="mim-tip-reference" title="Feng, Y., Chen, M. H., Moskowitz, I. P., Mendonza, A. M., Vidali, L., Nakamura, F., Kwiatkowski, D. J., Walsh, C. A. <strong>Filamin A (FLNA) is required for cell-cell contact in vascular development and cardiac morphogenesis.</strong> Proc. Nat. Acad. Sci. 103: 19836-19841, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17172441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17172441</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17172441[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0609628104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17172441">Feng et al. (2006)</a> noted that hemizygous human males with FLNA mutations die prenatally or survive after birth with cardiac malformations, often dying postnatally from blood vessel rupture. They found that Flna-null mice died at midgestation with widespread hemorrhage from abnormal vessels, persistent truncus arteriosus, and incomplete cardiac septation. Conditional Flna knockout in the neural crest caused abnormalities of the cardiac outflow tract despite apparently normal migration of Flna-deficient neural crest cells. Flna-null vascular endothelial cells displayed abnormal adherens junctions and defects in cell-cell contacts. <a href="#16" class="mim-tip-reference" title="Feng, Y., Chen, M. H., Moskowitz, I. P., Mendonza, A. M., Vidali, L., Nakamura, F., Kwiatkowski, D. J., Walsh, C. A. <strong>Filamin A (FLNA) is required for cell-cell contact in vascular development and cardiac morphogenesis.</strong> Proc. Nat. Acad. Sci. 103: 19836-19841, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17172441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17172441</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17172441[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0609628104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17172441">Feng et al. (2006)</a> suggested that cell motility-independent functions of FLNA at cell-cell contacts and adherens junctions affect the development of organs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17172441" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Adams, M., Simms, R. J., Abdelhamed, Z., Dawe, H. R., Szymanska, K., Logan, C. V., Wheway, G., Pitt, E., Gull, K., Knowles, M. A., Blair, E., Cross, S. H., Sayer, J. A., Johnson, C. A. <strong>A meckelin-filamin A interaction mediates ciliogenesis.</strong> Hum. Molec. Genet. 21: 1272-1286, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22121117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22121117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22121117[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddr557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22121117">Adams et al. (2012)</a> found that knockdown of Mks3 or the Flna ortholog in zebrafish resulted in similar phenotypes, including brain and body axis defects, cardiac edema, and otic placode and eye defects. Combined low doses of both Mks3 and Flna morpholinos increased both the incidence and severity of developmental defects. An Flna-null mouse strain showed similar defects. At embryonic day 13.5, male Flna hemizygous embryos were highly dysmorphic, with extensive disruption of ventricular zone of the neocortex and severe periventricular heterotopia. Basal body position was disrupted and neuroepithelial layer showed impaired ciliogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22121117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=300017[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p>In the largest reported pedigree with X-linked periventricular heterotopia (PVNH1; <a href="/entry/300049">300049</a>) (<a href="#32" class="mim-tip-reference" title="Huttenlocher, P. R., Taravath, S., Mojtahedi, S. <strong>Periventricular heterotopia and epilepsy.</strong> Neurology 44: 51-55, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8290091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8290091</a>] [<a href="https://doi.org/10.1212/wnl.44.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8290091">Huttenlocher et al., 1994</a>), <a href="#19" class="mim-tip-reference" title="Fox, J. W., Lamperti, E. D., Eksioglu, Y. Z., Hong, S. E., Feng, Y., Graham, D. A., Scheffer, I. E., Dobyns, W. B., Hirsch, B. A., Radtke, R. A., Berkovic, S. F., Huttenlocher, P. R., Walsh, C. A. <strong>Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.</strong> Neuron 21: 1315-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9883725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9883725</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80651-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9883725">Fox et al. (1998)</a> found a C-to-T substitution in exon 3 of the FLN1 gene, which converted a CAG (gln) to a TAG (stop) codon and truncated the FLN1 protein at amino acid residue 182 of the 2,647 total amino acids in the normal protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8290091+9883725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012514" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012514" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012514</a>
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<p>In affected members of a family with periventricular heterotopia (PVNH1; <a href="/entry/300049">300049</a>), <a href="#19" class="mim-tip-reference" title="Fox, J. W., Lamperti, E. D., Eksioglu, Y. Z., Hong, S. E., Feng, Y., Graham, D. A., Scheffer, I. E., Dobyns, W. B., Hirsch, B. A., Radtke, R. A., Berkovic, S. F., Huttenlocher, P. R., Walsh, C. A. <strong>Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.</strong> Neuron 21: 1315-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9883725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9883725</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80651-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9883725">Fox et al. (1998)</a> found a T-to-C substitution at the second base of intron 4 in the splice donor sequence of the FLN1 gene. The mutation was predicted to cause either exon skipping or a read-through of intron 4 which would introduce a stop codon after the translation of 30 additional amino acids. The mutation was present in both a mother and daughter with periventricular heterotopia but not in the unaffected maternal grandmother. Therefore, this mutation most likely arose de novo in this pedigree in the germline of either the maternal grandmother or grandfather, both of whom were clinically unaffected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9883725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398123622 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398123622;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs398123622" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs398123622" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012515 OR RCV000079706" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012515, RCV000079706" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012515...</a>
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<p>In a sporadic case of periventricular heterotopia (PVNH1; <a href="/entry/300049">300049</a>), <a href="#19" class="mim-tip-reference" title="Fox, J. W., Lamperti, E. D., Eksioglu, Y. Z., Hong, S. E., Feng, Y., Graham, D. A., Scheffer, I. E., Dobyns, W. B., Hirsch, B. A., Radtke, R. A., Berkovic, S. F., Huttenlocher, P. R., Walsh, C. A. <strong>Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.</strong> Neuron 21: 1315-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9883725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9883725</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80651-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9883725">Fox et al. (1998)</a> found that the consensus splice acceptor at the end of intron 3 (3 bases from exon 4) of the FLN1 gene was mutated by a C-to-G substitution. The 'C' at position -3 is conserved among more than 70% of vertebrate splice junctions, and the 'G' at this position is seen in only 1% (<a href="#54" class="mim-tip-reference" title="Shapiro, M. B., Senapathy, P. <strong>RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression.</strong> Nucleic Acids Res. 15: 7155-7174, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3658675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3658675</a>] [<a href="https://doi.org/10.1093/nar/15.17.7155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3658675">Shapiro and Senapathy, 1987</a>). The mutation appeared to have arisen de novo in the germline of the patient's mother or father. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3658675+9883725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs863223296 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863223296;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs863223296" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs863223296" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a sporadic case of periventricular heterotopia (PVNH1; <a href="/entry/300049">300049</a>), <a href="#19" class="mim-tip-reference" title="Fox, J. W., Lamperti, E. D., Eksioglu, Y. Z., Hong, S. E., Feng, Y., Graham, D. A., Scheffer, I. E., Dobyns, W. B., Hirsch, B. A., Radtke, R. A., Berkovic, S. F., Huttenlocher, P. R., Walsh, C. A. <strong>Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.</strong> Neuron 21: 1315-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9883725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9883725</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80651-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9883725">Fox et al. (1998)</a> found a G-to-A mutation at the first base of intron 2 of the FLN1 gene. The 'G' at position +1 of the intron is conserved in 100% of splice donor sequences of vertebrate genes (<a href="#54" class="mim-tip-reference" title="Shapiro, M. B., Senapathy, P. <strong>RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression.</strong> Nucleic Acids Res. 15: 7155-7174, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3658675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3658675</a>] [<a href="https://doi.org/10.1093/nar/15.17.7155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3658675">Shapiro and Senapathy, 1987</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3658675+9883725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
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FLNA, 5-BP DEL, NT287
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs863223297 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863223297;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs863223297?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs863223297" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs863223297" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012517" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012517" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012517</a>
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<p>In a sporadic case of periventricular heterotopia (PVNH1; <a href="/entry/300049">300049</a>), <a href="#19" class="mim-tip-reference" title="Fox, J. W., Lamperti, E. D., Eksioglu, Y. Z., Hong, S. E., Feng, Y., Graham, D. A., Scheffer, I. E., Dobyns, W. B., Hirsch, B. A., Radtke, R. A., Berkovic, S. F., Huttenlocher, P. R., Walsh, C. A. <strong>Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.</strong> Neuron 21: 1315-1325, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9883725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9883725</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80651-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9883725">Fox et al. (1998)</a> found deletion of 5 bases from the coding region of exon 2 of the FLN1 gene. Bases 287-291 were removed, producing a frameshift and the introduction of a premature stop codon after the addition of 8 inappropriate amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9883725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137853311 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853311;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137853311?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137853311" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137853311" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012518 OR RCV001753412 OR RCV001857335 OR RCV002273924" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012518, RCV001753412, RCV001857335, RCV002273924" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012518...</a>
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<p>In a sporadic male patient with unilateral periventricular heterotopia (PVNH1; <a href="/entry/300049">300049</a>), epilepsy, and normal intellect, <a href="#55" class="mim-tip-reference" title="Sheen, V. L., Dixon, P. H., Fox, J. W., Hong, S. E., Kinton, L., Sisodiya, S. M., Duncan, J. S., Dubeau, F., Scheffer, I. E., Schachter, S. C., Wilner, A., Henchy, R., and 18 others. <strong>Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females.</strong> Hum. Molec. Genet. 10: 1775-1783, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11532987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11532987</a>] [<a href="https://doi.org/10.1093/hmg/10.17.1775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11532987">Sheen et al. (2001)</a> found a C-to-T transition at position 1966, resulting in a leu656-to-phe (L656F) amino acid substitution in the fifth Ig-like domain of the FLN1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11532987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs781910090 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs781910090;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs781910090?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs781910090" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs781910090" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012519" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012519" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012519</a>
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<p>In a sporadic male patient with periventricular heterotopia (PVNH1; <a href="/entry/300049">300049</a>), epilepsy, and normal intellect, <a href="#55" class="mim-tip-reference" title="Sheen, V. L., Dixon, P. H., Fox, J. W., Hong, S. E., Kinton, L., Sisodiya, S. M., Duncan, J. S., Dubeau, F., Scheffer, I. E., Schachter, S. C., Wilner, A., Henchy, R., and 18 others. <strong>Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females.</strong> Hum. Molec. Genet. 10: 1775-1783, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11532987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11532987</a>] [<a href="https://doi.org/10.1093/hmg/10.17.1775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11532987">Sheen et al. (2001)</a> found a C-to-G transversion at position 6915. This was predicted to result in termination at residue 2305 and loss of the 344 C-terminal amino acids of the FLN1 gene, which include the receptor-binding region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11532987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28935169 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28935169;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28935169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28935169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012520 OR RCV003764561" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012520, RCV003764561" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012520...</a>
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<p>In a family with periventricular heterotopia (PVNH1; <a href="/entry/300049">300049</a>), <a href="#46" class="mim-tip-reference" title="Moro, F., Carrozzo, R., Veggiotti, P., Tortorella, G., Toniolo, D., Volzone, A., Guerrini, R. <strong>Familial periventricular heterotopia: missense and distal truncating mutations of the FLN1 gene.</strong> Neurology 58: 916-921, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11914408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11914408</a>] [<a href="https://doi.org/10.1212/wnl.58.6.916" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11914408">Moro et al. (2002)</a> identified a 245A-T mutation in exon 2 of the FLNA gene, leading to a glu82-to-val substitution (E82V) in the N-terminal part of the protein. The mutation likely modifies protein activity without complete loss of function. Affected females with the mutation showed a mild anatomic phenotype with few asymmetric, noncontiguous nodules on MRI, and gave birth to 5 presumably affected boys who died within a few days to several weeks or months of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11914408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 OTOPALATODIGITAL SYNDROME, TYPE I</strong>
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FLNA, PRO207LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28935469 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28935469;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28935469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28935469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012521 OR RCV000415125 OR RCV001000894 OR RCV002354156 OR RCV002509151 OR RCV003764562 OR RCV004545725" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012521, RCV000415125, RCV001000894, RCV002354156, RCV002509151, RCV003764562, RCV004545725" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012521...</a>
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<p>In 2 presumably unrelated families, <a href="#52" class="mim-tip-reference" title="Robertson, S. P., Twigg, S. R. F., Sutherland-Smith, A. J., Biancalana, V., Gorlin, R. J., Horn, D., Kenwrick, S. J., Kim, C. A., Morava, E., Newbury-Ecob, R., Orstavik, K. H., Quarrell, O. W. J., Schwartz, C. E., Shears, D. J., Suri, M., Kendrick-Jones, J., OPD-spectrum Disorders Clinical Collaborative Group, Wilkie, A. O. M. <strong>Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans.</strong> Nature Genet. 33: 487-491, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612583</a>] [<a href="https://doi.org/10.1038/ng1119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612583">Robertson et al. (2003)</a> found that individuals with otopalatodigital syndrome type I (OPD1; <a href="/entry/311300">311300</a>) had a 620C-T transition in exon 3 of the FLNA gene, predicted to result in a pro207-to-leu (P207L) amino acid substitution. All affected members had bowed bones and abnormal digits as well as cleft palate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#51" class="mim-tip-reference" title="Robertson, S. P., Thompson, S., Morgan, T., Holder-Espinasse, M., Martinot-Duquenoy, V., Wilkie, A. O. M., Manouvrier-Hanu, S. <strong>Postzygotic mutation and germline mosaicism in the otopalatodigital syndrome spectrum disorders.</strong> Europ. J. Hum. Genet. 14: 549-554, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16538226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16538226</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16538226">Robertson et al. (2006)</a> identified the P207L mutation in 2 brothers with OPD1. The mutation was not identified in leukocytes of the mother, suggesting germline mosaicism. The authors emphasized the importance of the finding for genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16538226" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 OTOPALATODIGITAL SYNDROME, TYPE II</strong>
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FLNA, GLU254LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28935470 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28935470;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28935470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28935470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012522 OR RCV000178843 OR RCV001851804" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012522, RCV000178843, RCV001851804" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012522...</a>
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<p>In 4 presumably unrelated families, each with at least 1 affected male, <a href="#52" class="mim-tip-reference" title="Robertson, S. P., Twigg, S. R. F., Sutherland-Smith, A. J., Biancalana, V., Gorlin, R. J., Horn, D., Kenwrick, S. J., Kim, C. A., Morava, E., Newbury-Ecob, R., Orstavik, K. H., Quarrell, O. W. J., Schwartz, C. E., Shears, D. J., Suri, M., Kendrick-Jones, J., OPD-spectrum Disorders Clinical Collaborative Group, Wilkie, A. O. M. <strong>Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans.</strong> Nature Genet. 33: 487-491, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612583</a>] [<a href="https://doi.org/10.1038/ng1119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612583">Robertson et al. (2003)</a> found that individuals with otopalatodigital syndrome type II (OPD2; <a href="/entry/304120">304120</a>) had a 760G-A transition in exon 5 of the FLNA gene, predicted to cause a glu254-to-lys (E254K) amino acid substitution. All 4 patients had omphalocele, perinatal death, bowed bones, and abnormal digits; 1 also had cleft palate, and 2 had hydrocephalus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Clark, A. R., Sawyer, G. M., Robertson, S. P., Sutherland-Smith, A. J. <strong>Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders.</strong> Hum. Molec. Genet. 18: 4791-4800, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19773341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19773341</a>] [<a href="https://doi.org/10.1093/hmg/ddp442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19773341">Clark et al. (2009)</a> showed that OPD E254K fibroblast lysates had equivalent concentrations of FLNA compared with controls, and that recombinant FLNA E254K actin-binding domain (ABD) had increased in vitro F-actin binding compared with wildtype. The FLNA ABD adopts a canonical compact conformation that is not greatly disturbed by the E254K mutation either in solution or in the crystal structure. Ex vivo characterization of E254K OPD patient fibroblasts revealed that they have similar motility and adhesion as control cells, implying that many core functions mediated by FLNA are unaffected, consistent with OPD affecting only specific tissues despite FLNA being widely expressed. The authors proposed a gain-of-function mechanism for the OPD disorders, which mechanistically distinguishes them from the loss-of-function phenotypes that manifest as disorders of neuronal migration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19773341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<strong>.0011 FRONTOMETAPHYSEAL DYSPLASIA 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28935471 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28935471;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28935471" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28935471" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012523" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012523" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012523</a>
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<p>In 2 affected members of a family, <a href="#52" class="mim-tip-reference" title="Robertson, S. P., Twigg, S. R. F., Sutherland-Smith, A. J., Biancalana, V., Gorlin, R. J., Horn, D., Kenwrick, S. J., Kim, C. A., Morava, E., Newbury-Ecob, R., Orstavik, K. H., Quarrell, O. W. J., Schwartz, C. E., Shears, D. J., Suri, M., Kendrick-Jones, J., OPD-spectrum Disorders Clinical Collaborative Group, Wilkie, A. O. M. <strong>Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans.</strong> Nature Genet. 33: 487-491, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612583</a>] [<a href="https://doi.org/10.1038/ng1119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612583">Robertson et al. (2003)</a> found that frontometaphyseal dysplasia (FMD1; <a href="/entry/305620">305620</a>) was related to a 3476A-C transversion in exon 22 of the FLNA gene, predicted to result in an asp1159-to-ala (D1159A) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28935472 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28935472;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28935472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28935472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012524 OR RCV000523000" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012524, RCV000523000" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012524...</a>
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<p>In 5 presumably unrelated patients with Melnick-Needles syndrome (<a href="/entry/309350">309350</a>), <a href="#52" class="mim-tip-reference" title="Robertson, S. P., Twigg, S. R. F., Sutherland-Smith, A. J., Biancalana, V., Gorlin, R. J., Horn, D., Kenwrick, S. J., Kim, C. A., Morava, E., Newbury-Ecob, R., Orstavik, K. H., Quarrell, O. W. J., Schwartz, C. E., Shears, D. J., Suri, M., Kendrick-Jones, J., OPD-spectrum Disorders Clinical Collaborative Group, Wilkie, A. O. M. <strong>Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans.</strong> Nature Genet. 33: 487-491, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612583</a>] [<a href="https://doi.org/10.1038/ng1119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612583">Robertson et al. (2003)</a> found a 3562G-A transition in exon 22 of the FLNA gene, predicted to result in an ala1188-to-thr (A1188T) amino acid change. All 5 patients had bowed bones and abnormal digits and all but one had short stature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28935473 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28935473;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28935473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28935473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012525 OR RCV001382364" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012525, RCV001382364" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012525...</a>
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<p>In 6 presumably unrelated females with Melnick-Needles syndrome (<a href="/entry/309350">309350</a>), <a href="#52" class="mim-tip-reference" title="Robertson, S. P., Twigg, S. R. F., Sutherland-Smith, A. J., Biancalana, V., Gorlin, R. J., Horn, D., Kenwrick, S. J., Kim, C. A., Morava, E., Newbury-Ecob, R., Orstavik, K. H., Quarrell, O. W. J., Schwartz, C. E., Shears, D. J., Suri, M., Kendrick-Jones, J., OPD-spectrum Disorders Clinical Collaborative Group, Wilkie, A. O. M. <strong>Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans.</strong> Nature Genet. 33: 487-491, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612583</a>] [<a href="https://doi.org/10.1038/ng1119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612583">Robertson et al. (2003)</a> found a 3596C-T transition in exon 22 of the FLNA gene, predicted to cause an ser1199-to-leu (S1199L) amino acid change. All 6 females were of short stature and had bowed bones and abnormal digits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#51" class="mim-tip-reference" title="Robertson, S. P., Thompson, S., Morgan, T., Holder-Espinasse, M., Martinot-Duquenoy, V., Wilkie, A. O. M., Manouvrier-Hanu, S. <strong>Postzygotic mutation and germline mosaicism in the otopalatodigital syndrome spectrum disorders.</strong> Europ. J. Hum. Genet. 14: 549-554, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16538226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16538226</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16538226">Robertson et al. (2006)</a> identified the S1199L mutation in a girl with Melnick-Needles syndrome. The girl had an unaffected twin sister who did not carry the mutation; the unaffected mother also did not carry the mutation. The twins were born with separate amniotic sacs within a single chorion, and zygosity analysis indicated a high probability that the girls were monozygotic twins. <a href="#51" class="mim-tip-reference" title="Robertson, S. P., Thompson, S., Morgan, T., Holder-Espinasse, M., Martinot-Duquenoy, V., Wilkie, A. O. M., Manouvrier-Hanu, S. <strong>Postzygotic mutation and germline mosaicism in the otopalatodigital syndrome spectrum disorders.</strong> Europ. J. Hum. Genet. 14: 549-554, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16538226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16538226</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16538226">Robertson et al. (2006)</a> concluded that the FLNA mutation occurred postzygotically in the affected twin and emphasized the importance of the finding for genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16538226" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED, WITH FRONTOMETAPHYSEAL DYSPLASIA</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2148101204 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2148101204;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2148101204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs2148101204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012526" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012526" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012526</a>
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<p>Periventricular nodular heterotopia (PVNH1; <a href="/entry/300049">300049</a>) and a group of skeletal dysplasias belonging to the otopalatodigital (OPD) spectrum are caused by mutation in the FLNA gene. They are considered mutually exclusive because of the different presumed effects of the respective FLNA gene mutations, leading to loss of function in PVNH and gain of function in OPD. In a girl manifesting PVNH in combination with frontometaphyseal dysplasia (see <a href="/entry/300049">300049</a>), a skeletal dysplasia of the OPD spectrum, <a href="#67" class="mim-tip-reference" title="Zenker, M., Rauch, A., Winterpacht, A., Tagariello, A., Kraus, C., Rupprecht, T., Sticht, H., Reis, A. <strong>A dual phenotype of periventricular nodular heterotopia and frontometaphyseal dysplasia in one patient caused by a single FLNA mutation leading to two functionally different aberrant transcripts.</strong> Am. J. Hum. Genet. 74: 731-737, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14988809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14988809</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14988809[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/383094" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14988809">Zenker et al. (2004)</a> identified a de novo 7315C-A transversion in exon 45 of the FLNA gene, resulting in 2 aberrant transcripts: 1 full-length transcript with a point mutation causing a substitution of a highly conserved leu2439 residue by met (L2439M) and a second shortened transcript lacking 21 bp due to the creation of an ectopic splice donor site in exon 45. <a href="#67" class="mim-tip-reference" title="Zenker, M., Rauch, A., Winterpacht, A., Tagariello, A., Kraus, C., Rupprecht, T., Sticht, H., Reis, A. <strong>A dual phenotype of periventricular nodular heterotopia and frontometaphyseal dysplasia in one patient caused by a single FLNA mutation leading to two functionally different aberrant transcripts.</strong> Am. J. Hum. Genet. 74: 731-737, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14988809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14988809</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14988809[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/383094" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14988809">Zenker et al. (2004)</a> proposed that the dual phenotype was caused by 2 functionally different, aberrant filamin A proteins and therefore represented an exceptional case of allelic gain-of-function and loss-of-function phenotypes due to a single mutation event. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14988809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853312 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853312;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137853312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137853312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012527 OR RCV000414151 OR RCV002051782 OR RCV002228026 OR RCV004795395" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012527, RCV000414151, RCV002051782, RCV002228026, RCV004795395" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012527...</a>
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<p>In a male patient with frontometaphyseal dysplasia (FMD1; <a href="/entry/305620">305620</a>), <a href="#52" class="mim-tip-reference" title="Robertson, S. P., Twigg, S. R. F., Sutherland-Smith, A. J., Biancalana, V., Gorlin, R. J., Horn, D., Kenwrick, S. J., Kim, C. A., Morava, E., Newbury-Ecob, R., Orstavik, K. H., Quarrell, O. W. J., Schwartz, C. E., Shears, D. J., Suri, M., Kendrick-Jones, J., OPD-spectrum Disorders Clinical Collaborative Group, Wilkie, A. O. M. <strong>Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans.</strong> Nature Genet. 33: 487-491, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612583</a>] [<a href="https://doi.org/10.1038/ng1119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612583">Robertson et al. (2003)</a> identified a 3557C-T transition in exon 22 of the FLNA gene, resulting in a ser1186-to-leu (S1186L) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Giuliano, F., Paquis-Flucklinger, V., Collignon, P., Philip, N., Bardot, J. <strong>A new three-generational family with frontometaphyseal dysplasia, male-to-female transmission, and a previously reported FLNA mutation. (Letter)</strong> Am. J. Med. Genet. 132A: 222 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15523633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15523633</a>] [<a href="https://doi.org/10.1002/ajmg.a.30396" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15523633">Giuliano et al. (2005)</a> reported a 3-generation family with FMD and identified the S1186L mutation in the proband and his mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15523633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The S1186L missense mutation in repeat 10 of the filamin A rod domain was reported in patients with frontometaphyseal dysplasia by <a href="#66" class="mim-tip-reference" title="Zenker, M., Nahrlich, L., Sticht, H., Reis, A., Horn, D. <strong>Genotype-epigenotype-phenotype correlations in females with frontometaphyseal dysplasia.</strong> Am. J. Med. Genet. 140A: 1069-1073, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16596676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16596676</a>] [<a href="https://doi.org/10.1002/ajmg.a.31213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16596676">Zenker et al. (2006)</a>. The proposita in the family reported by <a href="#66" class="mim-tip-reference" title="Zenker, M., Nahrlich, L., Sticht, H., Reis, A., Horn, D. <strong>Genotype-epigenotype-phenotype correlations in females with frontometaphyseal dysplasia.</strong> Am. J. Med. Genet. 140A: 1069-1073, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16596676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16596676</a>] [<a href="https://doi.org/10.1002/ajmg.a.31213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16596676">Zenker et al. (2006)</a> was a 68-year-old woman whose son had died with a diagnosis of FMD. She had had scoliosis from childhood. Prominent supraorbital ridges, hypertelorism, and a small pointed chin as well as moderate thoracolumbar scoliosis were noted. The son developed massive frontal hyperostosis from childhood leading to the diagnosis of FMD with hypertelorism, micrognathia, oligodontia, progressive sensorineural hearing loss, amblyopia, pectus excavatum, and scoliosis. During adolescence, he developed sleep apnea and had been treated with continuous positive airway pressure. <a href="#14" class="mim-tip-reference" title="Ehrenstein, T., Maurer, J., Liokumowitsch, M., Mack, M., Felix, R., Bier, J. <strong>CT and MR findings in frontometaphyseal dysplasia.</strong> J. Comput. Assist. Tomogr. 21: 218-220, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9071288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9071288</a>] [<a href="https://doi.org/10.1097/00004728-199703000-00009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9071288">Ehrenstein et al. (1997)</a> reported the radiologic findings. The patient died unexpectedly at the age of 25 years. In contrast to most previous reports on manifesting females or carriers of the FLNA-related skeletal dysplasias, the proband showed only mild to moderate skewing of X inactivation against the mutant allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9071288+16596676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a boy from Sri Lanka with FMD1, <a href="#12" class="mim-tip-reference" title="Dissanayake, R., Senanayake, M. P., Fernando, J., Robertson, S. P., Dissanayake, V. H. W., Sirisena, N. D. <strong>Frontometaphyseal dysplasia 1 in a patient from Sri Lanka.</strong> Am. J. Med. Genet. 185A: 1317-1320, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33372358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33372358</a>] [<a href="https://doi.org/10.1002/ajmg.a.62058" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33372358">Dissanayake et al. (2021)</a> identified hemizygosity for the c.3557C-T transition (c.3557C-T, NM_001110556.1) in the FLNA gene resulting in the S1186L mutation. His mother, who had prominent supraorbital ridges but was otherwise unaffected, was heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33372358" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs863223298 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863223298;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs863223298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs863223298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 6 affected females with cranial hyperostosis and various skeletal abnormalities from a 4-generation pedigree, <a href="#60" class="mim-tip-reference" title="Stefanova, M., Meinecke, P., Gal, A., Bolz, H. <strong>A novel 9 bp deletion in the filamin A gene causes an otopalatodigital-spectrum disorder with a variable, intermediate phenotype.</strong> Am. J. Med. Genet. 132A: 386-390, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15654694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15654694</a>] [<a href="https://doi.org/10.1002/ajmg.a.30484" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15654694">Stefanova et al. (2005)</a> identified heterozygosity for a 9-bp deletion from position 4904 to 4912 in exon 29 of the FLNA gene, predicting the loss of 3 amino acid residues (codons 1635-1637) in rod domain repeat 14. The mutation was not found in 2 unaffected females. The phenotype of affected females resembled frontometaphyseal dysplasia with some overlap to otopalatodigital syndrome types 1 and 2, but no signs specific for Melnick-Needles syndrome. However, males had severe extraskeletal malformations and died early, thus constituting an overlap with OPD2 and MNS. <a href="#60" class="mim-tip-reference" title="Stefanova, M., Meinecke, P., Gal, A., Bolz, H. <strong>A novel 9 bp deletion in the filamin A gene causes an otopalatodigital-spectrum disorder with a variable, intermediate phenotype.</strong> Am. J. Med. Genet. 132A: 386-390, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15654694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15654694</a>] [<a href="https://doi.org/10.1002/ajmg.a.30484" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15654694">Stefanova et al. (2005)</a> concluded that the disorder in this family is best described as an intermediate OPD spectrum phenotype that bridges the FMD and OPD2 phenotypes; see <a href="/entry/311300">311300</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15654694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1569551736 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569551736;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1569551736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1569551736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 13-year-old female with periventricular heterotopia (PVNH1; <a href="/entry/300049">300049</a>), <a href="#57" class="mim-tip-reference" title="Sheen, V. L., Jansen, A., Chen, M. H., Parrini, E., Morgan, T., Ravenscroft, R., Ganesh, V., Underwood, T., Wiley, J., Leventer, R., Vaid, R. R., Ruiz, D. E., and 21 others. <strong>Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome.</strong> Neurology 64: 254-262, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15668422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15668422</a>] [<a href="https://doi.org/10.1212/01.WNL.0000149512.79621.DF" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15668422">Sheen et al. (2005)</a> found a 1-bp deletion in exon 19 of the FLNA gene (2762delG). The patient showed typical features of Ehlers-Danlos syndrome (EDS), including joint hypermobility as well as myxomatous borders along the mitral and aortic valves. The authors suggested that this was an EDS variant of PVNH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15668422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs863223299 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863223299;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs863223299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs863223299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012530" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012530" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012530</a>
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<p>In a 16-year-old female with periventricular heterotopia (PVNH1; <a href="/entry/300049">300049</a>), <a href="#57" class="mim-tip-reference" title="Sheen, V. L., Jansen, A., Chen, M. H., Parrini, E., Morgan, T., Ravenscroft, R., Ganesh, V., Underwood, T., Wiley, J., Leventer, R., Vaid, R. R., Ruiz, D. E., and 21 others. <strong>Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome.</strong> Neurology 64: 254-262, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15668422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15668422</a>] [<a href="https://doi.org/10.1212/01.WNL.0000149512.79621.DF" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15668422">Sheen et al. (2005)</a> found a 1-bp deletion in exon 25 of the FLNA gene (4147delG). The patient had aortic aneurysm and joint hypermobility. The authors suggested that this was an Ehlers-Danlos variant of PVNH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15668422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853313 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853313;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137853313" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137853313" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012531" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012531" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012531</a>
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<p>In a 15-year-old female with periventricular heterotopia (PVNH1; <a href="/entry/300049">300049</a>), <a href="#57" class="mim-tip-reference" title="Sheen, V. L., Jansen, A., Chen, M. H., Parrini, E., Morgan, T., Ravenscroft, R., Ganesh, V., Underwood, T., Wiley, J., Leventer, R., Vaid, R. R., Ruiz, D. E., and 21 others. <strong>Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome.</strong> Neurology 64: 254-262, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15668422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15668422</a>] [<a href="https://doi.org/10.1212/01.WNL.0000149512.79621.DF" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15668422">Sheen et al. (2005)</a> identified a 116C-G transversion in exon 2 of the FLNA gene, resulting in an ala39-to-gly (A39G) substitution. The patient had radiologic findings of periventricular heterotopia, seizures, mild cognitive delay with psychotic behavior, joint hypermobility, and aortic aneurysm. The authors suggested that this was an Ehlers-Danlos variant of PVNH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15668422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0020 OTOPALATODIGITAL SYNDROME, TYPE I</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853314 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853314;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137853314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137853314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012532" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012532" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012532</a>
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<p>In a 26-year-old Mexican female with OPD1 (<a href="/entry/311300">311300</a>), <a href="#29" class="mim-tip-reference" title="Hidalgo-Bravo, A., Pompa-Mera, E. N., Kofman-Alfaro, S., Gonzalez-Bonilla, C. R., Zenteno, J. C. <strong>A novel filamin A D203Y mutation in a female patient with otopalatodigital type 1 syndrome and extremely skewed X chromosome inactivation.</strong> Am. J. Med. Genet. 136A: 190-193, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15940695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15940695</a>] [<a href="https://doi.org/10.1002/ajmg.a.30792" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15940695">Hidalgo-Bravo et al. (2005)</a> identified heterozygosity for a 607G-T transversion in exon 3 of the FLNA gene, resulting in an asp203-to-tyr (D203Y) substitution in the actin binding domain. Her parents did not have the mutation. The patient had prominent features of OPD1, including cleft palate; an extremely skewed pattern of X inactivation toward the maternal allele was noted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15940695" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0021 HETEROTOPIA, PERIVENTRICULAR, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853315 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853315;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137853315" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137853315" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012533" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012533" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012533</a>
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<p>In 3 female patients from a 3-generation Spanish family with periventricular heterotopia and features of Ehlers-Danlos syndrome (PVNH1; <a href="/entry/300049">300049</a>), <a href="#23" class="mim-tip-reference" title="Gomez-Garre, P., Seijo, M., Gutierrez-Delicado, E., Castro del Rio, M., de la Torre, C., Gomez-Abad, C., Morales-Corraliza, J., Puig, M., Serratosa, J. M. <strong>Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation.</strong> J. Med. Genet. 43: 232-237, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15994863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15994863</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15994863[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2004.029173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15994863">Gomez-Garre et al. (2006)</a> identified heterozygosity for a 383C-T transition in exon 3 of the FLNA gene, resulting in an ala128-to-val (A128V) substitution. The mutation was not found in unaffected family members or in 184 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15994863" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0022 OTOPALATODIGITAL SPECTRUM DISORDER</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853316 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853316;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137853316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137853316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012534" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012534" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012534</a>
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<p><a href="#66" class="mim-tip-reference" title="Zenker, M., Nahrlich, L., Sticht, H., Reis, A., Horn, D. <strong>Genotype-epigenotype-phenotype correlations in females with frontometaphyseal dysplasia.</strong> Am. J. Med. Genet. 140A: 1069-1073, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16596676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16596676</a>] [<a href="https://doi.org/10.1002/ajmg.a.31213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16596676">Zenker et al. (2006)</a> described a de novo mutation in the FLNA gene in a girl with manifestations of frontometaphyseal dysplasia and otopalatodigital syndrome type 1 (see <a href="/entry/311300">311300</a>). The 5182G-T mutation in exon 31 was predicted to lead to the exchange of a highly conserved glycine residue at position 1728 by cysteine (G1728C) in repeat 15 of the filamin A rod domain. A short neck and deep-set ears were noted at birth. On the first day of life, presence of inspiratory stridor and episodic cyanosis led to the diagnosis of laryngomalacia and a large atrial septal defect with signs of persistent pulmonary hypertension which resolved spontaneously within 24 hours. Echocardiography showed dysplastic tricuspid valve and noncompaction of the right ventricular myocardium. The latter disappeared during infancy. The atrial septal defect was corrected at age 9 years. Conductive hearing deficit, first diagnosed in childhood, was progressive, necessitating hearing aids by the age of 12 years. At age 16 years, typical craniofacial findings of FMD were impressive supraorbital hyperostosis, hypertelorism, antimongoloid palpebral fissures, a deeply grooved philtrum, and a pointed and slightly receding chin. The terminal phalanges of thumbs and halluces were short and broad. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16596676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0023 MOVED TO <a href="/entry/300017#0015">300017.0015</a></strong>
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<strong>.0024 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80338841 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338841;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80338841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80338841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012536 OR RCV000020423 OR RCV001348560 OR RCV001563663 OR RCV001753413 OR RCV004734511" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012536, RCV000020423, RCV001348560, RCV001563663, RCV001753413, RCV004734511" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012536...</a>
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<p><a href="#28" class="mim-tip-reference" title="Hehr, U., Hehr, A., Uyanik, G., Phelan, E., Winkler, J., Reardon, W. <strong>A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome. (Letter)</strong> J. Med. Genet. 43: 541-544, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16299064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16299064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16299064[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.038505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16299064">Hehr et al. (2006)</a> described a male patient with periventricular nodular heterotopia (PVNH1; <a href="/entry/300049">300049</a>) associated with a splice mutation in exon 13 of the FLNA gene (1923C-T). In addition to PVNH, the patient also presented with craniofacial features and severe constipation. <a href="#28" class="mim-tip-reference" title="Hehr, U., Hehr, A., Uyanik, G., Phelan, E., Winkler, J., Reardon, W. <strong>A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome. (Letter)</strong> J. Med. Genet. 43: 541-544, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16299064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16299064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16299064[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.038505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16299064">Hehr et al. (2006)</a> postulated that the predominant expression of the full-length mRNA in addition to a mutant shorter transcript lacking the 3-prime part of exon 13 had rescued a sufficient amount of FLNA protein function to result in this novel phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16299064" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#63" class="mim-tip-reference" title="Unger, S., Mainberger, A., Spitz, C., Bahr, A., Zeschnigk, C., Zabel, B., Superti-Furga, A., Morris-Rosendahl, D. J. <strong>Filamin A mutation is one cause of FG syndrome.</strong> Am. J. Med. Genet. 143A: 1876-1879, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632775</a>] [<a href="https://doi.org/10.1002/ajmg.a.31751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632775">Unger et al. (2007)</a> suggested that the patient reported by <a href="#28" class="mim-tip-reference" title="Hehr, U., Hehr, A., Uyanik, G., Phelan, E., Winkler, J., Reardon, W. <strong>A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome. (Letter)</strong> J. Med. Genet. 43: 541-544, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16299064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16299064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16299064[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.038505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16299064">Hehr et al. (2006)</a> actually had FG syndrome-2 (FGS2; <a href="/entry/300321">300321</a>), especially given the presence of craniofacial dysmorphic features and severe constipation. <a href="#63" class="mim-tip-reference" title="Unger, S., Mainberger, A., Spitz, C., Bahr, A., Zeschnigk, C., Zabel, B., Superti-Furga, A., Morris-Rosendahl, D. J. <strong>Filamin A mutation is one cause of FG syndrome.</strong> Am. J. Med. Genet. 143A: 1876-1879, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632775</a>] [<a href="https://doi.org/10.1002/ajmg.a.31751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632775">Unger et al. (2007)</a> identified a different mutation in the FLNA gene (<a href="#0028">300017.0028</a>) in a patient with FGS2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16299064+17632775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0025 INTESTINAL PSEUDOOBSTRUCTION, NEURONAL, CHRONIC IDIOPATHIC, X-LINKED</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80338840 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338840;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80338840?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80338840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80338840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012537" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012537" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012537</a>
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<p>In an affected male in the Italian family of X-linked chronic idiopathic intestinal pseudoobstruction (<a href="/entry/300048">300048</a>) described originally by <a href="#2" class="mim-tip-reference" title="Auricchio, A., Brancolini, V., Casari, G., Milla, P. J., Smith, V. V., Devoto, M., Ballabio, A. <strong>The locus for a novel syndromic form of neuronal intestinal pseudoobstruction maps to Xq28.</strong> Am. J. Hum. Genet. 58: 743-748, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644737</a>]" pmid="8644737">Auricchio et al. (1996)</a>, <a href="#20" class="mim-tip-reference" title="Gargiulo, A., Auricchio, R., Barone, M. V., Cotugno, G., Reardon, W., Milla, P. J., Ballabio, A., Ciccodicola, A., Auricchio, A. <strong>Filamin A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement.</strong> Am. J. Hum. Genet. 80: 751-758, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357080</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357080[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357080">Gargiulo et al. (2007)</a> found a 2-bp deletion in exon 2 of the FLNA gene: 65-66delAC. Segregation analysis of the FLNA mutation confirmed that all obligate carriers, by pedigree or established by linkage analysis, were heterozygous for the 2-bp deletion. The mutation was absent in 164 control X chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8644737+17357080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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OTOPALATODIGITAL SYNDROME, TYPE II, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853317 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853317;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137853317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137853317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012538 OR RCV000012539 OR RCV000153245 OR RCV000560177" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012538, RCV000012539, RCV000153245, RCV000560177" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012538...</a>
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<p>In a patient with OPD type I (<a href="/entry/311300">311300</a>), <a href="#52" class="mim-tip-reference" title="Robertson, S. P., Twigg, S. R. F., Sutherland-Smith, A. J., Biancalana, V., Gorlin, R. J., Horn, D., Kenwrick, S. J., Kim, C. A., Morava, E., Newbury-Ecob, R., Orstavik, K. H., Quarrell, O. W. J., Schwartz, C. E., Shears, D. J., Suri, M., Kendrick-Jones, J., OPD-spectrum Disorders Clinical Collaborative Group, Wilkie, A. O. M. <strong>Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans.</strong> Nature Genet. 33: 487-491, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612583</a>] [<a href="https://doi.org/10.1038/ng1119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612583">Robertson et al. (2003)</a> identified a 586C-T transition in exon 3 of the FLNA gene, resulting in an arg196-to-trp (R196W) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12612583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Kondoh, T., Okamoto, N., Norimatsu, N., Uetani, M., Nishimura, G., Moriuchi, H. <strong>A Japanese case of oto-palato-digital syndrome type II: an apparent lack of phenotype-genotype correlation.</strong> J. Hum. Genet. 52: 370-373, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17264970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17264970</a>] [<a href="https://doi.org/10.1007/s10038-007-0108-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17264970">Kondoh et al. (2007)</a> identified the R196W mutation in a 12-year-old Japanese boy with OPD type II (<a href="/entry/304120">304120</a>). The patient had some additional unusual features, including congenital cataract, glaucoma, and congenital heart defects. <a href="#37" class="mim-tip-reference" title="Kondoh, T., Okamoto, N., Norimatsu, N., Uetani, M., Nishimura, G., Moriuchi, H. <strong>A Japanese case of oto-palato-digital syndrome type II: an apparent lack of phenotype-genotype correlation.</strong> J. Hum. Genet. 52: 370-373, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17264970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17264970</a>] [<a href="https://doi.org/10.1007/s10038-007-0108-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17264970">Kondoh et al. (2007)</a> noted the different phenotype caused by the same mutation and suggested that additional factors play a role in the pathogenesis of OPD spectrum disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17264970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0027 OTOPALATODIGITAL SYNDROME, TYPE II</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853318 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853318;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137853318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137853318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012540" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012540" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012540</a>
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<p>In a male fetus with otopalatodigital syndrome type II (<a href="/entry/304120">304120</a>), <a href="#44" class="mim-tip-reference" title="Marino-Enriquez, A., Lapunzina, P., Robertson, S. P., Rodriguez, J. I. <strong>Otopalatodigital syndrome type 2 in two siblings with a novel filamin A 629G-T mutation: clinical, pathological, and molecular findings.</strong> Am. J. Med. Genet. 143A: 1120-1125, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17431908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17431908</a>] [<a href="https://doi.org/10.1002/ajmg.a.31696" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17431908">Marino-Enriquez et al. (2007)</a> identified a 629G-T transversion in exon 3 of the FLNA gene, predicted to cause a cys210-to-phe (C210F) substitution within the second calponin homology domain of the actin-binding domain. Analysis of exon 3 in relatives revealed that the mutation had arisen de novo in the mother; a previous pregnancy had ended in stillbirth of a male diagnosed with OPD2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17431908" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0028 FG SYNDROME 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137853319 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853319;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137853319?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137853319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137853319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012541 OR RCV000869767 OR RCV001549941 OR RCV002313705 OR RCV004532324" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012541, RCV000869767, RCV001549941, RCV002313705, RCV004532324" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012541...</a>
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<p>In an 18-month-old boy with FG syndrome-2 (FGS2; <a href="/entry/300321">300321</a>), <a href="#63" class="mim-tip-reference" title="Unger, S., Mainberger, A., Spitz, C., Bahr, A., Zeschnigk, C., Zabel, B., Superti-Furga, A., Morris-Rosendahl, D. J. <strong>Filamin A mutation is one cause of FG syndrome.</strong> Am. J. Med. Genet. 143A: 1876-1879, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632775</a>] [<a href="https://doi.org/10.1002/ajmg.a.31751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632775">Unger et al. (2007)</a> identified a hemizygous 3872C-T transition in exon 23 of the FLNA gene, resulting in a pro1291-to-leu (P1291L) substitution. His asymptomatic mother also carried the mutation, which was absent in 100 control chromosomes. The patient had severe constipation, large rounded forehead, prominent ears, frontal hair upsweep, and mild delay in language acquisition. Although the authors noted that the mutation does not affect a highly conserved residue, they referred to a patient reported by <a href="#28" class="mim-tip-reference" title="Hehr, U., Hehr, A., Uyanik, G., Phelan, E., Winkler, J., Reardon, W. <strong>A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome. (Letter)</strong> J. Med. Genet. 43: 541-544, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16299064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16299064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16299064[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.038505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16299064">Hehr et al. (2006)</a> with periventricular nodular heterotopia (<a href="/entry/300049">300049</a>) and a FLNA mutation (<a href="#0024">300017.0024</a>), who also had craniofacial dysmorphic features and severe constipation. <a href="#63" class="mim-tip-reference" title="Unger, S., Mainberger, A., Spitz, C., Bahr, A., Zeschnigk, C., Zabel, B., Superti-Furga, A., Morris-Rosendahl, D. J. <strong>Filamin A mutation is one cause of FG syndrome.</strong> Am. J. Med. Genet. 143A: 1876-1879, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632775</a>] [<a href="https://doi.org/10.1002/ajmg.a.31751" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632775">Unger et al. (2007)</a> suggested that the patient reported by <a href="#28" class="mim-tip-reference" title="Hehr, U., Hehr, A., Uyanik, G., Phelan, E., Winkler, J., Reardon, W. <strong>A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome. (Letter)</strong> J. Med. Genet. 43: 541-544, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16299064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16299064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16299064[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.038505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16299064">Hehr et al. (2006)</a> actually had FGS2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16299064+17632775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387907371 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907371;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387907371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387907371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012542 OR RCV001091828 OR RCV001205323 OR RCV001292939" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012542, RCV001091828, RCV001205323, RCV001292939" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012542...</a>
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<p>In affected members of 3 families segregating terminal osseous dysplasia (TOD; <a href="/entry/300244">300244</a>), 2 of which were previously described by <a href="#7" class="mim-tip-reference" title="Breuning, M. H., Oranje, A. P., Langemeijer, R. A. T. M., Hovius, S. E. R., Diepstraten, A. F. M., den Hollander, J. C., Baumgartner, N., Dwek, J. R., Sommer, A., Toriello, H. <strong>Recurrent digital fibroma, focal dermal hypoplasia, and limb malformations.</strong> Am. J. Med. Genet. 94: 91-101, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10982965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10982965</a>] [<a href="https://doi.org/10.1002/1096-8628(20000911)94:2<91::aid-ajmg1>3.0.co;2-d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10982965">Breuning et al. (2000)</a> and <a href="#5" class="mim-tip-reference" title="Baroncini, A., Castelluccio, P., Morleo, M., Soli, F., Franco, B. <strong>Terminal osseous dysplasia with pigmentary defects: clinical description of a new family.</strong> Am. J. Med. Genet. 143A: 51-57, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17152064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17152064</a>] [<a href="https://doi.org/10.1002/ajmg.a.31557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17152064">Baroncini et al. (2007)</a>, and in 3 sporadic case individuals, who were previously described by <a href="#30" class="mim-tip-reference" title="Horii, E., Sugiura, Y., Nakamura, R. <strong>A syndrome of digital fibromas, facial pigmentary dysplasia, and metacarpal and metatarsal disorganization.</strong> Am. J. Med. Genet. 80: 1-5, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9800904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9800904</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19981102)80:1<1::aid-ajmg1>3.0.co;2-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9800904">Horii et al. (1998)</a>, <a href="#13" class="mim-tip-reference" title="Drut, R., Pedemonte, L., Rositto, A. <strong>Noninclusion-body infantile digital fibromatosis: a lesion heralding terminal osseous dysplasia and pigmentary defects syndrome.</strong> Int. J. Surg. Path. 13: 181-184, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15864382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15864382</a>] [<a href="https://doi.org/10.1177/106689690501300209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15864382">Drut et al. (2005)</a>, and <a href="#7" class="mim-tip-reference" title="Breuning, M. H., Oranje, A. P., Langemeijer, R. A. T. M., Hovius, S. E. R., Diepstraten, A. F. M., den Hollander, J. C., Baumgartner, N., Dwek, J. R., Sommer, A., Toriello, H. <strong>Recurrent digital fibroma, focal dermal hypoplasia, and limb malformations.</strong> Am. J. Med. Genet. 94: 91-101, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10982965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10982965</a>] [<a href="https://doi.org/10.1002/1096-8628(20000911)94:2<91::aid-ajmg1>3.0.co;2-d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10982965">Breuning et al. (2000)</a>, respectively, <a href="#61" class="mim-tip-reference" title="Sun, Y., Almomani, R., Aten, E., Celli, J., van der Heijden, J., Venselaar, H., Robertson, S. P., Baroncini, A., Franco, B., Basel-Vanagaite, L., Horii, E., Drut, R., Ariyurek, Y., den Dunnen, J. T., Breuning, M. H. <strong>Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene.</strong> Am. J. Hum. Genet. 87: 146-153, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20598277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20598277</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20598277[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.06.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20598277">Sun et al. (2010)</a> identified a causative mutation in the last nucleotide of exon 31 of the FLNA gene: a c.5217G-A transition activated a cryptic splice site, removing the last 48 nucleotides from exon 31 and resulting in a loss of 16 amino acids (val1724_thr1739del). <a href="#61" class="mim-tip-reference" title="Sun, Y., Almomani, R., Aten, E., Celli, J., van der Heijden, J., Venselaar, H., Robertson, S. P., Baroncini, A., Franco, B., Basel-Vanagaite, L., Horii, E., Drut, R., Ariyurek, Y., den Dunnen, J. T., Breuning, M. H. <strong>Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene.</strong> Am. J. Hum. Genet. 87: 146-153, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20598277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20598277</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20598277[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.06.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20598277">Sun et al. (2010)</a> showed that because of nonrandom X chromosome inactivation, the mutant allele was not expressed in the patient fibroblasts. RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. The mutation was not found in 400 control X chromosomes, pilot data from 1000 Genomes Project, or the FLNA gene variant database. Because the mutation was predicted to remove a sequence at the surface of filamin repeat 15, <a href="#61" class="mim-tip-reference" title="Sun, Y., Almomani, R., Aten, E., Celli, J., van der Heijden, J., Venselaar, H., Robertson, S. P., Baroncini, A., Franco, B., Basel-Vanagaite, L., Horii, E., Drut, R., Ariyurek, Y., den Dunnen, J. T., Breuning, M. H. <strong>Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene.</strong> Am. J. Hum. Genet. 87: 146-153, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20598277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20598277</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20598277[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.06.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20598277">Sun et al. (2010)</a> suggested that the missing region in the filamin A protein affects or prevents the interaction of filamin A with other proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17152064+9800904+10982965+20598277+15864382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Turkish girl with terminal osseous dysplasia with pigmentary defects, <a href="#3" class="mim-tip-reference" title="Azakli, H., Akkaya, A. D., Aygun, M. S., Demirkesen, C., Eraslan, S., Kayserili, H. <strong>Terminal osseous dysplasia with pigmentary defects (TODPD) in a Turkish girl with new skin findings.</strong> Am. J. Med. Genet. 179A: 123-129, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30561107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30561107</a>] [<a href="https://doi.org/10.1002/ajmg.a.60686" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30561107">Azakli et al. (2019)</a> identified heterozygosity for the recurrent c.5217G-A transition in the FLNA gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30561107" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0030 CARDIAC VALVULAR DYSPLASIA, X-LINKED</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267606815 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606815;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs267606815?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267606815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267606815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a large 5-generation Caucasian French pedigree with X-linked cardiac valvular dysplasia (CVDPX; <a href="/entry/314400">314400</a>), originally reported by <a href="#6" class="mim-tip-reference" title="Benichou, B., Kyndt, F., Schott, J.-J., Trochu, J.-N., Baranger, F., Herbert, O., Scott, V., Fressinaud, E., David, A., Moisan, J.-P., Bouhour, J.-B., Le Marec, H. <strong>Mapping of X-linked valvular dysplasia to chromosome Xq28. (Abstract)</strong> Am. J. Hum. Genet. 61 (suppl.): A268 only, 1997."None>Benichou et al. (1997)</a> and <a href="#40" class="mim-tip-reference" title="Kyndt, F., Schott, J.-J., Trochu, J.-N., Baranger, F., Herbert, O., Scott, V., Fressinaud, E., David, A., Moisan, J.-P., Bouhour, J.-B., Le Marec, H., Benichou, B. <strong>Mapping of X-linked myxomatous valvular dystrophy to chromosome Xq28.</strong> Am. J. Hum. Genet. 62: 627-632, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9497244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9497244</a>] [<a href="https://doi.org/10.1086/301747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9497244">Kyndt et al. (1998)</a>, <a href="#39" class="mim-tip-reference" title="Kyndt, F., Gueffet, J.-P., Probst, V., Jaafar, P., Legendre, A., Le Bouffant, F., Toquet, C., Roy, E., McGregor, L., Lynch, S. A., Newbury-Ecob, R., Tran, V., Young, I., Trochu, J.-N., Le Marec, H., Schott, J.-J. <strong>Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy.</strong> Circulation 115: 40-49, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17190868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17190868</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.106.622621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17190868">Kyndt et al. (2007)</a> identified a 1910C-A transversion in exon 13 of the FLNA gene, resulting in a pro637-to-gln (P637Q) substitution at a highly conserved residue within the fourth repeat consensus sequence. The mutation segregated with disease in the family and was not found in 500 control chromosomes of white or African origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9497244+17190868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606816 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606816;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267606816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267606816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012544 OR RCV004820820" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012544, RCV004820820" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012544...</a>
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<p>In a British family with X-linked cardiac valvular dysplasia (CVDPX; <a href="/entry/314400">314400</a>), originally described by <a href="#47" class="mim-tip-reference" title="Newbury-Ecob, R. A., Zuccollo, J. M., Rutter, N., Young, I. D. <strong>Sex linked valvular dysplasia.</strong> J. Med. Genet. 30: 873-874, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8230166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8230166</a>] [<a href="https://doi.org/10.1136/jmg.30.10.873" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8230166">Newbury-Ecob et al. (1993)</a>, <a href="#39" class="mim-tip-reference" title="Kyndt, F., Gueffet, J.-P., Probst, V., Jaafar, P., Legendre, A., Le Bouffant, F., Toquet, C., Roy, E., McGregor, L., Lynch, S. A., Newbury-Ecob, R., Tran, V., Young, I., Trochu, J.-N., Le Marec, H., Schott, J.-J. <strong>Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy.</strong> Circulation 115: 40-49, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17190868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17190868</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.106.622621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17190868">Kyndt et al. (2007)</a> identified an 862G-A transition in exon 5 of the FLNA gene, resulting in a gly288-to-arg (G288R) substitution at a highly conserved residue within the first repeat consensus sequence. The mutation segregated with disease in the family and was not found in 500 control chromosomes of white or African origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8230166+17190868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0032 CARDIAC VALVULAR DYSPLASIA, X-LINKED</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606817 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606817;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267606817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267606817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012545" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012545" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012545</a>
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<p>In a 4-month-old boy with cardiac valvular dysplasia (CVDPX; <a href="/entry/314400">314400</a>), born of black African parents, <a href="#39" class="mim-tip-reference" title="Kyndt, F., Gueffet, J.-P., Probst, V., Jaafar, P., Legendre, A., Le Bouffant, F., Toquet, C., Roy, E., McGregor, L., Lynch, S. A., Newbury-Ecob, R., Tran, V., Young, I., Trochu, J.-N., Le Marec, H., Schott, J.-J. <strong>Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy.</strong> Circulation 115: 40-49, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17190868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17190868</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.106.622621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17190868">Kyndt et al. (2007)</a> identified a 2132T-A transversion in exon 14 of the FLNA gene, resulting in a val711-to-asp (V711D) substitution at a highly conserved residue in the fifth repeat consensus sequence. The patient was diagnosed prenatally with abnormally thick cardiac valves by ultrasound and fetal echocardiography; postnatal echocardiography confirmed that all valves were thickened and dystrophic, with moderate tricuspid incompetence, trivial mitral and pulmonary incompetence, and mild aortic incompetence. His carrier mother showed no evidence of cardiac involvement on clinical examination. The mutation was not found in 500 control chromosomes of white or African origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17190868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0033 CARDIAC VALVULAR DYSPLASIA, X-LINKED</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012546" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012546" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012546</a>
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<p>In 2 brothers of Hong Kong Chinese origin with cardiac valvular dysplasia (CVDPX; <a href="/entry/314400">314400</a>), <a href="#39" class="mim-tip-reference" title="Kyndt, F., Gueffet, J.-P., Probst, V., Jaafar, P., Legendre, A., Le Bouffant, F., Toquet, C., Roy, E., McGregor, L., Lynch, S. A., Newbury-Ecob, R., Tran, V., Young, I., Trochu, J.-N., Le Marec, H., Schott, J.-J. <strong>Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy.</strong> Circulation 115: 40-49, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17190868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17190868</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.106.622621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17190868">Kyndt et al. (2007)</a> identified a 1,944-bp genomic deletion from intron 15 to intron 19 of the FLNA gene, predicting an in-frame deletion of 182 residues from val761 to gln943 that results in a truncated protein lacking repeat consensus sequences 5 to 7. The deletion was not found in 200 control chromosomes, including 100 Asian chromosomes. In the 12-year-old proband, a heart murmur was detected at 4 months of age, and echocardiography revealed myxomatous thickening of the mitral, tricuspid, and aortic valves; he had significant mitral and tricuspid regurgitation and mild aortic regurgitation. His 4-year-old brother was found to have mitral incompetence and stenosis, tricuspid regurgitation, and mild aortic regurgitation. Their 38-year-old asymptomatic carrier mother had mild aortic and pulmonary incompetence on echocardiography. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17190868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0034 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122812 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122812;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs398122812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs398122812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022819" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022819" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022819</a>
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<p>In an 18-month-old girl with periventricular nodular heterotopia (PVNH1; <a href="/entry/300049">300049</a>) and seizures, <a href="#34" class="mim-tip-reference" title="Jefferies, J. L., Taylor, M. D., Rossano, J., Belmont, J. W., Craigen, W. J. <strong>Novel cardiac findings in periventricular nodular heterotopia.</strong> Am. J. Med. Genet. 152A: 165-168, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20014127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20014127</a>] [<a href="https://doi.org/10.1002/ajmg.a.33110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20014127">Jefferies et al. (2010)</a> identified a heterozygous 7896G-A transition in the FLNA gene, resulting in a trp2632-to-ter (W2632X) substitution. Echocardiogram showed a redundant and unobstructed pulmonary valve, a cleft in the anterior leaflet of the mitral valve with mitral regurgitation, and a patent foramen ovale with mild left-to-right shunting. There was no evidence of a persistent patent ductus arteriosus. Since there was no family history of the disorder, the mutation was assumed to have occurred de novo. <a href="#34" class="mim-tip-reference" title="Jefferies, J. L., Taylor, M. D., Rossano, J., Belmont, J. W., Craigen, W. J. <strong>Novel cardiac findings in periventricular nodular heterotopia.</strong> Am. J. Med. Genet. 152A: 165-168, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20014127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20014127</a>] [<a href="https://doi.org/10.1002/ajmg.a.33110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20014127">Jefferies et al. (2010)</a> noted that other cardiac defects, such as patent ductus arteriosus, bicuspid aortic valve, and dilation of the sinuses of Valsalva, had been reported in patients with X-linked periventricular heterotopia, and that myxomatous valvular disease was also associated with FLNA mutations, but emphasized that the findings in this patient had not previously been reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20014127" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0035 CONGENITAL SHORT BOWEL SYNDROME, X-LINKED</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122521 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122521;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs398122521" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs398122521" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000043474 OR RCV000577880" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043474, RCV000577880" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043474...</a>
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<p>In affected members of an Italian family segregating isolated congenital X-linked short bowel syndrome (see <a href="/entry/300048">300048</a>) and in an unrelated singleton with the disorder, <a href="#65" class="mim-tip-reference" title="van der Werf, C. S., Sribudiani, Y., Verheij, J. B. G. M., Carroll, M., O'Loughlin, E., Chen, C.-H., Brooks, A. S., Liszewski, M. K., Atkinson, J. P., Hofstra, R. M. W. <strong>Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations.</strong> Genet. Med. 15: 310-313, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23037936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23037936</a>] [<a href="https://doi.org/10.1038/gim.2012.123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23037936">van der Werf et al. (2013)</a> identified a 2-bp deletion in exon 2 of the FLNA gene (16_17delTC). The family had been reported by <a href="#36" class="mim-tip-reference" title="Kern, I. B., Leece, A., Bohane, T. <strong>Congenital short gut, malrotation, and dysmotility of the small bowel.</strong> J. Pediat. Gastroent. Nutr. 11: 411-415, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2123245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2123245</a>] [<a href="https://doi.org/10.1097/00005176-199010000-00023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2123245">Kern et al. (1990)</a> and the single patient by <a href="#58" class="mim-tip-reference" title="Siva, C., Brasington, R., Totty, W., Sotelo, A., Atkinson, J. <strong>Synovial lipomatosis (lipoma arborescens) affecting multiple joints in a patient with congenital short bowel syndrome.</strong> J. Rheum. 29: 1088-1092, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12022328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12022328</a>]" pmid="12022328">Siva et al. (2002)</a>. In the family, all obligate carriers were heterozygous for the deletion. The mother of the isolated case did not carry the deletion, indicating that it occurred as a de novo event. <a href="#65" class="mim-tip-reference" title="van der Werf, C. S., Sribudiani, Y., Verheij, J. B. G. M., Carroll, M., O'Loughlin, E., Chen, C.-H., Brooks, A. S., Liszewski, M. K., Atkinson, J. P., Hofstra, R. M. W. <strong>Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations.</strong> Genet. Med. 15: 310-313, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23037936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23037936</a>] [<a href="https://doi.org/10.1038/gim.2012.123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23037936">Van der Werf et al. (2013)</a> stated that they could not exclude involvement of the central nervous system in these patients because no magnetic resonance imaging brain scans were available. This mutation was absent in 92 controls and was not reported in the Exome Variant Server database. The 16_17delTC mutation is located between the first and second methionines and results in frameshift and premature termination at amino acid 103. Based on its location, <a href="#65" class="mim-tip-reference" title="van der Werf, C. S., Sribudiani, Y., Verheij, J. B. G. M., Carroll, M., O'Loughlin, E., Chen, C.-H., Brooks, A. S., Liszewski, M. K., Atkinson, J. P., Hofstra, R. M. W. <strong>Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations.</strong> Genet. Med. 15: 310-313, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23037936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23037936</a>] [<a href="https://doi.org/10.1038/gim.2012.123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23037936">van der Werf et al. (2013)</a> predicted that the 16_17delTC mutation has a similar effect to the 65delAC mutation (<a href="#0025">300017.0025</a>) reported by <a href="#2" class="mim-tip-reference" title="Auricchio, A., Brancolini, V., Casari, G., Milla, P. J., Smith, V. V., Devoto, M., Ballabio, A. <strong>The locus for a novel syndromic form of neuronal intestinal pseudoobstruction maps to Xq28.</strong> Am. J. Hum. Genet. 58: 743-748, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644737</a>]" pmid="8644737">Auricchio et al. (1996)</a> and <a href="#20" class="mim-tip-reference" title="Gargiulo, A., Auricchio, R., Barone, M. V., Cotugno, G., Reardon, W., Milla, P. J., Ballabio, A., Ciccodicola, A., Auricchio, A. <strong>Filamin A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement.</strong> Am. J. Hum. Genet. 80: 751-758, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357080</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357080[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357080">Gargiulo et al. (2007)</a>, which results in loss of only the long form of FLNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8644737+12022328+17357080+23037936+2123245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0036 HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT, WITH MELNICK-NEEDLES SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs797045163 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797045163;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs797045163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs797045163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a woman and her 3 daughters with a complex phenotype comprising both periventricular nodular heterotopia (<a href="/entry/300049">300049</a>) and Melnick-Needles syndrome (<a href="/entry/309350">309350</a>), <a href="#48" class="mim-tip-reference" title="Parrini, E., Mei, D., Pisanti, M. A., Catarzi, S., Pucatti, D., Bianchini, C., Mascalchi, M., Bertini, E., Morrone, A., Cavaliere, M. L., Guerrini, R. <strong>Familial periventricular nodular heterotopia, epilepsy and Melnick-Needles syndrome caused by a single FLNA mutation with combined gain-of-function and loss-of-function effects.</strong> J. Med. Genet. 52: 405-412, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25755106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25755106</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102959" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25755106">Parrini et al. (2015)</a> identified a c.622G-C transversion (c.622G-C, NM_001110556.1) in exon 3 of the FLNA gene, resulting in a gly208-to-arg (G208R) substitution at a conserved residue in the N-terminal domain. The mutation was not found in the Exome Sequencing Project (ESP6500) database or in 250 control DNA samples. The c.622G-C mutation was also predicted to result in a splice site mutation, and RT-PCR analysis of patient cells showed the presence of an aberrant transcript with intron 3 retention, a frameshift, and premature termination (Leu209GlufsTer37), consistent with a loss of function. The loss of function resulted in the periventricular nodular heterotopia phenotype. Transcript levels of the G208R mutation were low (3.5 to 7.6%) in patient cells, similar to that observed in patients with MNS, and this missense mutation was predicted to result in a gain of function and the MNS phenotype. Western blot analysis of patient cells showed reduced levels of FLNA protein compared to controls. The 3 daughters had onset of seizures in the first decade. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25755106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1603362402 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1603362402;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1603362402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1603362402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000787477" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000787477" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000787477</a>
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<p>In 2 affected male cousins from a 3-generation Italian family, originally reported by <a href="#11" class="mim-tip-reference" title="Di Ferrante, N., Leachman, R. D., Angelini, P., Donnelly, P. V., Francis, G., Almazan, A., segni, G. <strong>Lysyl oxidase deficiency in Ehlers-Danlos syndrome type V.</strong> Connect. Tissue Res. 3: 49-53, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/240645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">240645</a>] [<a href="https://doi.org/10.3109/03008207509152341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="240645">Di Ferrante et al. (1975)</a>, in which 5 affected males and 1 female had died of congestive heart failure due to multivalvular disease (CVDPX; <a href="/entry/314400">314400</a>), <a href="#50" class="mim-tip-reference" title="Ritelli, M., Morlino, S., Giacopuzzi, E., Carini, G., Cinquina, V., Chiarelli, N., Majore, S., Colombi, M., Castori, M. <strong>Ehlers-Danlos syndrome with lethal cardiac valvular dystrophy in males carrying a novel splice mutation in FLNA.</strong> Am. J. Med. Genet. 173A: 169-176, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27739212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27739212</a>] [<a href="https://doi.org/10.1002/ajmg.a.38004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27739212">Ritelli et al. (2017)</a> identified hemizygosity for a splicing mutation (c.1829-1G-C, NM_001456.3) in intron 12 of the FLNA gene, predicted to abolish the canonical splice acceptor site of exon 13 and activate use of a cryptic acceptor site 15 bp downstream, resulting in the in-frame deletion of 5 amino acid residues (Phe611_Gly615del). Other family members were unavailable for segregation analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=240645+27739212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0038 CARDIAC VALVULAR DYSPLASIA, X-LINKED</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1603360542 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1603360542;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1603360542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1603360542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000787478 OR RCV001269936 OR RCV004822196" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000787478, RCV001269936, RCV004822196" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000787478...</a>
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<p>In 2 affected male cousins from a 3-generation family with multivalvular dysplasia (CVDPX; <a href="/entry/314400">314400</a>), originally reported by <a href="#4" class="mim-tip-reference" title="Balaji, S., Dennis, N. R., Keeton, B. R. <strong>Familial Ebstein's anomaly: a report of six cases in two generations associated with mild skeletal abnormalities.</strong> Brit. Heart J. 66: 26-28, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1854572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1854572</a>] [<a href="https://doi.org/10.1136/hrt.66.1.26" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1854572">Balaji et al. (1991)</a>, <a href="#45" class="mim-tip-reference" title="Mercer, C. L., Andreoletti, G., Carroll, A., Salmon, A. P., Temple, I. K., Ennis, S. <strong>Familial Ebstein anomaly: whole exome sequencing identifies novel phenotype associated with FLNA.</strong> Circ. Cardiovasc. Genet. 10: e001683, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29237676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29237676</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.116.001683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29237676">Mercer et al. (2017)</a> identified hemizygosity for a c.4660G-A transition in the FLNA gene, resulting in a gly1554-to-arg (G1554R) substitution within the 14th repeated rod domain. The mutation was present in heterozygosity in the 4 female patients, who were more mildly affected than the hemizygous males. DNA was unavailable from the male proband, who died at 10 days of age with severe Ebstein anomaly of the tricuspid valve. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29237676+1854572" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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Adams, M., Simms, R. J., Abdelhamed, Z., Dawe, H. R., Szymanska, K., Logan, C. V., Wheway, G., Pitt, E., Gull, K., Knowles, M. A., Blair, E., Cross, S. H., Sayer, J. A., Johnson, C. A.
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<strong>A meckelin-filamin A interaction mediates ciliogenesis.</strong>
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Hum. Molec. Genet. 21: 1272-1286, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22121117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22121117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22121117[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22121117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddr557" target="_blank">Full Text</a>]
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Auricchio, A., Brancolini, V., Casari, G., Milla, P. J., Smith, V. V., Devoto, M., Ballabio, A.
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<strong>The locus for a novel syndromic form of neuronal intestinal pseudoobstruction maps to Xq28.</strong>
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Am. J. Hum. Genet. 58: 743-748, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644737</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8644737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/513321" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1994.1288" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.30396" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2004.029173" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1993.1354" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1083/jcb.111.3.1089" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.molimm.2003.11.035" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2005.038505" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.30792" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(sici)1096-8628(19981102)80:1<1::aid-ajmg1>3.0.co;2-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.44.1.51" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1119" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.gde.2005.04.001" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/nar/15.17.7155" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/10.17.1775" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/11.23.2845" target="_blank">Full Text</a>]
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<strong>Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome.</strong>
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[<a href="https://doi.org/10.1212/01.WNL.0000149512.79621.DF" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s003359900435" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.30484" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2010.06.008" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI30376" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31751" target="_blank">Full Text</a>]
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Vadlamudi, R. K., Li, F., Adam, L., Nguyen, D., Ohta, Y., Stossel, T. P., Kumar, R.
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<strong>Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198493</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12198493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ncb838" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/gim.2012.123" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31213" target="_blank">Full Text</a>]
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<strong>A dual phenotype of periventricular nodular heterotopia and frontometaphyseal dysplasia in one patient caused by a single FLNA mutation leading to two functionally different aberrant transcripts.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14988809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14988809</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14988809[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14988809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/383094" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Sonja A. Rasmussen - updated : 07/07/2022
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Hilary J. Vernon - updated : 07/01/2020<br>Marla J. F. O'Neill - updated : 07/17/2019<br>Cassandra L. Kniffin - updated : 9/21/2015<br>Patricia A. Hartz - updated : 10/15/2014<br>Ada Hamosh - updated : 9/2/2014<br>Patricia A. Hartz - updated : 7/12/2013<br>Ada Hamosh - updated : 5/2/2013<br>Ada Hamosh - updated : 11/21/2011<br>Cassandra L. Kniffin - updated : 1/5/2011<br>George E. Tiller - updated : 11/1/2010<br>Marla J. F. O'Neill - updated : 10/28/2010<br>Nara Sobreira - updated : 10/22/2010<br>Cassandra L. Kniffin - updated : 5/19/2009<br>Cassandra L. Kniffin - updated : 4/17/2009<br>Paul J. Converse - updated : 7/24/2008<br>Marla J. F. O'Neill - updated : 2/1/2008<br>Cassandra L. Kniffin - updated : 5/15/2007<br>Patricia A. Hartz - updated : 4/23/2007<br>Victor A. McKusick - updated : 3/27/2007<br>Marla J. F. O'Neill - updated : 3/15/2007<br>Victor A. McKusick - updated : 7/5/2006<br>Victor A. McKusick - updated : 6/9/2006<br>Cassandra L. Kniffin - updated : 6/2/2006<br>Marla J. F. O'Neill - updated : 5/11/2006<br>Paul J. Converse - updated : 4/4/2006<br>Marla J. F. O'Neill - updated : 12/28/2005<br>Victor A. McKusick - updated : 5/10/2005<br>Marla J. F. O'Neill - updated : 3/1/2005<br>Marla J. F. O'Neill - updated : 1/28/2005<br>Victor A. McKusick - updated : 4/8/2004<br>George E. Tiller - updated : 3/31/2004<br>Victor A. McKusick - updated : 6/5/2003<br>Victor A. McKusick - updated : 5/16/2003<br>Victor A. McKusick - updated : 3/19/2003<br>Cassandra L. Kniffin - updated : 11/8/2002<br>Patricia A. Hartz - updated : 10/28/2002<br>George E. Tiller - updated : 1/24/2002<br>Victor A. McKusick - updated : 12/18/2000<br>Victor A. McKusick - updated : 4/13/1999
|
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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|
Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
|
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Victor A. McKusick : 7/8/1993
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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|
alopez : 09/30/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/11/2022<br>carol : 07/11/2022<br>alopez : 07/07/2022<br>carol : 07/01/2020<br>carol : 07/17/2019<br>alopez : 11/07/2018<br>alopez : 04/06/2018<br>carol : 01/05/2018<br>carol : 01/04/2018<br>carol : 10/26/2016<br>alopez : 09/19/2016<br>carol : 11/23/2015<br>carol : 11/9/2015<br>carol : 9/23/2015<br>carol : 9/22/2015<br>ckniffin : 9/21/2015<br>mgross : 10/15/2014<br>alopez : 9/2/2014<br>mgross : 7/12/2013<br>carol : 7/10/2013<br>alopez : 5/2/2013<br>carol : 7/17/2012<br>alopez : 11/28/2011<br>terry : 11/21/2011<br>wwang : 4/7/2011<br>carol : 1/28/2011<br>wwang : 1/24/2011<br>ckniffin : 1/5/2011<br>alopez : 11/5/2010<br>terry : 11/1/2010<br>terry : 11/1/2010<br>wwang : 10/28/2010<br>terry : 10/28/2010<br>carol : 10/27/2010<br>terry : 10/22/2010<br>terry : 10/22/2010<br>carol : 2/24/2010<br>carol : 7/28/2009<br>carol : 7/23/2009<br>wwang : 5/29/2009<br>ckniffin : 5/19/2009<br>wwang : 4/30/2009<br>ckniffin : 4/17/2009<br>carol : 1/21/2009<br>mgross : 8/15/2008<br>mgross : 8/15/2008<br>terry : 7/24/2008<br>carol : 6/10/2008<br>wwang : 2/7/2008<br>terry : 2/1/2008<br>terry : 9/18/2007<br>wwang : 5/17/2007<br>ckniffin : 5/15/2007<br>wwang : 4/23/2007<br>alopez : 3/28/2007<br>terry : 3/27/2007<br>wwang : 3/16/2007<br>terry : 3/15/2007<br>terry : 8/24/2006<br>alopez : 7/10/2006<br>terry : 7/5/2006<br>carol : 6/22/2006<br>alopez : 6/9/2006<br>wwang : 6/5/2006<br>ckniffin : 6/2/2006<br>wwang : 5/11/2006<br>mgross : 5/11/2006<br>terry : 4/4/2006<br>wwang : 12/29/2005<br>terry : 12/28/2005<br>wwang : 5/17/2005<br>wwang : 5/11/2005<br>terry : 5/10/2005<br>wwang : 3/7/2005<br>terry : 3/1/2005<br>carol : 2/3/2005<br>terry : 1/28/2005<br>ckniffin : 10/25/2004<br>tkritzer : 4/26/2004<br>tkritzer : 4/16/2004<br>terry : 4/8/2004<br>tkritzer : 3/31/2004<br>tkritzer : 3/31/2004<br>tkritzer : 6/19/2003<br>tkritzer : 6/13/2003<br>terry : 6/5/2003<br>tkritzer : 5/27/2003<br>terry : 5/16/2003<br>alopez : 4/2/2003<br>alopez : 3/21/2003<br>terry : 3/19/2003<br>mgross : 12/10/2002<br>carol : 11/13/2002<br>ckniffin : 11/8/2002<br>mgross : 10/28/2002<br>carol : 4/2/2002<br>cwells : 3/13/2002<br>cwells : 2/14/2002<br>cwells : 1/24/2002<br>mcapotos : 1/18/2001<br>mcapotos : 1/5/2001<br>terry : 12/18/2000<br>alopez : 9/5/2000<br>terry : 4/14/1999<br>terry : 4/13/1999<br>alopez : 12/4/1998<br>terry : 11/18/1998<br>dkim : 7/17/1998<br>mark : 4/10/1997<br>joanna : 1/31/1996<br>jason : 6/7/1994<br>mimadm : 2/27/1994<br>carol : 8/23/1993<br>carol : 8/16/1993<br>carol : 7/13/1993<br>carol : 7/8/1993
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
|
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<strong>*</strong> 300017
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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FILAMIN A; FLNA
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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FILAMIN, ALPHA<br />
|
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FILAMIN 1; FLN1<br />
|
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FLN<br />
|
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ACTIN-BINDING PROTEIN 280; ABP280
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: FLNA</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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|
<strong>SNOMEDCT:</strong> 1186709006, 13449007, 42432003, 448227009, 54036001, 784010006;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
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<em>
|
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Cytogenetic location: Xq28
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|
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Genomic coordinates <span class="small">(GRCh38)</span> : X:154,348,531-154,374,634 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="10">
|
|
<span class="mim-font">
|
|
Xq28
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?FG syndrome 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
300321
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
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|
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</tr>
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|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiac valvular dysplasia, X-linked
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
314400
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Congenital short bowel syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
300048
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Frontometaphyseal dysplasia 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
305620
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Heterotopia, periventricular, 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
300049
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Intestinal pseudoobstruction, neuronal
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
300048
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Melnick-Needles syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
309350
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Otopalatodigital syndrome, type I
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
311300
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Otopalatodigital syndrome, type II
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
304120
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Terminal osseous dysplasia
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
300244
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The FLNA gene encodes filamin A, a widely expressed 280-kD actin-binding protein that regulates reorganization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes, and second messengers. Filamins crosslink actin filaments into orthogonal networks in the cytoplasm and participate in the anchoring of membrane proteins to the actin cytoskeleton. Remodeling of the cytoskeleton is central to the modulation of cell shape and migration (Maestrini et al., 1993; Fox et al., 1998). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>By analysis of the native ABP280 protein and cloning of the human endothelial ABP280 cDNA, Gorlin et al. (1990) demonstrated that ABP280 is a 2,647-amino acid protein with 3 functional domains: an N-terminal filamentous actin-binding domain, a C-terminal self-association domain, and a membrane glycoprotein-binding domain. The N-terminal actin-binding domain of ABP280 displays strong structural and functional similarity to the N-terminal domains of dystrophin (300377), alpha-actinin (102575), and beta-spectrin (182870). </p><p>In a search for muscle- and heart-specific isoforms that might be involved in Emery muscular dystrophy (EDMD; 310300), Maestrini et al. (1993) identified several different ABP280 mRNAs. Two were X-linked and were produced by alternative splicing of a small exon of 24 nucleotides. Both of these were ubiquitous in distribution. At least 1 additional gene encoding an RNA more than 70% identical to ABP280 was found and was shown to map to chromosome 7 by study of human/hamster somatic cell hybrids (FLNC; 102565). </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Patrosso et al. (1994) found that the FLN1 gene is composed of 47 exons spanning approximately 26 kb. The first and part of the second exon are untranslated. The actin-binding domain at the N terminus is encoded by exons 2 to 5. The 96-amino acid repeats corresponding to the elongated backbone of the protein are encoded by the remaining 42 exons. </p><p>Fox et al. (1998) stated that FLN1 consists of 48 exons covering 26 kb of genomic sequence, with a 7.9-kb open reading frame. </p><p>Chakarova et al. (2000) compared the genomic structure of the filamin gene family. A previously unknown intron was found in FLNA. The comparison of FLNA with the 2 paralogs, FLNB (603381) and FLNC, demonstrated a highly conserved exon/intron structure with significant differences in exon 32 of all paralogs encoding the hinge I region, as well as the insertion of a novel exon 40A in FLNC only. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</h4>
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<span class="mim-text-font">
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<p>When sequences from CpG islands in the Xq28 region (Maestrini et al., 1990) were compared to sequences in databases, the gene for ABP280 was found. It is located in the distal part of Xq28, 50-60 kb downstream of the colorblindness genes. A similar localization was reported by Kunst et al. (1992). </p><p>Kunst et al. (1992) mapped the ABP280 cDNA to Xq28 by somatic hybrid cell panel analysis and fluorescence in situ hybridization (FISH).</p><p>Gorlin et al. (1993) mapped the FLN gene to Xq28 by Southern blot analysis of somatic cell hybrid lines, by FISH, and by identification of portions of the FLN gene within cosmids and YACs mapped to Xq28. Specifically, the FLN gene was located within a 200-kb region between the G6PD locus at the telomeric end and the colorblindness loci and the DXS52 marker at the proximal end. Because of its similarities to dystrophin, Gorlin et al. (1993) suggested FLN as a candidate gene for 2 myopathies that map to Xq28: EDMD and Barth syndrome (302060). </p><p>Fox et al. (1998) stated that the FLN1 gene is adjacent to the emerin gene (300384), which is mutant in EDMD, and the 2 genes are flanked by inverted repeats, causing the genomic segment containing these 2 genes to be present in 2 orientations in the population at large (Small et al., 1997). Notably, all large-scale rearrangements of emerin associated with EDMD failed to include FLN1, suggesting that loss of FLN1 function might be embryonically lethal. </p><p>Gariboldi et al. (1994) mapped the mouse homolog to the X chromosome in a region of syntenic homology with Xq28. </p>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Clark et al. (2009) determined the crystal structures of wildtype and E254K (300017.0010)-mutant FLNA actin-binding domains (ABDs) at 2.3-angstrom resolution, revealing that they adopt similar closed conformations. The E254K mutation removes a conserved salt bridge but does not disrupt the ABD structure. The solution structures are also equivalent as determined by circular dichroism spectroscopy, but differential scanning fluorimetry denaturation showed reduced thermal stability for E254K. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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<p>Vadlamudi et al. (2002) identified FLNA as a binding partner of PAK1 (602590) in a yeast 2-hybrid screen of a mammary gland cDNA library. By mutation analysis, they localized the PAK1-binding region in FLNA to tandem repeat 23 in the C terminus, and the FLNA-binding region in PAK1 between amino acids 52 and 132 in the conserved CDC42 (116952)/RAC (602048)-interacting domain. Endogenous FLNA was phosphorylated by PAK1 on ser2152 following stimulation with physiologic signaling molecules. Following stimulation, FLNA colocalized with PAK1 in membrane ruffles. The ruffle-forming activity of PAK1 was found in FLNA-expressing cells, but not in cells deficient in FLNA. </p><p>Androgen receptor (AR; 313700), a nuclear transcription factor, mediates male sexual differentiation. Loy et al. (2003) characterized a negative regulatory domain in the AR hinge region that interacts with filamin A. Filamin A interferes with AR interdomain interactions and competes with the coactivator transcriptional intermediary factor-2 (TIF2; 601993) to downregulate AR function specifically. Although full-length filamin A is predominantly cytoplasmic, a C-terminal 100-kD fragment colocalized with AR to the nucleus. This naturally occurring filamin A fragment repressed AR transactivation and disrupted AR interdomain interactions and TIF2-activated AR function in a manner reminiscent of full-length filamin A, raising the possibility that the inhibitory effects of cytoplasmic filamin A may be transduced through this fragment, which can localize to the nucleus and form part of the preinitiation complex. This unanticipated role of filamin A added to the evidence for the involvement of cytoskeletal proteins in transcription regulation. </p><p>Mutation in the X-linked FLNA gene can cause the neurologic disorder periventricular heterotopia (300049). Although periventricular heterotopia is characterized by a failure in neuronal migration into the cerebral cortex with consequent formation of nodules in the ventricular and subventricular zones, many neurons appear to migrate normally, even in males, suggesting compensatory mechanisms. Sheen et al. (2002) showed that, in mice, Flna mRNA was widely expressed in all brain cortical layers, whereas a homolog, Flnb (603381), was most highly expressed in the ventricular and subventricular zones during development. In adulthood, widespread but reduced expression of Flna and Flnb persisted throughout the cerebral cortex. Flna and Flnb proteins were highly expressed in both the leading processes and somata of migratory neurons during corticogenesis. Postnatally, Flna immunoreactivity was largely localized to the cell body, whereas Flnb was localized to the soma and neuropil during neuronal differentiation. The putative Flnb homodimerization domain strongly interacted with itself or the corresponding homologous region of Flna, as shown by yeast 2-hybrid interaction. The 2 proteins colocalized within neuronal precursors by immunocytochemistry, and the existence of Flna-Flnb heterodimers could be detected by coimmunoprecipitation. Sheen et al. (2002) suggested that FLNA and FLNB may form both homodimers and heterodimers, and that their interaction could potentially compensate for the loss of FLNA function during cortical development within patients with periventricular heterotopia. </p><p>Using a yeast 2-hybrid screen, Grimbert et al. (2004) identified FLNA as a binding partner for both CMIP (610112) and its truncated isoform, TCMIP. Coimmunoprecipitation analysis confirmed the interactions. Immunofluorescence microscopy demonstrated homogeneous colocalization of CMIP and FLNA in the cytoplasm, but restriction of TCMIP/FLNA colocalization to points of intercellular contact. Western blot analysis showed increased FLNA expression in patients with relapse of minimal change nephrotic syndrome, a glomerular disease thought to result from abnormal T-cell activation. Grimbert et al. (2004) proposed that FLNA and CMIP/TCMIP interact in a T-cell signaling pathway. </p><p>Using proteomic approaches, Thelin et al. (2007) showed that FLNA associates with the extreme CFTR (602421) N terminus. Cell studies revealed that filamin tethers plasma membrane CFTR to the underlying actin network, stabilizing CFTR at the cell surface and regulating the plasma membrane dynamics and confinement of the channel. In the absence of filamin binding, CFTR is rapidly internalized from the cell surface, where it accumulates prematurely in lysosomes and is ultimately degraded. </p><p>Using yeast 2-hybrid analysis and protein pull-down assays, Jimenez-Baranda et al. (2007) showed that the human immunodeficiency virus (HIV)-1 (see 609423) receptor CD4 (186940) and the HIV-1 coreceptors CCR5 (601373) and CXCR4 (162643) interacted with FLNA, which regulated clustering of the HIV-1 receptors on the cell surface. Binding of HIV-1 gp120 to the receptors induced transient cofilin (see CFL1; 601442) phosphorylation inactivation through a RHOA (165390)-ROCK (see 601702)-dependent mechanism. Blockade of FLNA interaction with CD4 and/or the coreceptors inhibited gp120-induced RHOA activation and cofilin inactivation. Jimenez-Baranda et al. (2007) concluded that FLNA is an adaptor protein that links HIV-1 receptors to the actin skeleton remodeling machinery, possibly facilitating virus infection. </p><p>Ehrlicher et al. (2011) identified the actin-binding protein filamin A (FLNA) as a central mechanotransduction element of the cytoskeleton, and reconstituted a minimal system consisting of actin filaments, FLNA, and 2 FLNA-binding partners: the cytoplasmic tail of beta-integrin (135630) and FilGAP (610586). Integrins form an essential mechanical linkage between extracellular and intracellular environments, with beta-integrin tails connecting to the actin cytoskeleton by binding directly to filamin. FilGAP is an FLNA-binding GTPase-activating protein specific for RAC, which in vivo regulates cell spreading and bleb formation. Using fluorescence loss after photoconversion, Ehrlicher et al. (2011) demonstrated that both externally imposed bulk shear and myosin-II-driven forces differentially regulate the binding of these partners to FLNA. Consistent with structural predictions, strain increases beta-integrin binding to FLNA, whereas it causes FilGAP to dissociate from FLNA, providing a direct and specific molecular basis for cellular mechanotransduction. Ehrlicher et al. (2011) concluded that their results identified a molecular mechanotransduction element within the actin cytoskeleton, revealing that mechanical strain of key proteins regulates the binding of signaling molecules. </p><p>By yeast 2-hybrid and immunoprecipitation analyses, Adams et al. (2012) found that the C-terminal cytoplasmic tail of meckelin (TMEM67; 609884) interacted with filamin A. Loss of filamin A or meckelin in immortalized fibroblasts from patients with null mutations in the genes or by small interfering RNA in mouse IMCD3 cells resulted in similar cellular phenotypes, including abnormal basal body positioning and ciliogenesis, aberrant remodeling of the actin cytoskeleton, deregulation of RHOA (165390) activity, and hyperactivation of canonical Wnt (see 606359) signaling. Adams et al. (2012) concluded that the meckelin-filamin A signaling axis is a key regulator of ciliogenesis and normal Wnt signaling. </p><p>Using yeast 2-hybrid and immunoprecipitation analyses, Hu et al. (2014) found that mouse Flna and Flnb (603381) interacted directly with the actin-nucleating protein Fmn1 (136535). The filamins and Fmn1 colocalized in cytoplasm and, to a lesser extent, nucleus, and they were coexpressed in chondrocytes. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Periventricular Heterotopia 1</em></strong></p><p>
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X-linked dominant periventricular heterotopia (PVNH1; 300049) is a disorder in which many neurons fail to migrate to the cerebral cortex and persist as nodules lining the ventricular surface. Heterozygous females with the disorder present with epilepsy and other signs, including patent ductus arteriosus (see 607411) and coagulopathy, whereas hemizygous affected males die embryonically. Fox et al. (1998) identified the cause as mutations in the FLN1 gene (300017.0001-300017.0005), which is required for locomotion of many cell types. They demonstrated a previously unrecognized high level of expression of FLN1 in the developing cortex. Their studies demonstrated that FLN1 is required for neuronal migration to the cortex and is essential for embryogenesis. </p><p>In identifying filamin-1 as the gene mutant in periventricular heterotopia, Fox et al. (1998) first narrowed the map location to an interval approximately 1 cM between marker DXS15 and the pseudoautosomal region of Xq28 by the study of additional markers. Subsequent analysis of a large duplication of Xq28 in a male patient with periventricular heterotopia (Fink et al., 1997) with a severe, albeit nonlethal, phenotype allowed the candidate interval to be refined even further. They defined the exact centromeric boundary of the duplicated segment of Xq28 as base 3377 of 3,395 bases in intron 1 of the isocitrate dehydrogenase gene (IDH3G; 300089), approximately 600 kb distal to DXS15. However, none of the genes identified at the breakpoints or insertion site of the duplication harbored independent mutations in other patients with periventricular heterotopia. Therefore, Fox et al. (1998) concluded that the duplication of FLN1 itself was responsible for the disorder in this patient. </p><p>Fox et al. (1998) studied the pattern of X inactivation in females with FLN1 mutations in nucleated peripheral blood cells. No evidence of preferential lyonization in these cells was found, suggesting that FLN1 is not required in a cell-autonomous fashion for survival of mixed peripheral white blood cells. However, an essential cell-autonomous role for FLN1 in a subset of nucleated cells or nonnucleated cells (e.g., platelets) could not be excluded. </p><p>Sheen et al. (2001) performed SSCP analysis of FLN1 throughout its entire coding region in 6 periventricular heterotopia pedigrees, 31 sporadic female patients, and 24 sporadic male periventricular heterotopia patients. The authors detected FLN1 mutations in 83% of periventricular heterotopia pedigrees and 19% of sporadic females with periventricular heterotopia. Moreover, 0 of 7 females with periventricular heterotopia with atypical radiographic features showed FLN1 mutations, suggesting that other genes may cause atypical periventricular heterotopia. Two of 24 males analyzed with periventricular heterotopia (9%) also carried FLN1 mutations. Whereas FLN1 mutations in periventricular heterotopia pedigrees caused severe predicted loss of FLN1 protein function, both male FLN1 mutations were consistent with partial loss of function of the protein. Moreover, sporadic female FLN1 mutations associated with periventricular heterotopia appear to cause either severe or partial loss of function. </p><p>Sheen et al. (2005) reported 2 familial cases and 9 sporadic cases with what they designated an Ehlers-Danlos variant of periventricular heterotopia, characterized by nodular brain heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular periventricular heterotopia, indistinguishable from periventricular heterotopia due to FLNA mutations. Mutations in the FLNA gene were identified in 3 affected females (300017.0017-300017.0019); in another pedigree with no detectable exonic mutation, positive linkage to the FLNA locus on Xq28 was demonstrated, and an affected individual in this family had no detectable FLNA protein. </p><p>In 3 female patients from a 3-generation Spanish family with what the authors called Ehlers-Danlos syndrome and periventricular heterotopia, Gomez-Garre et al. (2006) identified heterozygosity for a missense mutation in the FLNA gene (300017.0021). </p><p>Jamuar et al. (2014) used a customized panel of known and candidate genes associated with brain malformations to apply targeted high-coverage sequencing (depth greater than or equal to 200x) to leukocyte-derived DNA samples from 158 individuals with brain malformations. They found that, of 8 patients carrying somatic mutations, 1 was a female patient with periventricular nodular heterotopia carrying a mutation in FLNA. </p><p><strong><em>Multiple Malformation Syndromes</em></strong></p><p>
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Loss-of-function mutations of FLNA are, as indicated, embryonic lethal in males but are manifest in females as a localized neuronal migration disorder, periventricular nodular heterotopia (PVNH). Robertson et al. (2003) described localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations, affecting craniofacial structures, skeleton, brain, viscera, and urogenital tract, in 4 X-linked human disorders: otopalatodigital syndrome types I (OPD1; 311300) and II (OPD2; 304120), frontometaphyseal dysplasia (FMD1; 305620), and Melnick-Needles syndrome (MNS; 309350). Several of the mutations were recurrent, and all were clustered in 4 regions of the gene: the actin-binding domain and rod domain repeats 3, 10, and 14/15. The patterns of mutation, X-chromosome inactivation, and phenotypic manifestations in this class of mutations indicated gain-of-function effects, implicating filamin A in signaling pathways that mediate organogenesis in multiple systems during embryonic development. </p><p>In a 26-year-old Mexican female with OPD1, Hidalgo-Bravo et al. (2005) identified a heterozygous missense mutation in the FLNA gene (300017.0020). The patient had prominent features of OPD1, including cleft palate; an extremely skewed pattern of X inactivation toward the maternal allele was noted. </p><p>In 6 affected females with cranial hyperostosis and various skeletal abnormalities from a 4-generation pedigree, Stefanova et al. (2005) identified heterozygosity for a deletion in the FLNA gene (300017.0016). The disorder resulted in early lethality in male children in this family. The phenotype of the females was variable, rather mild, and bridged the phenotypes of various OPD spectrum disorders (see 311300). </p><p>Zenker et al. (2006) reported a gly1728-to-cys mutation (300017.0022) in repeat 15 of the filamin A rod domain of the FLNA gene in a girl with manifestations of frontometaphyseal dysplasia and otopalatodigital syndrome 1. In a second family with FMD, they identified a ser1186-to-leu mutation (S1186L; 300017.0015) in a mother and her son. In contrast to most previous reports on manifesting females or carriers of FLNA-related skeletal dysplasias, the affected females in these 2 families showed only mild to moderate skewing of X-inactivation against the mutant allele. Zenker et al. (2006) suggested that the data may indicate that in females, genotype-phenotype correlation between certain FLNA mutations and OPD1 and FMD, respectively, is less strict than previously assumed. They proposed that X-inactivation is an important epigenetic modifier of the phenotype in females with the FLNA-related skeletal dysplasias. </p><p>Hehr et al. (2006) described a male patient with periventricular nodular heterotopia (PVNH), craniofacial features, and severe constipation. The phenotype was associated with a splice mutation in exon 13 of the FLNA gene (300017.0024). Hehr et al. (2006) suggested that the patient retained enough FLNA function to avoid the usual lethality associated with loss-of-function mutations in FLNA in males. </p><p>In an 18-month-old German boy with FG syndrome-2 (FGS2; 300321), Unger et al. (2007) identified a hemizygous mutation in the FLNA gene (P1291L; 300017.0028). He had severe constipation, large rounded forehead, prominent ears, frontal hair upsweep, and mild delay in language acquisition. The parents declined brain MRI studies. Unger et al. (2007) suggested that the patient reported by Hehr et al. (2006) actually had FGS2, due to the presence of severe constipation and dysmorphic facial features. </p><p>Dissanayake et al. (2021) identified hemizygosity for the previously identified S1186L mutation (300017.0015) in a boy from Sri Lanka with FMD1. His mother, who had prominent supraorbital ridges but was otherwise unaffected, was heterozygous for the mutation. </p><p><strong><em>Intestinal Pseudoobstruction/Congenital Short Bowel Syndrome</em></strong></p><p>
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In an Italian family with an X-linked recessive form of chronic idiopathic intestinal pseudoobstruction (CIIP) mapping to chromosome Xq28 (CIIPX; 300048), Gargiulo et al. (2007) detected a 2-bp deletion in exon 2 of the FLNA gene that was present in heterozygous state in the carrier females of the family (300017.0025). The frameshift mutation was located between 2 close methionines at the filamin N terminus and was predicted to produce a protein truncated shortly after the first predicted methionine. Because loss-of-function FLNA mutations have been associated with X-linked dominant nodular ventricular heterotopia (PVNH1; 300049), a central nervous system migration defect that presents with seizures in females and lethality in males, it was notable that the male bearing the FLNA mutation had signs of central nervous system (CNS) involvement and possibly PVNH. To understand how the severe frameshift mutation found by Gargiulo et al. (2007) explained the CIIPX phenotype and its X-linked recessive inheritance, Gargiulo et al. (2007) transiently expressed both the wildtype and the mutant filamin in cell culture and found filamin translation to start from either of the 2 initial methionines in these conditions. Therefore, translation of a normal, shorter filamin can occur in vitro from the second methionine downstream of the 2-bp insertion. Gargiulo et al. (2007) confirmed this, demonstrating that the filamin protein was present in the patient's lymphoblastoid cell line that shows abnormal cytoskeletal actin organization compared with normal lymphoblasts. The authors concluded that the filamin N-terminal region between the initial 2 methionines is crucial for proper enteric neuron development. </p><p>Clayton-Smith et al. (2009) identified a duplication of the FLNA gene in affected members of 2 families with intestinal pseudoobstruction, patent ductus arteriosus, and thrombocytopenia with giant platelets (300048). One of the families had been reported by FitzPatrick et al. (1997). </p><p>Van der Werf et al. (2013) reported a 2-basepair deletion in exon 2 of filamin A (300017.0035) in 1 family segregating X-linked congenital short bowel syndrome (see 300048) and in an unrelated affected individual. In the family, all obligate carriers were heterozygous for the mutation; in the isolated male, the mutation had occurred as a de novo event. Van der Werf et al. (2013) stated that they could not exclude involvement of the central nervous system in these patients because no magnetic resonance imaging brain scans were available. </p><p><strong><em>Terminal Osseous Dysplasia</em></strong></p><p>
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In affected members of 3 families segregating terminal osseous dysplasia (TOD; 300244), 2 of which were previously described by Breuning et al. (2000) and Baroncini et al. (2007), and in 3 sporadic case individuals, who were previously described by Horii et al. (1998), Drut et al. (2005), and Breuning et al. (2000), respectively, Sun et al. (2010) identified a causative mutation in the FLNA gene: a c.5217G-A transition activated a cryptic splice site, removing the last 48 nucleotides from exon 31 and resulting in a loss of 16 amino acids (300017.0029). In the families, the variant segregated with the disease. Sun et al. (2010) showed that because of nonrandom X chromosome inactivation, the mutant allele was not expressed in the patient fibroblasts. RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. The mutation was not found in 400 control X chromosomes, pilot data from 1000 Genomes Project, or the FLNA gene variant database. Because the mutation was predicted to remove a sequence at the surface of filamin repeat 15, Sun et al. (2010) suggested that the missing region in the filamin A protein affects or prevents the interaction of filamin A with other proteins. </p><p>In a Turkish girl with terminal osseous dysplasia with pigmentary defects, Azakli et al. (2019) identified the recurrent c.5217G-A mutation in the FLNA gene. </p><p><strong><em>X-Linked Cardiac Valvular Dysplasia</em></strong></p><p>
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In a large 5-generation French pedigree with X-linked cardiac valvular dysplasia (CVDPX; 314400) mapping to Xq28, originally reported by Benichou et al. (1997) and Kyndt et al. (1998), Kyndt et al. (2007) analyzed candidate genes and identified a missense mutation in the FLNA gene that segregated with disease (P637Q; 300017.0030). In 3 more families with cardiac valvular disease, Kyndt et al. (2007) identified 2 different missense mutations and an in-frame deletion (300017.0031-300017.0033, respectively). No signs of periventricular heterotopia, otopalatodigital syndrome, frontometaphyseal dysplasia, or Melnick-Needles or Ehlers-Danlos syndromes were observed in these families. The missense mutations all involve highly conserved residues within the first, fourth, and fifth repeat consensus sequences of FLNA, respectively, and the deletion results in a truncated protein lacking repeats 5 through 7. </p><p>In 2 affected male cousins from a 3-generation Italian family in which 5 affected males and 1 female had died of congestive heart failure due to multivalvular disease, Ritelli et al. (2017) identified hemizygosity for a splicing mutation in the FLNA gene (300017.0037). In addition to cardiac valvular disease, these patients exhibited skin hyperextensibility and joint hypermobility. </p><p>In a 3-generation family with multivalvular dysplasia, Mercer et al. (2017) identified a missense mutation in the FLNA gene (G1554R; 300017.0038) that segregated with disease. Other features in these patients included joint stiffness from early childhood and keloid scarring. </p><p><strong><em>Reviews</em></strong></p><p>
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For a review of the disorders caused by mutations in the FLNA gene, see Robertson (2005). </p>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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<span class="mim-text-font">
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<p>Robert J. Gorlin (2003) was responsible for the initial description of 3 of the conditions that had been shown to be caused by mutations in the FLNA gene: OPD1, OPD2, and frontometaphyseal dysplasia. Furthermore, he correctly interpreted the genetics of Melnick-Needles syndrome as X-linked recessive rather than autosomal recessive. His son, Jed Gorlin, sequenced the FLNA gene (Gorlin et al., 1990) and mapped it to chromosome Xq28 (Gorlin et al., 1993). </p>
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<span class="mim-font">
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<strong>Animal Model</strong>
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<span class="mim-text-font">
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<p>Feng et al. (2006) noted that hemizygous human males with FLNA mutations die prenatally or survive after birth with cardiac malformations, often dying postnatally from blood vessel rupture. They found that Flna-null mice died at midgestation with widespread hemorrhage from abnormal vessels, persistent truncus arteriosus, and incomplete cardiac septation. Conditional Flna knockout in the neural crest caused abnormalities of the cardiac outflow tract despite apparently normal migration of Flna-deficient neural crest cells. Flna-null vascular endothelial cells displayed abnormal adherens junctions and defects in cell-cell contacts. Feng et al. (2006) suggested that cell motility-independent functions of FLNA at cell-cell contacts and adherens junctions affect the development of organs. </p><p>Adams et al. (2012) found that knockdown of Mks3 or the Flna ortholog in zebrafish resulted in similar phenotypes, including brain and body axis defects, cardiac edema, and otic placode and eye defects. Combined low doses of both Mks3 and Flna morpholinos increased both the incidence and severity of developmental defects. An Flna-null mouse strain showed similar defects. At embryonic day 13.5, male Flna hemizygous embryos were highly dysmorphic, with extensive disruption of ventricular zone of the neocortex and severe periventricular heterotopia. Basal body position was disrupted and neuroepithelial layer showed impaired ciliogenesis. </p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>ALLELIC VARIANTS</strong>
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</span>
|
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<strong>38 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0001 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLNA, GLN182TER
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<br />
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SNP: rs137853310,
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ClinVar: RCV000012513
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In the largest reported pedigree with X-linked periventricular heterotopia (PVNH1; 300049) (Huttenlocher et al., 1994), Fox et al. (1998) found a C-to-T substitution in exon 3 of the FLN1 gene, which converted a CAG (gln) to a TAG (stop) codon and truncated the FLN1 protein at amino acid residue 182 of the 2,647 total amino acids in the normal protein. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
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</span>
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</h4>
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</div>
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<div>
|
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<span class="mim-text-font">
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FLNA, IVS4DS, T-C, +2
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<br />
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SNP: rs863223295,
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ClinVar: RCV000012514
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|
</span>
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</div>
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<div>
|
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<span class="mim-text-font">
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|
<p>In affected members of a family with periventricular heterotopia (PVNH1; 300049), Fox et al. (1998) found a T-to-C substitution at the second base of intron 4 in the splice donor sequence of the FLN1 gene. The mutation was predicted to cause either exon skipping or a read-through of intron 4 which would introduce a stop codon after the translation of 30 additional amino acids. The mutation was present in both a mother and daughter with periventricular heterotopia but not in the unaffected maternal grandmother. Therefore, this mutation most likely arose de novo in this pedigree in the germline of either the maternal grandmother or grandfather, both of whom were clinically unaffected. </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
|
</div>
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|
</div>
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|
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|
|
<div>
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|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, IVS3AS, C-G, -3
|
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|
<br />
|
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|
|
SNP: rs398123622,
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|
|
ClinVar: RCV000012515, RCV000079706
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic case of periventricular heterotopia (PVNH1; 300049), Fox et al. (1998) found that the consensus splice acceptor at the end of intron 3 (3 bases from exon 4) of the FLN1 gene was mutated by a C-to-G substitution. The 'C' at position -3 is conserved among more than 70% of vertebrate splice junctions, and the 'G' at this position is seen in only 1% (Shapiro and Senapathy, 1987). The mutation appeared to have arisen de novo in the germline of the patient's mother or father. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, IVS2DS, G-A, +1
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs863223296,
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|
|
|
|
|
|
|
ClinVar: RCV000012516
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic case of periventricular heterotopia (PVNH1; 300049), Fox et al. (1998) found a G-to-A mutation at the first base of intron 2 of the FLN1 gene. The 'G' at position +1 of the intron is conserved in 100% of splice donor sequences of vertebrate genes (Shapiro and Senapathy, 1987). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, 5-BP DEL, NT287
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs863223297,
|
|
|
|
|
|
gnomAD: rs863223297,
|
|
|
|
|
|
ClinVar: RCV000012517
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic case of periventricular heterotopia (PVNH1; 300049), Fox et al. (1998) found deletion of 5 bases from the coding region of exon 2 of the FLN1 gene. Bases 287-291 were removed, producing a frameshift and the introduction of a premature stop codon after the addition of 8 inappropriate amino acids. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, LEU656PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137853311,
|
|
|
|
|
|
gnomAD: rs137853311,
|
|
|
|
|
|
ClinVar: RCV000012518, RCV001753412, RCV001857335, RCV002273924
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic male patient with unilateral periventricular heterotopia (PVNH1; 300049), epilepsy, and normal intellect, Sheen et al. (2001) found a C-to-T transition at position 1966, resulting in a leu656-to-phe (L656F) amino acid substitution in the fifth Ig-like domain of the FLN1 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, 6915C-G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs781910090,
|
|
|
|
|
|
gnomAD: rs781910090,
|
|
|
|
|
|
ClinVar: RCV000012519
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic male patient with periventricular heterotopia (PVNH1; 300049), epilepsy, and normal intellect, Sheen et al. (2001) found a C-to-G transversion at position 6915. This was predicted to result in termination at residue 2305 and loss of the 344 C-terminal amino acids of the FLN1 gene, which include the receptor-binding region. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, GLU82VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28935169,
|
|
|
|
|
|
|
|
ClinVar: RCV000012520, RCV003764561
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with periventricular heterotopia (PVNH1; 300049), Moro et al. (2002) identified a 245A-T mutation in exon 2 of the FLNA gene, leading to a glu82-to-val substitution (E82V) in the N-terminal part of the protein. The mutation likely modifies protein activity without complete loss of function. Affected females with the mutation showed a mild anatomic phenotype with few asymmetric, noncontiguous nodules on MRI, and gave birth to 5 presumably affected boys who died within a few days to several weeks or months of life. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 OTOPALATODIGITAL SYNDROME, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, PRO207LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28935469,
|
|
|
|
|
|
|
|
ClinVar: RCV000012521, RCV000415125, RCV001000894, RCV002354156, RCV002509151, RCV003764562, RCV004545725
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 presumably unrelated families, Robertson et al. (2003) found that individuals with otopalatodigital syndrome type I (OPD1; 311300) had a 620C-T transition in exon 3 of the FLNA gene, predicted to result in a pro207-to-leu (P207L) amino acid substitution. All affected members had bowed bones and abnormal digits as well as cleft palate. </p><p>Robertson et al. (2006) identified the P207L mutation in 2 brothers with OPD1. The mutation was not identified in leukocytes of the mother, suggesting germline mosaicism. The authors emphasized the importance of the finding for genetic counseling. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 OTOPALATODIGITAL SYNDROME, TYPE II</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, GLU254LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28935470,
|
|
|
|
|
|
|
|
ClinVar: RCV000012522, RCV000178843, RCV001851804
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 presumably unrelated families, each with at least 1 affected male, Robertson et al. (2003) found that individuals with otopalatodigital syndrome type II (OPD2; 304120) had a 760G-A transition in exon 5 of the FLNA gene, predicted to cause a glu254-to-lys (E254K) amino acid substitution. All 4 patients had omphalocele, perinatal death, bowed bones, and abnormal digits; 1 also had cleft palate, and 2 had hydrocephalus. </p><p>Clark et al. (2009) showed that OPD E254K fibroblast lysates had equivalent concentrations of FLNA compared with controls, and that recombinant FLNA E254K actin-binding domain (ABD) had increased in vitro F-actin binding compared with wildtype. The FLNA ABD adopts a canonical compact conformation that is not greatly disturbed by the E254K mutation either in solution or in the crystal structure. Ex vivo characterization of E254K OPD patient fibroblasts revealed that they have similar motility and adhesion as control cells, implying that many core functions mediated by FLNA are unaffected, consistent with OPD affecting only specific tissues despite FLNA being widely expressed. The authors proposed a gain-of-function mechanism for the OPD disorders, which mechanistically distinguishes them from the loss-of-function phenotypes that manifest as disorders of neuronal migration. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 FRONTOMETAPHYSEAL DYSPLASIA 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, ASP1159ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28935471,
|
|
|
|
|
|
|
|
ClinVar: RCV000012523
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected members of a family, Robertson et al. (2003) found that frontometaphyseal dysplasia (FMD1; 305620) was related to a 3476A-C transversion in exon 22 of the FLNA gene, predicted to result in an asp1159-to-ala (D1159A) amino acid change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 MELNICK-NEEDLES SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, ALA1188THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28935472,
|
|
|
|
|
|
|
|
ClinVar: RCV000012524, RCV000523000
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 presumably unrelated patients with Melnick-Needles syndrome (309350), Robertson et al. (2003) found a 3562G-A transition in exon 22 of the FLNA gene, predicted to result in an ala1188-to-thr (A1188T) amino acid change. All 5 patients had bowed bones and abnormal digits and all but one had short stature. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 MELNICK-NEEDLES SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, SER1199LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28935473,
|
|
|
|
|
|
|
|
ClinVar: RCV000012525, RCV001382364
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 6 presumably unrelated females with Melnick-Needles syndrome (309350), Robertson et al. (2003) found a 3596C-T transition in exon 22 of the FLNA gene, predicted to cause an ser1199-to-leu (S1199L) amino acid change. All 6 females were of short stature and had bowed bones and abnormal digits. </p><p>Robertson et al. (2006) identified the S1199L mutation in a girl with Melnick-Needles syndrome. The girl had an unaffected twin sister who did not carry the mutation; the unaffected mother also did not carry the mutation. The twins were born with separate amniotic sacs within a single chorion, and zygosity analysis indicated a high probability that the girls were monozygotic twins. Robertson et al. (2006) concluded that the FLNA mutation occurred postzygotically in the affected twin and emphasized the importance of the finding for genetic counseling. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED, WITH FRONTOMETAPHYSEAL DYSPLASIA</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLNA, 7315C-A
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<br />
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SNP: rs2148101204,
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ClinVar: RCV000012526
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Periventricular nodular heterotopia (PVNH1; 300049) and a group of skeletal dysplasias belonging to the otopalatodigital (OPD) spectrum are caused by mutation in the FLNA gene. They are considered mutually exclusive because of the different presumed effects of the respective FLNA gene mutations, leading to loss of function in PVNH and gain of function in OPD. In a girl manifesting PVNH in combination with frontometaphyseal dysplasia (see 300049), a skeletal dysplasia of the OPD spectrum, Zenker et al. (2004) identified a de novo 7315C-A transversion in exon 45 of the FLNA gene, resulting in 2 aberrant transcripts: 1 full-length transcript with a point mutation causing a substitution of a highly conserved leu2439 residue by met (L2439M) and a second shortened transcript lacking 21 bp due to the creation of an ectopic splice donor site in exon 45. Zenker et al. (2004) proposed that the dual phenotype was caused by 2 functionally different, aberrant filamin A proteins and therefore represented an exceptional case of allelic gain-of-function and loss-of-function phenotypes due to a single mutation event. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0015 FRONTOMETAPHYSEAL DYSPLASIA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLNA, SER1186LEU
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<br />
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SNP: rs137853312,
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ClinVar: RCV000012527, RCV000414151, RCV002051782, RCV002228026, RCV004795395
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a male patient with frontometaphyseal dysplasia (FMD1; 305620), Robertson et al. (2003) identified a 3557C-T transition in exon 22 of the FLNA gene, resulting in a ser1186-to-leu (S1186L) amino acid change. </p><p>Giuliano et al. (2005) reported a 3-generation family with FMD and identified the S1186L mutation in the proband and his mother. </p><p>The S1186L missense mutation in repeat 10 of the filamin A rod domain was reported in patients with frontometaphyseal dysplasia by Zenker et al. (2006). The proposita in the family reported by Zenker et al. (2006) was a 68-year-old woman whose son had died with a diagnosis of FMD. She had had scoliosis from childhood. Prominent supraorbital ridges, hypertelorism, and a small pointed chin as well as moderate thoracolumbar scoliosis were noted. The son developed massive frontal hyperostosis from childhood leading to the diagnosis of FMD with hypertelorism, micrognathia, oligodontia, progressive sensorineural hearing loss, amblyopia, pectus excavatum, and scoliosis. During adolescence, he developed sleep apnea and had been treated with continuous positive airway pressure. Ehrenstein et al. (1997) reported the radiologic findings. The patient died unexpectedly at the age of 25 years. In contrast to most previous reports on manifesting females or carriers of the FLNA-related skeletal dysplasias, the proband showed only mild to moderate skewing of X inactivation against the mutant allele. </p><p>In a boy from Sri Lanka with FMD1, Dissanayake et al. (2021) identified hemizygosity for the c.3557C-T transition (c.3557C-T, NM_001110556.1) in the FLNA gene resulting in the S1186L mutation. His mother, who had prominent supraorbital ridges but was otherwise unaffected, was heterozygous for the mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0016 OTOPALATODIGITAL SPECTRUM DISORDER</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLNA, 9-BP DEL, NT4904
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<br />
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SNP: rs863223298,
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ClinVar: RCV000012528
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 6 affected females with cranial hyperostosis and various skeletal abnormalities from a 4-generation pedigree, Stefanova et al. (2005) identified heterozygosity for a 9-bp deletion from position 4904 to 4912 in exon 29 of the FLNA gene, predicting the loss of 3 amino acid residues (codons 1635-1637) in rod domain repeat 14. The mutation was not found in 2 unaffected females. The phenotype of affected females resembled frontometaphyseal dysplasia with some overlap to otopalatodigital syndrome types 1 and 2, but no signs specific for Melnick-Needles syndrome. However, males had severe extraskeletal malformations and died early, thus constituting an overlap with OPD2 and MNS. Stefanova et al. (2005) concluded that the disorder in this family is best described as an intermediate OPD spectrum phenotype that bridges the FMD and OPD2 phenotypes; see 311300. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0017 HETEROTOPIA, PERIVENTRICULAR, 1</strong>
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|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLNA, 1-BP DEL, 2762G
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<br />
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SNP: rs1569551736,
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ClinVar: RCV000012529
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a 13-year-old female with periventricular heterotopia (PVNH1; 300049), Sheen et al. (2005) found a 1-bp deletion in exon 19 of the FLNA gene (2762delG). The patient showed typical features of Ehlers-Danlos syndrome (EDS), including joint hypermobility as well as myxomatous borders along the mitral and aortic valves. The authors suggested that this was an EDS variant of PVNH. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 HETEROTOPIA, PERIVENTRICULAR, 1</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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FLNA, 1-BP DEL, 4147G
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<br />
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SNP: rs863223299,
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ClinVar: RCV000012530
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 16-year-old female with periventricular heterotopia (PVNH1; 300049), Sheen et al. (2005) found a 1-bp deletion in exon 25 of the FLNA gene (4147delG). The patient had aortic aneurysm and joint hypermobility. The authors suggested that this was an Ehlers-Danlos variant of PVNH. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 HETEROTOPIA, PERIVENTRICULAR, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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FLNA, ALA39GLY
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<br />
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|
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SNP: rs137853313,
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|
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ClinVar: RCV000012531
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|
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|
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</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 15-year-old female with periventricular heterotopia (PVNH1; 300049), Sheen et al. (2005) identified a 116C-G transversion in exon 2 of the FLNA gene, resulting in an ala39-to-gly (A39G) substitution. The patient had radiologic findings of periventricular heterotopia, seizures, mild cognitive delay with psychotic behavior, joint hypermobility, and aortic aneurysm. The authors suggested that this was an Ehlers-Danlos variant of PVNH. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
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</div>
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</div>
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<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 OTOPALATODIGITAL SYNDROME, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, ASP203TYR
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|
<br />
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|
|
SNP: rs137853314,
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|
|
ClinVar: RCV000012532
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|
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|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 26-year-old Mexican female with OPD1 (311300), Hidalgo-Bravo et al. (2005) identified heterozygosity for a 607G-T transversion in exon 3 of the FLNA gene, resulting in an asp203-to-tyr (D203Y) substitution in the actin binding domain. Her parents did not have the mutation. The patient had prominent features of OPD1, including cleft palate; an extremely skewed pattern of X inactivation toward the maternal allele was noted. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 HETEROTOPIA, PERIVENTRICULAR, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, ALA128VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137853315,
|
|
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|
|
|
|
|
ClinVar: RCV000012533
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 female patients from a 3-generation Spanish family with periventricular heterotopia and features of Ehlers-Danlos syndrome (PVNH1; 300049), Gomez-Garre et al. (2006) identified heterozygosity for a 383C-T transition in exon 3 of the FLNA gene, resulting in an ala128-to-val (A128V) substitution. The mutation was not found in unaffected family members or in 184 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 OTOPALATODIGITAL SPECTRUM DISORDER</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, GLY1728CYS
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs137853316,
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|
|
|
|
|
ClinVar: RCV000012534
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Zenker et al. (2006) described a de novo mutation in the FLNA gene in a girl with manifestations of frontometaphyseal dysplasia and otopalatodigital syndrome type 1 (see 311300). The 5182G-T mutation in exon 31 was predicted to lead to the exchange of a highly conserved glycine residue at position 1728 by cysteine (G1728C) in repeat 15 of the filamin A rod domain. A short neck and deep-set ears were noted at birth. On the first day of life, presence of inspiratory stridor and episodic cyanosis led to the diagnosis of laryngomalacia and a large atrial septal defect with signs of persistent pulmonary hypertension which resolved spontaneously within 24 hours. Echocardiography showed dysplastic tricuspid valve and noncompaction of the right ventricular myocardium. The latter disappeared during infancy. The atrial septal defect was corrected at age 9 years. Conductive hearing deficit, first diagnosed in childhood, was progressive, necessitating hearing aids by the age of 12 years. At age 16 years, typical craniofacial findings of FMD were impressive supraorbital hyperostosis, hypertelorism, antimongoloid palpebral fissures, a deeply grooved philtrum, and a pointed and slightly receding chin. The terminal phalanges of thumbs and halluces were short and broad. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-text-font">
|
|
<strong>.0023 MOVED TO 300017.0015</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, 1923C-T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80338841,
|
|
|
|
|
|
|
|
ClinVar: RCV000012536, RCV000020423, RCV001348560, RCV001563663, RCV001753413, RCV004734511
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Hehr et al. (2006) described a male patient with periventricular nodular heterotopia (PVNH1; 300049) associated with a splice mutation in exon 13 of the FLNA gene (1923C-T). In addition to PVNH, the patient also presented with craniofacial features and severe constipation. Hehr et al. (2006) postulated that the predominant expression of the full-length mRNA in addition to a mutant shorter transcript lacking the 3-prime part of exon 13 had rescued a sufficient amount of FLNA protein function to result in this novel phenotype. </p><p>Unger et al. (2007) suggested that the patient reported by Hehr et al. (2006) actually had FG syndrome-2 (FGS2; 300321), especially given the presence of craniofacial dysmorphic features and severe constipation. Unger et al. (2007) identified a different mutation in the FLNA gene (300017.0028) in a patient with FGS2. </p>
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 INTESTINAL PSEUDOOBSTRUCTION, NEURONAL, CHRONIC IDIOPATHIC, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, 2-BP DEL, 65AC
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80338840,
|
|
|
|
|
|
gnomAD: rs80338840,
|
|
|
|
|
|
ClinVar: RCV000012537
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an affected male in the Italian family of X-linked chronic idiopathic intestinal pseudoobstruction (300048) described originally by Auricchio et al. (1996), Gargiulo et al. (2007) found a 2-bp deletion in exon 2 of the FLNA gene: 65-66delAC. Segregation analysis of the FLNA mutation confirmed that all obligate carriers, by pedigree or established by linkage analysis, were heterozygous for the 2-bp deletion. The mutation was absent in 164 control X chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 OTOPALATODIGITAL SYNDROME, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
OTOPALATODIGITAL SYNDROME, TYPE II, INCLUDED
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, ARG196TRP
|
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|
|
|
|
<br />
|
|
|
|
SNP: rs137853317,
|
|
|
|
|
|
|
|
ClinVar: RCV000012538, RCV000012539, RCV000153245, RCV000560177
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with OPD type I (311300), Robertson et al. (2003) identified a 586C-T transition in exon 3 of the FLNA gene, resulting in an arg196-to-trp (R196W) substitution. </p><p>Kondoh et al. (2007) identified the R196W mutation in a 12-year-old Japanese boy with OPD type II (304120). The patient had some additional unusual features, including congenital cataract, glaucoma, and congenital heart defects. Kondoh et al. (2007) noted the different phenotype caused by the same mutation and suggested that additional factors play a role in the pathogenesis of OPD spectrum disorders. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
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<span class="mim-font">
|
|
<strong>.0027 OTOPALATODIGITAL SYNDROME, TYPE II</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLNA, CYS210PHE
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|
<br />
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|
SNP: rs137853318,
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|
|
ClinVar: RCV000012540
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|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a male fetus with otopalatodigital syndrome type II (304120), Marino-Enriquez et al. (2007) identified a 629G-T transversion in exon 3 of the FLNA gene, predicted to cause a cys210-to-phe (C210F) substitution within the second calponin homology domain of the actin-binding domain. Analysis of exon 3 in relatives revealed that the mutation had arisen de novo in the mother; a previous pregnancy had ended in stillbirth of a male diagnosed with OPD2. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>.0028 FG SYNDROME 2</strong>
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</span>
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</h4>
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</div>
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<div>
|
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<span class="mim-text-font">
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|
FLNA, PRO1291LEU
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<br />
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SNP: rs137853319,
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gnomAD: rs137853319,
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ClinVar: RCV000012541, RCV000869767, RCV001549941, RCV002313705, RCV004532324
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|
</span>
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|
</div>
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<div>
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<span class="mim-text-font">
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|
<p>In an 18-month-old boy with FG syndrome-2 (FGS2; 300321), Unger et al. (2007) identified a hemizygous 3872C-T transition in exon 23 of the FLNA gene, resulting in a pro1291-to-leu (P1291L) substitution. His asymptomatic mother also carried the mutation, which was absent in 100 control chromosomes. The patient had severe constipation, large rounded forehead, prominent ears, frontal hair upsweep, and mild delay in language acquisition. Although the authors noted that the mutation does not affect a highly conserved residue, they referred to a patient reported by Hehr et al. (2006) with periventricular nodular heterotopia (300049) and a FLNA mutation (300017.0024), who also had craniofacial dysmorphic features and severe constipation. Unger et al. (2007) suggested that the patient reported by Hehr et al. (2006) actually had FGS2. </p>
|
|
</span>
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|
</div>
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<div>
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|
<br />
|
|
</div>
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</div>
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|
<div>
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|
<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 TERMINAL OSSEOUS DYSPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
FLNA, 5217G-A, 48-BP DEL
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<br />
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|
SNP: rs387907371,
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ClinVar: RCV000012542, RCV001091828, RCV001205323, RCV001292939
|
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|
|
</span>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>In affected members of 3 families segregating terminal osseous dysplasia (TOD; 300244), 2 of which were previously described by Breuning et al. (2000) and Baroncini et al. (2007), and in 3 sporadic case individuals, who were previously described by Horii et al. (1998), Drut et al. (2005), and Breuning et al. (2000), respectively, Sun et al. (2010) identified a causative mutation in the last nucleotide of exon 31 of the FLNA gene: a c.5217G-A transition activated a cryptic splice site, removing the last 48 nucleotides from exon 31 and resulting in a loss of 16 amino acids (val1724_thr1739del). Sun et al. (2010) showed that because of nonrandom X chromosome inactivation, the mutant allele was not expressed in the patient fibroblasts. RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. The mutation was not found in 400 control X chromosomes, pilot data from 1000 Genomes Project, or the FLNA gene variant database. Because the mutation was predicted to remove a sequence at the surface of filamin repeat 15, Sun et al. (2010) suggested that the missing region in the filamin A protein affects or prevents the interaction of filamin A with other proteins. </p><p>In a Turkish girl with terminal osseous dysplasia with pigmentary defects, Azakli et al. (2019) identified heterozygosity for the recurrent c.5217G-A transition in the FLNA gene. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 CARDIAC VALVULAR DYSPLASIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, PRO637GLN
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|
<br />
|
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|
|
SNP: rs267606815,
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|
|
gnomAD: rs267606815,
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|
|
ClinVar: RCV000012543
|
|
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|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a large 5-generation Caucasian French pedigree with X-linked cardiac valvular dysplasia (CVDPX; 314400), originally reported by Benichou et al. (1997) and Kyndt et al. (1998), Kyndt et al. (2007) identified a 1910C-A transversion in exon 13 of the FLNA gene, resulting in a pro637-to-gln (P637Q) substitution at a highly conserved residue within the fourth repeat consensus sequence. The mutation segregated with disease in the family and was not found in 500 control chromosomes of white or African origin. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 CARDIAC VALVULAR DYSPLASIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, GLY288ARG
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|
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|
<br />
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|
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SNP: rs267606816,
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|
|
ClinVar: RCV000012544, RCV004820820
|
|
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|
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a British family with X-linked cardiac valvular dysplasia (CVDPX; 314400), originally described by Newbury-Ecob et al. (1993), Kyndt et al. (2007) identified an 862G-A transition in exon 5 of the FLNA gene, resulting in a gly288-to-arg (G288R) substitution at a highly conserved residue within the first repeat consensus sequence. The mutation segregated with disease in the family and was not found in 500 control chromosomes of white or African origin. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
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<br />
|
|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 CARDIAC VALVULAR DYSPLASIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, VAL711ASP
|
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|
<br />
|
|
|
|
SNP: rs267606817,
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|
|
ClinVar: RCV000012545
|
|
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|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 4-month-old boy with cardiac valvular dysplasia (CVDPX; 314400), born of black African parents, Kyndt et al. (2007) identified a 2132T-A transversion in exon 14 of the FLNA gene, resulting in a val711-to-asp (V711D) substitution at a highly conserved residue in the fifth repeat consensus sequence. The patient was diagnosed prenatally with abnormally thick cardiac valves by ultrasound and fetal echocardiography; postnatal echocardiography confirmed that all valves were thickened and dystrophic, with moderate tricuspid incompetence, trivial mitral and pulmonary incompetence, and mild aortic incompetence. His carrier mother showed no evidence of cardiac involvement on clinical examination. The mutation was not found in 500 control chromosomes of white or African origin. </p>
|
|
</span>
|
|
</div>
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|
<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 CARDIAC VALVULAR DYSPLASIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, 1,944-BP DEL
|
|
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|
|
<br />
|
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|
|
|
|
ClinVar: RCV000012546
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers of Hong Kong Chinese origin with cardiac valvular dysplasia (CVDPX; 314400), Kyndt et al. (2007) identified a 1,944-bp genomic deletion from intron 15 to intron 19 of the FLNA gene, predicting an in-frame deletion of 182 residues from val761 to gln943 that results in a truncated protein lacking repeat consensus sequences 5 to 7. The deletion was not found in 200 control chromosomes, including 100 Asian chromosomes. In the 12-year-old proband, a heart murmur was detected at 4 months of age, and echocardiography revealed myxomatous thickening of the mitral, tricuspid, and aortic valves; he had significant mitral and tricuspid regurgitation and mild aortic regurgitation. His 4-year-old brother was found to have mitral incompetence and stenosis, tricuspid regurgitation, and mild aortic regurgitation. Their 38-year-old asymptomatic carrier mother had mild aortic and pulmonary incompetence on echocardiography. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0034 HETEROTOPIA, PERIVENTRICULAR NODULAR, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, TRP2632TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122812,
|
|
|
|
|
|
|
|
ClinVar: RCV000022819
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 18-month-old girl with periventricular nodular heterotopia (PVNH1; 300049) and seizures, Jefferies et al. (2010) identified a heterozygous 7896G-A transition in the FLNA gene, resulting in a trp2632-to-ter (W2632X) substitution. Echocardiogram showed a redundant and unobstructed pulmonary valve, a cleft in the anterior leaflet of the mitral valve with mitral regurgitation, and a patent foramen ovale with mild left-to-right shunting. There was no evidence of a persistent patent ductus arteriosus. Since there was no family history of the disorder, the mutation was assumed to have occurred de novo. Jefferies et al. (2010) noted that other cardiac defects, such as patent ductus arteriosus, bicuspid aortic valve, and dilation of the sinuses of Valsalva, had been reported in patients with X-linked periventricular heterotopia, and that myxomatous valvular disease was also associated with FLNA mutations, but emphasized that the findings in this patient had not previously been reported. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0035 CONGENITAL SHORT BOWEL SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, 2-BP DEL, 16TC
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122521,
|
|
|
|
|
|
|
|
ClinVar: RCV000043474, RCV000577880
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of an Italian family segregating isolated congenital X-linked short bowel syndrome (see 300048) and in an unrelated singleton with the disorder, van der Werf et al. (2013) identified a 2-bp deletion in exon 2 of the FLNA gene (16_17delTC). The family had been reported by Kern et al. (1990) and the single patient by Siva et al. (2002). In the family, all obligate carriers were heterozygous for the deletion. The mother of the isolated case did not carry the deletion, indicating that it occurred as a de novo event. Van der Werf et al. (2013) stated that they could not exclude involvement of the central nervous system in these patients because no magnetic resonance imaging brain scans were available. This mutation was absent in 92 controls and was not reported in the Exome Variant Server database. The 16_17delTC mutation is located between the first and second methionines and results in frameshift and premature termination at amino acid 103. Based on its location, van der Werf et al. (2013) predicted that the 16_17delTC mutation has a similar effect to the 65delAC mutation (300017.0025) reported by Auricchio et al. (1996) and Gargiulo et al. (2007), which results in loss of only the long form of FLNA. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0036 HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT, WITH MELNICK-NEEDLES SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, GLY208ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs797045163,
|
|
|
|
|
|
|
|
ClinVar: RCV000191017
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a woman and her 3 daughters with a complex phenotype comprising both periventricular nodular heterotopia (300049) and Melnick-Needles syndrome (309350), Parrini et al. (2015) identified a c.622G-C transversion (c.622G-C, NM_001110556.1) in exon 3 of the FLNA gene, resulting in a gly208-to-arg (G208R) substitution at a conserved residue in the N-terminal domain. The mutation was not found in the Exome Sequencing Project (ESP6500) database or in 250 control DNA samples. The c.622G-C mutation was also predicted to result in a splice site mutation, and RT-PCR analysis of patient cells showed the presence of an aberrant transcript with intron 3 retention, a frameshift, and premature termination (Leu209GlufsTer37), consistent with a loss of function. The loss of function resulted in the periventricular nodular heterotopia phenotype. Transcript levels of the G208R mutation were low (3.5 to 7.6%) in patient cells, similar to that observed in patients with MNS, and this missense mutation was predicted to result in a gain of function and the MNS phenotype. Western blot analysis of patient cells showed reduced levels of FLNA protein compared to controls. The 3 daughters had onset of seizures in the first decade. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0037 CARDIAC VALVULAR DYSPLASIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, IVS12AS, G-C, -1
|
|
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|
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|
<br />
|
|
|
|
SNP: rs1603362402,
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|
|
|
|
ClinVar: RCV000787477
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected male cousins from a 3-generation Italian family, originally reported by Di Ferrante et al. (1975), in which 5 affected males and 1 female had died of congestive heart failure due to multivalvular disease (CVDPX; 314400), Ritelli et al. (2017) identified hemizygosity for a splicing mutation (c.1829-1G-C, NM_001456.3) in intron 12 of the FLNA gene, predicted to abolish the canonical splice acceptor site of exon 13 and activate use of a cryptic acceptor site 15 bp downstream, resulting in the in-frame deletion of 5 amino acid residues (Phe611_Gly615del). Other family members were unavailable for segregation analysis. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0038 CARDIAC VALVULAR DYSPLASIA, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLNA, GLY1554ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1603360542,
|
|
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|
|
|
|
|
ClinVar: RCV000787478, RCV001269936, RCV004822196
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected male cousins from a 3-generation family with multivalvular dysplasia (CVDPX; 314400), originally reported by Balaji et al. (1991), Mercer et al. (2017) identified hemizygosity for a c.4660G-A transition in the FLNA gene, resulting in a gly1554-to-arg (G1554R) substitution within the 14th repeated rod domain. The mutation was present in heterozygosity in the 4 female patients, who were more mildly affected than the hemizygous males. DNA was unavailable from the male proband, who died at 10 days of age with severe Ebstein anomaly of the tricuspid valve. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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</div>
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van der Werf, C. S., Sribudiani, Y., Verheij, J. B. G. M., Carroll, M., O'Loughlin, E., Chen, C.-H., Brooks, A. S., Liszewski, M. K., Atkinson, J. P., Hofstra, R. M. W.
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<strong>Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations.</strong>
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Genet. Med. 15: 310-313, 2013.
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[PubMed: 23037936]
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[Full Text: https://doi.org/10.1038/gim.2012.123]
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Zenker, M., Nahrlich, L., Sticht, H., Reis, A., Horn, D.
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<strong>Genotype-epigenotype-phenotype correlations in females with frontometaphyseal dysplasia.</strong>
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Am. J. Med. Genet. 140A: 1069-1073, 2006.
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[PubMed: 16596676]
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[Full Text: https://doi.org/10.1002/ajmg.a.31213]
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Zenker, M., Rauch, A., Winterpacht, A., Tagariello, A., Kraus, C., Rupprecht, T., Sticht, H., Reis, A.
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<strong>A dual phenotype of periventricular nodular heterotopia and frontometaphyseal dysplasia in one patient caused by a single FLNA mutation leading to two functionally different aberrant transcripts.</strong>
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Am. J. Hum. Genet. 74: 731-737, 2004.
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[PubMed: 14988809]
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[Full Text: https://doi.org/10.1086/383094]
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Contributors:
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Sonja A. Rasmussen - updated : 07/07/2022<br>Hilary J. Vernon - updated : 07/01/2020<br>Marla J. F. O'Neill - updated : 07/17/2019<br>Cassandra L. Kniffin - updated : 9/21/2015<br>Patricia A. Hartz - updated : 10/15/2014<br>Ada Hamosh - updated : 9/2/2014<br>Patricia A. Hartz - updated : 7/12/2013<br>Ada Hamosh - updated : 5/2/2013<br>Ada Hamosh - updated : 11/21/2011<br>Cassandra L. Kniffin - updated : 1/5/2011<br>George E. Tiller - updated : 11/1/2010<br>Marla J. F. O'Neill - updated : 10/28/2010<br>Nara Sobreira - updated : 10/22/2010<br>Cassandra L. Kniffin - updated : 5/19/2009<br>Cassandra L. Kniffin - updated : 4/17/2009<br>Paul J. Converse - updated : 7/24/2008<br>Marla J. F. O'Neill - updated : 2/1/2008<br>Cassandra L. Kniffin - updated : 5/15/2007<br>Patricia A. Hartz - updated : 4/23/2007<br>Victor A. McKusick - updated : 3/27/2007<br>Marla J. F. O'Neill - updated : 3/15/2007<br>Victor A. McKusick - updated : 7/5/2006<br>Victor A. McKusick - updated : 6/9/2006<br>Cassandra L. Kniffin - updated : 6/2/2006<br>Marla J. F. O'Neill - updated : 5/11/2006<br>Paul J. Converse - updated : 4/4/2006<br>Marla J. F. O'Neill - updated : 12/28/2005<br>Victor A. McKusick - updated : 5/10/2005<br>Marla J. F. O'Neill - updated : 3/1/2005<br>Marla J. F. O'Neill - updated : 1/28/2005<br>Victor A. McKusick - updated : 4/8/2004<br>George E. Tiller - updated : 3/31/2004<br>Victor A. McKusick - updated : 6/5/2003<br>Victor A. McKusick - updated : 5/16/2003<br>Victor A. McKusick - updated : 3/19/2003<br>Cassandra L. Kniffin - updated : 11/8/2002<br>Patricia A. Hartz - updated : 10/28/2002<br>George E. Tiller - updated : 1/24/2002<br>Victor A. McKusick - updated : 12/18/2000<br>Victor A. McKusick - updated : 4/13/1999
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Victor A. McKusick : 7/8/1993
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