4513 lines
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Entry
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- *605420 - ARISTALESS HOMEOBOX 4; ALX4
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*605420</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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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 role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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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="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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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/605420">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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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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</ul>
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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=ENSG00000052850;t=ENST00000652299" 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=60529" 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=605420" 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=ENSG00000052850;t=ENST00000652299" 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_021926" 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_021926" 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=605420" 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=05661&isoform_id=05661_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/ALX4" 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/10863749,11125350,11125719,13774326,55743092,119588472,254763249,929654647" 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/Q9H161" 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=60529" 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=ENSG00000052850;t=ENST00000652299" 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=ALX4" 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=ALX4" 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+60529" 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/ALX4" 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:60529" 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/60529" 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=chr11&hgg_gene=ENST00000652299.1&hgg_start=44260440&hgg_end=44310139&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:450" 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://medlineplus.gov/genetics/gene/alx4" 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=605420[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>
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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=605420[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/ALX4/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/ENSG00000052850" 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=ALX4" 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=ALX4" 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=ALX4" 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="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ALX4&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/PA24755" 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:450" 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/FBgn0023489.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:108359" 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/ALX4#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:108359" 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/60529/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://omia.org/OMIA001009/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=60529" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00001096;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00001096 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00044330;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00044330 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-050208-140" 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://reactome.org/content/query?q=ALX4&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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</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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605420
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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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ARISTALESS HOMEOBOX 4; ALX4
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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>
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<div>
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<h4>
|
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<span class="mim-font">
|
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ARISTALESS-LIKE 4, MOUSE, HOMOLOG OF
|
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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>
|
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<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=ALX4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ALX4</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>
|
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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: <a href="/geneMap/11/329?start=-3&limit=10&highlight=329">11p11.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:44260440-44310139&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'})">11:44,260,440-44,310,139</a> </span>
|
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</em>
|
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</strong>
|
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<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>
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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="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
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Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=615529,613451,609597" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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|
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</th>
|
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<th>
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|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
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Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
|
|
<tr>
|
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<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/11/329?start=-3&limit=10&highlight=329">
|
|
11p11.2
|
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</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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{Craniosynostosis 5, susceptibility to}
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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/615529"> 615529 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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">
|
|
Frontonasal dysplasia 2
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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/613451"> 613451 </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="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
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</span>
|
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</td>
|
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</tr>
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PheneGene Graphics <span class="caret"></span>
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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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<p>The ALX4 gene encodes a homeodomain transcription factor important for many developmental processes (summary by <a href="#2" class="mim-tip-reference" title="Bertola, D. R., Rodrigues, M. G., Quaio, C. R. D. C., Kim, C. A., Passos-Bueno, M. R. <strong>Vertical transmission of a frontonasal phenotype caused by a novel ALX4 mutation.</strong> Am. J. Med. Genet. 161A: 600-604, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23401352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23401352</a>] [<a href="https://doi.org/10.1002/ajmg.a.35762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23401352">Bertola et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23401352" 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="#13" class="mim-tip-reference" title="Wu, Y.-Q., Badano, J. L., McCaskill, C., Vogel, H., Potocki, L., Shaffer, L. G. <strong>Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome.</strong> Am. J. Hum. Genet. 67: 1327-1332, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11017806[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/S0002-9297(07)62963-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017806">Wu et al. (2000)</a> identified a human BAC clone mapping to chromosome 11p11.2 that contained a region homologous to the MSX2 gene (<a href="/entry/123101">123101</a>), which is mutated in parietal foramina-1 (PFM1; <a href="/entry/168500">168500</a>). Further sequence analysis demonstrated that this region contained the human ortholog of the mouse Aristaless-like-4 gene (Alx4). <a href="#13" class="mim-tip-reference" title="Wu, Y.-Q., Badano, J. L., McCaskill, C., Vogel, H., Potocki, L., Shaffer, L. G. <strong>Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome.</strong> Am. J. Hum. Genet. 67: 1327-1332, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11017806[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/S0002-9297(07)62963-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017806">Wu et al. (2000)</a> assembled a full-length ALX4 cDNA encoding a deduced 410-amino acid protein that shares 80% sequence identity with the mouse Alx4 protein. Northern blot analysis demonstrated that expression of both the human and mouse genes is restricted to bone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11017806" 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>The ALX4 coding region comprises 4 exons (<a href="#13" class="mim-tip-reference" title="Wu, Y.-Q., Badano, J. L., McCaskill, C., Vogel, H., Potocki, L., Shaffer, L. G. <strong>Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome.</strong> Am. J. Hum. Genet. 67: 1327-1332, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11017806[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/S0002-9297(07)62963-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017806">Wu et al., 2000</a>; <a href="#14" class="mim-tip-reference" title="Wuyts, W., Cleiren, E., Homfray, T., Rasore-Quartino, A., Vanhoenacker, F., Van Hul, W. <strong>The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500).</strong> J. Med. Genet. 37: 916-920, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11106354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11106354</a>] [<a href="https://doi.org/10.1136/jmg.37.12.916" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11106354">Wuyts et al., 2000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11017806+11106354" 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="#13" class="mim-tip-reference" title="Wu, Y.-Q., Badano, J. L., McCaskill, C., Vogel, H., Potocki, L., Shaffer, L. G. <strong>Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome.</strong> Am. J. Hum. Genet. 67: 1327-1332, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11017806[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/S0002-9297(07)62963-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017806">Wu et al. (2000)</a> identified the ALX4 gene within the critical region of Potocki-Shaffer syndrome (<a href="/entry/601224">601224</a>), also known as the proximal 11p deletion syndrome (P11pDS), which includes parietal foramina as a feature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11017806" 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="#11" class="mim-tip-reference" title="Qu, S., Tucker, S. C., Ehrlich, J. S., Levorse, J. M., Flaherty, L. A., Wisdom, R., Vogt, T. F. <strong>Mutations in mouse Aristaless-like4 cause Strong's luxoid polydactyly.</strong> Development 125: 2711-2721, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9636085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9636085</a>] [<a href="https://doi.org/10.1242/dev.125.14.2711" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9636085">Qu et al. (1998)</a> mapped the mouse Alx4 gene of a region of chromosome 2 that shares homology of synteny with human chromosome 11p12-q12. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9636085" 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="#9" class="mim-tip-reference" title="McGaughran, J. M., Ward, H. B., Evans, D. G. <strong>WAGR syndrome and multiple exostoses in a patient with del(11)(p11.2p14.2).</strong> J. Med. Genet. 32: 823-824, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8558565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8558565</a>] [<a href="https://doi.org/10.1136/jmg.32.10.823" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8558565">McGaughran et al. (1995)</a> described a patient with the combination of multiple exostoses (<a href="/entry/133701">133701</a>), features of Potocki-Shaffer syndrome (<a href="/entry/601224">601224</a>), and WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation; <a href="/entry/194072">194072</a>) associated with a del(11)(p14.2p11.2). The ALX4 gene contains 4 exons and maps centromeric to D11S2095 in reverse orientation to the EXT2 gene (<a href="/entry/608210">608210</a>); hence ALX4 lies just outside the P11pDS critical interval proposed by <a href="#15" class="mim-tip-reference" title="Wuyts, W., Van Hul, W., Wauters, J., Nemtsova, M., Reyniers, E., Van Hul, E. V., De Boulle, K., de Vries, B. B., Hendrickx, J., Herrygers, I., Bossuyt, P., Balemans, W., Fransen, E., Vits, L., Coucke, P., Nowak, N. J., Shows, T. B., Mallet, L., van den Ouweland, A. M., McGaughran, J., Halley, D. J., Willems, P. J. <strong>Positional cloning of a gene involved in hereditary multiple exostoses.</strong> Hum. Molec. Genet. 5: 1547-1557, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8894688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8894688</a>] [<a href="https://doi.org/10.1093/hmg/5.10.1547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8894688">Wuyts et al. (1996)</a>. In the patient defining this centromeric boundary (<a href="#9" class="mim-tip-reference" title="McGaughran, J. M., Ward, H. B., Evans, D. G. <strong>WAGR syndrome and multiple exostoses in a patient with del(11)(p11.2p14.2).</strong> J. Med. Genet. 32: 823-824, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8558565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8558565</a>] [<a href="https://doi.org/10.1136/jmg.32.10.823" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8558565">McGaughran et al., 1995</a>), ALX4 expression may have been abrogated by a position effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8894688+8558565" 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>Parietal Foramina 2</em></strong></p><p>
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Using FISH, <a href="#13" class="mim-tip-reference" title="Wu, Y.-Q., Badano, J. L., McCaskill, C., Vogel, H., Potocki, L., Shaffer, L. G. <strong>Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome.</strong> Am. J. Hum. Genet. 67: 1327-1332, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11017806[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/S0002-9297(07)62963-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11017806">Wu et al. (2000)</a> tested for the presence or heterozygous deletion of the region corresponding to the BAC clone containing ALX4 on 11p in 2 patients with the Potocki-Shaffer syndrome and found that this region was deleted in these patients. The authors stated that the involvement of Alx4 in murine skull development (<a href="#10" class="mim-tip-reference" title="Qu, S., Niswender, K. D., Ji, Q., van der Meer, R., Keeney, D., Magnuson, M. A., Wisdom, R. <strong>Polydactyly and ectopic ZPA formation in Alx-4 mutant mice.</strong> Development 124: 3999-4008, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9374397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9374397</a>] [<a href="https://doi.org/10.1242/dev.124.20.3999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9374397">Qu et al., 1997</a>), its bone-specific expression pattern, the finding that Alx4 is a dosage-sensitive gene in the mouse, and the localization of a human genomic clone containing ALX4 to 11p11.2, with hemizygosity in patients with deletion of 11p11.2 who have biparietal foramina, supported the contention that ALX4 is a candidate gene for parietal foramina in the Potocki-Shaffer syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9374397+11017806" 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="#14" class="mim-tip-reference" title="Wuyts, W., Cleiren, E., Homfray, T., Rasore-Quartino, A., Vanhoenacker, F., Van Hul, W. <strong>The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500).</strong> J. Med. Genet. 37: 916-920, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11106354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11106354</a>] [<a href="https://doi.org/10.1136/jmg.37.12.916" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11106354">Wuyts et al. (2000)</a> identified heterozygous mutations in the ALX4 gene in affected members of 2 families segregating parietal foramina (PFM2; <a href="/entry/609597">609597</a>). One mutation resulted in a premature stop codon (<a href="#0004">605420.0004</a>) and the second was a missense mutation in a conserved region of the homeobox domain (R272P; <a href="#0005">605420.0005</a>), which <a href="#14" class="mim-tip-reference" title="Wuyts, W., Cleiren, E., Homfray, T., Rasore-Quartino, A., Vanhoenacker, F., Van Hul, W. <strong>The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500).</strong> J. Med. Genet. 37: 916-920, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11106354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11106354</a>] [<a href="https://doi.org/10.1136/jmg.37.12.916" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11106354">Wuyts et al. (2000)</a> concluded would disrupt DNA binding. <a href="#14" class="mim-tip-reference" title="Wuyts, W., Cleiren, E., Homfray, T., Rasore-Quartino, A., Vanhoenacker, F., Van Hul, W. <strong>The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500).</strong> J. Med. Genet. 37: 916-920, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11106354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11106354</a>] [<a href="https://doi.org/10.1136/jmg.37.12.916" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11106354">Wuyts et al. (2000)</a> did not find a mutation in either ALX4 or MSX2 in a third family with PFM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11106354" 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 4 families segregating PFM, <a href="#7" class="mim-tip-reference" title="Mavrogiannis, L. A., Antonopoulou, I., Baxova, A., Kutilek, S., Kim, C. A., Sugayama, S. M., Salamanca, A., Wall, S. A., Morriss-Kay, G. M., Wilkie, A. O. M. <strong>Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects.</strong> Nature Genet. 27: 17-18, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137991</a>] [<a href="https://doi.org/10.1038/83703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137991">Mavrogiannis et al. (2001)</a> identified 3 distinct heterozygous ALX4 mutations in 19 affected individuals (<a href="#0001">605420.0001</a>-<a href="#0003">605420.0003</a>). The cranial phenotype associated with the ALX4 mutations ranged from severe deficiency in mineralization of the skull vault in infancy (cranium bifidum) to apparent nonpenetrance; most individuals had classic PFM. <a href="#7" class="mim-tip-reference" title="Mavrogiannis, L. A., Antonopoulou, I., Baxova, A., Kutilek, S., Kim, C. A., Sugayama, S. M., Salamanca, A., Wall, S. A., Morriss-Kay, G. M., Wilkie, A. O. M. <strong>Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects.</strong> Nature Genet. 27: 17-18, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137991</a>] [<a href="https://doi.org/10.1038/83703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137991">Mavrogiannis et al. (2001)</a> found no significant difference in the size of PFM between ALX4 and MSX2 mutations, but cranium bifidum had not been described in association with mutations of MSX2. It remained to be determined whether MSX2 and ALX4 act hierarchically or in parallel developmental pathways. PFM and craniosynostosis (premature fusion of the cranial sutures) may result from opposite perturbations in osteogenic differentiation in the skull vault. Both occur with different mutations in the MSX2 gene, suggesting that ALX4 is a candidate gene for craniosynostosis as well as for PFM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11137991" 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="#2" class="mim-tip-reference" title="Bertola, D. R., Rodrigues, M. G., Quaio, C. R. D. C., Kim, C. A., Passos-Bueno, M. R. <strong>Vertical transmission of a frontonasal phenotype caused by a novel ALX4 mutation.</strong> Am. J. Med. Genet. 161A: 600-604, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23401352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23401352</a>] [<a href="https://doi.org/10.1002/ajmg.a.35762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23401352">Bertola et al. (2013)</a> and <a href="#1" class="mim-tip-reference" title="Altunoglu, U., Satkin, B., Uyguner, Z. O., Kayserili, H. <strong>Mild nasal clefting may be predictive for ALX4 heterozygotes.</strong> Am. J. Med. Genet. 164A: 2054-2058, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24764194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24764194</a>] [<a href="https://doi.org/10.1002/ajmg.a.36578" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24764194">Altunoglu et al. (2014)</a> independently identified heterozygous ALX4 mutations (<a href="#0012">605420.0012</a> and <a href="#0013">605420.0013</a>) in affected members of 2 unrelated families with autosomal dominant PFM associated with mild features of frontonasal dysplasia. The reports expanded the phenotype associated with ALX4 heterozygous mutations. The authors postulated that a dominant-negative effect may cause frontonasal abnormalities in addition to PFM, whereas haploinsufficiency may result in isolated PFM. <a href="#1" class="mim-tip-reference" title="Altunoglu, U., Satkin, B., Uyguner, Z. O., Kayserili, H. <strong>Mild nasal clefting may be predictive for ALX4 heterozygotes.</strong> Am. J. Med. Genet. 164A: 2054-2058, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24764194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24764194</a>] [<a href="https://doi.org/10.1002/ajmg.a.36578" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24764194">Altunoglu et al. (2014)</a> discussed the implications for genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24764194+23401352" 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>Frontonasal Dysplasia 2</em></strong></p><p>
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In affected members of 2 consanguineous Turkish families segregating frontonasal dysplasia mapping to chromosome 11p11.2-q12.3 (FND2; <a href="/entry/613451">613451</a>), <a href="#6" class="mim-tip-reference" title="Kayserili, H., Uz, E., Niessen, C., Vargel, I., Alanay, Y., Tuncbilek, G., Yigit, G., Uyguner, O., Candan, S., Okur, H., Kaygin, S., Balci, S., Mavili, E., Alikasifoglu, M., Haase, I., Wollnik, B., Akarsu, N. A. <strong>ALX4 dysfunction disrupts craniofacial and epidermal development.</strong> Hum. Molec. Genet. 18: 4357-4366, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19692347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19692347</a>] [<a href="https://doi.org/10.1093/hmg/ddp391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19692347">Kayserili et al. (2009)</a> identified homozygosity for a nonsense mutation in the ALX4 gene (<a href="#0008">605420.0008</a>). Affected individuals exhibited a large skull defect, coronal craniosynostosis, hypertelorism, severely depressed nasal bridge and ridge, bifid nasal tip, cryptorchidism, agenesis of the corpus callosum, total alopecia, and mental retardation. Skin from a biopsy of an affected individual demonstrated a hypomorphic interfollicular epidermis with reduced suprabasal layers associated with impaired interfollicular epidermal differentiation. Hair follicle-like structures were present but showed altered differentiation. <a href="#6" class="mim-tip-reference" title="Kayserili, H., Uz, E., Niessen, C., Vargel, I., Alanay, Y., Tuncbilek, G., Yigit, G., Uyguner, O., Candan, S., Okur, H., Kaygin, S., Balci, S., Mavili, E., Alikasifoglu, M., Haase, I., Wollnik, B., Akarsu, N. A. <strong>ALX4 dysfunction disrupts craniofacial and epidermal development.</strong> Hum. Molec. Genet. 18: 4357-4366, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19692347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19692347</a>] [<a href="https://doi.org/10.1093/hmg/ddp391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19692347">Kayserili et al. (2009)</a> concluded that ALX4 plays a critical role in craniofacial development as well as in skin and hair follicle development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19692347" 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, born of consanguineous Turkish parents, with a mild form of FND2, <a href="#5" class="mim-tip-reference" title="Kayserili, H., Altunoglu, U., Ozgur, H., Basaran, S., Uyguner, Z. O. <strong>Mild nasal malformations and parietal foramina caused by homozygous ALX4 mutations.</strong> Am. J. Med. Genet. 158A: 236-244, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22140057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22140057</a>] [<a href="https://doi.org/10.1002/ajmg.a.34390" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22140057">Kayserili et al. (2012)</a> identified a homozygous missense mutation in the ALX4 gene (Q225E; <a href="#0011">605420.0011</a>). Functional studies were not performed. The parents, who were heterozygous for the mutation, had uncovered bilateral parietal foramina of small size. The patient had mild nasal malformations, parietal foramina, and a hypoplastic and kinked corpus callosum, but normal psychomotor development. <a href="#5" class="mim-tip-reference" title="Kayserili, H., Altunoglu, U., Ozgur, H., Basaran, S., Uyguner, Z. O. <strong>Mild nasal malformations and parietal foramina caused by homozygous ALX4 mutations.</strong> Am. J. Med. Genet. 158A: 236-244, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22140057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22140057</a>] [<a href="https://doi.org/10.1002/ajmg.a.34390" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22140057">Kayserili et al. (2012)</a> postulated that the less severe phenotype observed in this patient compared to the patients reported by <a href="#6" class="mim-tip-reference" title="Kayserili, H., Uz, E., Niessen, C., Vargel, I., Alanay, Y., Tuncbilek, G., Yigit, G., Uyguner, O., Candan, S., Okur, H., Kaygin, S., Balci, S., Mavili, E., Alikasifoglu, M., Haase, I., Wollnik, B., Akarsu, N. A. <strong>ALX4 dysfunction disrupts craniofacial and epidermal development.</strong> Hum. Molec. Genet. 18: 4357-4366, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19692347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19692347</a>] [<a href="https://doi.org/10.1093/hmg/ddp391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19692347">Kayserili et al. (2009)</a> was due to the missense mutation retaining some functionality. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22140057+19692347" 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>Susceptibility to Craniosynostosis 5</em></strong></p><p>
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<a href="#16" class="mim-tip-reference" title="Yagnik, G., Ghuman, A., Kim, S., Stevens, C. G., Kimonis, V., Stoler, J., Sanchez-Lara, P. A., Bernstein, J. A., Naydenov, C., Drissi, H., Cunningham, M. L., Kim, J., Boyadjiev, S. A. <strong>ALX4 gain-of-function mutations in nonsyndromic craniosynostosis.</strong> Hum. Mutat. 33: 1626-1629, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22829454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22829454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22829454[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/10.1002/humu.22166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22829454">Yagnik et al. (2012)</a> studied 203 patients with nonsyndromic craniosynostosis (see CRS5, <a href="/entry/615529">615529</a>), of whom 197 had single sagittal suture fusion and 6 had multiple-suture fusion with sagittal involvement. In 111 of the 203 probands with single-suture fusion and all 6 probands with multiple-suture fusion, <a href="#3" class="mim-tip-reference" title="Boyadjiev, S. A. <strong>Genetic analysis of non-syndromic craniosynostosis.</strong> Orthod. Craniofac. Res. 10: 129-137, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17651129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17651129</a>] [<a href="https://doi.org/10.1111/j.1601-6343.2007.00393.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17651129">Boyadjiev (2007)</a> had previously excluded mutations in hotspot areas of the FGFR1 (<a href="/entry/136350">136350</a>), FGFR2 (<a href="/entry/176943">176943</a>), and FGFR3 (<a href="/entry/134934">134934</a>) genes, and the entire TWIST1 gene (<a href="/entry/601622">601622</a>). <a href="#16" class="mim-tip-reference" title="Yagnik, G., Ghuman, A., Kim, S., Stevens, C. G., Kimonis, V., Stoler, J., Sanchez-Lara, P. A., Bernstein, J. A., Naydenov, C., Drissi, H., Cunningham, M. L., Kim, J., Boyadjiev, S. A. <strong>ALX4 gain-of-function mutations in nonsyndromic craniosynostosis.</strong> Hum. Mutat. 33: 1626-1629, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22829454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22829454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22829454[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/10.1002/humu.22166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22829454">Yagnik et al. (2012)</a> sequenced the entire coding region of the candidate gene ALX4 (<a href="/entry/605420">605420</a>) in the 203 CRS probands and identified heterozygous missense variants, V7F (<a href="#0009">605420.0009</a>) and K211E (<a href="#0010">605420.0010</a>), in 2 of the probands. Functional analysis showed a gain of function for both variants, which were also present in an unaffected parent from each family. <a href="#16" class="mim-tip-reference" title="Yagnik, G., Ghuman, A., Kim, S., Stevens, C. G., Kimonis, V., Stoler, J., Sanchez-Lara, P. A., Bernstein, J. A., Naydenov, C., Drissi, H., Cunningham, M. L., Kim, J., Boyadjiev, S. A. <strong>ALX4 gain-of-function mutations in nonsyndromic craniosynostosis.</strong> Hum. Mutat. 33: 1626-1629, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22829454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22829454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22829454[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/10.1002/humu.22166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22829454">Yagnik et al. (2012)</a> concluded that the variants represent low-penetrance mutations that predispose to CRS but are not causative by themselves. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22829454+17651129" 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>The zone of polarizing activity (ZPA) is a group of mesenchymal cells localized to the posterior margin of the limb bud mesoderm that express Shh (<a href="/entry/600725">600725</a>) and function as a signaling center for patterning the anterior-posterior axis. Mice with the 'Strong luxoid' (lst) phenotype exhibit preaxial polydactyly that is preceded during development by formation of an ectopic ZPA and expression of Shh in the anterior mesenchyme of the limb bud. <a href="#11" class="mim-tip-reference" title="Qu, S., Tucker, S. C., Ehrlich, J. S., Levorse, J. M., Flaherty, L. A., Wisdom, R., Vogt, T. F. <strong>Mutations in mouse Aristaless-like4 cause Strong's luxoid polydactyly.</strong> Development 125: 2711-2721, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9636085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9636085</a>] [<a href="https://doi.org/10.1242/dev.125.14.2711" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9636085">Qu et al. (1998)</a> identified 3 inactivating mutations in the Alx4 gene in 3 independent strains of mice with the Strong luxoid phenotype, in addition to other strain-specific phenotypes. The 3 Alx4 mutations included a large deletion encompassing the Alx4 gene, a 16-bp deletion within the region encoding the paired-type homeodomain, resulting in a frameshift, and a missense mutation, arg206 to gln (R206Q), affecting a critical conserved arginine within the paired-type homeodomain. <a href="#11" class="mim-tip-reference" title="Qu, S., Tucker, S. C., Ehrlich, J. S., Levorse, J. M., Flaherty, L. A., Wisdom, R., Vogt, T. F. <strong>Mutations in mouse Aristaless-like4 cause Strong's luxoid polydactyly.</strong> Development 125: 2711-2721, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9636085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9636085</a>] [<a href="https://doi.org/10.1242/dev.125.14.2711" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9636085">Qu et al. (1998)</a> showed that wildtype Alx4 bound as a dimer to the high-affinity P3 palindromic DNA sequence, whereas the R206Q homeodomain failed to bind P3 as either a dimer or monomer. When expressed in human 293 cells, wildtype Alx4 efficiently activated transcription of a reporter construct containing the P3 sequence, but the R206Q mutant did not. <a href="#11" class="mim-tip-reference" title="Qu, S., Tucker, S. C., Ehrlich, J. S., Levorse, J. M., Flaherty, L. A., Wisdom, R., Vogt, T. F. <strong>Mutations in mouse Aristaless-like4 cause Strong's luxoid polydactyly.</strong> Development 125: 2711-2721, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9636085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9636085</a>] [<a href="https://doi.org/10.1242/dev.125.14.2711" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9636085">Qu et al. (1998)</a> concluded that the Alx4 mutations caused the polydactyly and abnormal ZPA signaling in the Strong luxoid mice, while the variable phenotypes present in heterozygous and homozygous mice, including hemimelia, ventral body wall defects, and alopecia, resulted from strain-specific rather than allele-specific effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9636085" 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>Independently, <a href="#12" class="mim-tip-reference" title="Takahashi, M., Tamura, K., Buscher, D., Masuya, H., Yonei-Tamura, S., Matsumoto, K., Naitoh-Matsuo, M., Takeuchi, J., Ogura, K., Shiroishi, T., Ogura, T., Izpisua Belmonte, J. C. <strong>The role of Alx-4 in the establishment of anteroposterior polarity during vertebrate limb development.</strong> Development 125: 4417-4425, 1998. Note: Erratum: Development 125: preceding 4595, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9778501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9778501</a>] [<a href="https://doi.org/10.1242/dev.125.22.4417" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9778501">Takahashi et al. (1998)</a> identified the semidominant 16-bp deletion in the Alx4 gene in Strong luxoid mice. Using chicken embryos, they found that Alx4 expression originated from the anterior half of the apical ectodermal ridge. Alx4 acted downstream of early events that established anterior-posterior gene asymmetries, and Alx4 expression was downregulated prior to Shh upregulation. Local application of Shh and fibroblast growth factor (see <a href="/entry/131220">131220</a>), or removal of the apical ectodermal ridge, suggested that Alx4 and Shh interact in a negative-feedback loop during limb outgrowth. The interaction of Alx4 and Shh in mice was independent of the negative Shh regulator Gli3 (<a href="/entry/165240">165240</a>). <a href="#12" class="mim-tip-reference" title="Takahashi, M., Tamura, K., Buscher, D., Masuya, H., Yonei-Tamura, S., Matsumoto, K., Naitoh-Matsuo, M., Takeuchi, J., Ogura, K., Shiroishi, T., Ogura, T., Izpisua Belmonte, J. C. <strong>The role of Alx-4 in the establishment of anteroposterior polarity during vertebrate limb development.</strong> Development 125: 4417-4425, 1998. Note: Erratum: Development 125: preceding 4595, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9778501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9778501</a>] [<a href="https://doi.org/10.1242/dev.125.22.4417" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9778501">Takahashi et al. (1998)</a> concluded that ALX4 is required for correct ZPA positioning. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9778501" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>14 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605420[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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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894191 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894191;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=rs104894191" 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=rs104894191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family segregating parietal foramina-2 (PFM2; <a href="/entry/609597">609597</a>), <a href="#7" class="mim-tip-reference" title="Mavrogiannis, L. A., Antonopoulou, I., Baxova, A., Kutilek, S., Kim, C. A., Sugayama, S. M., Salamanca, A., Wall, S. A., Morriss-Kay, G. M., Wilkie, A. O. M. <strong>Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects.</strong> Nature Genet. 27: 17-18, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137991</a>] [<a href="https://doi.org/10.1038/83703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137991">Mavrogiannis et al. (2001)</a> identified a heterozygous c.418C-T transition in the ALX4 gene, resulting in a gln140-to-ter (Q140X) substitution. The mutation was predicted to completely or partially eliminate the DNA-binding homeodomain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11137991" 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">rs104894192 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894192;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=rs104894192" 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=rs104894192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family segregating parietal foramina-2 (PFM2; <a href="/entry/609597">609597</a>), <a href="#7" class="mim-tip-reference" title="Mavrogiannis, L. A., Antonopoulou, I., Baxova, A., Kutilek, S., Kim, C. A., Sugayama, S. M., Salamanca, A., Wall, S. A., Morriss-Kay, G. M., Wilkie, A. O. M. <strong>Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects.</strong> Nature Genet. 27: 17-18, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137991</a>] [<a href="https://doi.org/10.1038/83703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137991">Mavrogiannis et al. (2001)</a> identified a heterozygous c.736C-T transition in the ALX4 gene, resulting in a gln246-to-ter (Q246X) substitution. The mutation was predicted to completely or partially eliminate the DNA-binding homeodomain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11137991" 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"><span class="text-primary">●</span> rs104894193 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894193;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/rs104894193?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=rs104894193" 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=rs104894193" 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=RCV000005318" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005318" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005318</a>
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<p>In affected members of 2 unrelated families with parietal foramina-2 (PFM2; <a href="/entry/609597">609597</a>), <a href="#7" class="mim-tip-reference" title="Mavrogiannis, L. A., Antonopoulou, I., Baxova, A., Kutilek, S., Kim, C. A., Sugayama, S. M., Salamanca, A., Wall, S. A., Morriss-Kay, G. M., Wilkie, A. O. M. <strong>Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects.</strong> Nature Genet. 27: 17-18, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137991</a>] [<a href="https://doi.org/10.1038/83703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137991">Mavrogiannis et al. (2001)</a> identified a heterozygous c.653G-A transition in the ALX4 gene, resulting in an arg218-to-gln (R218Q) substitution. The mutation substituted a highly conserved residue in the N-terminal arm of the homeodomain that contacts the minor groove of DNA. In mouse, the identical mutation underlies the Strong luxoid allele, Alx4(lst), and abolishes DNA binding and transcriptional activation in vitro, with no detectable dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11137991" 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 review of 7 patients from 2 unrelated families with parietal foramina due to the R218Q mutation, <a href="#8" class="mim-tip-reference" title="Mavrogiannis, L. A., Taylor, I. B., Davies, S. J., Ramos, F. J., Olivares, J. L., Wilkie, A. O. M. <strong>Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype.</strong> Europ. J. Hum. Genet. 14: 151-158, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16319823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16319823</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16319823[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/sj.ejhg.5201526" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16319823">Mavrogiannis et al. (2006)</a> found that the patients had disproportionately wide defects compared to patients with other mutations. The authors postulated a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16319823" 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 PARIETAL FORAMINA 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">rs587776614 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776614;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=rs587776614" 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=rs587776614" 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=RCV000005319" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005319" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005319</a>
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<p>In a family segregating parietal foramina-2 (PFM2; <a href="/entry/609597">609597</a>), <a href="#14" class="mim-tip-reference" title="Wuyts, W., Cleiren, E., Homfray, T., Rasore-Quartino, A., Vanhoenacker, F., Van Hul, W. <strong>The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500).</strong> J. Med. Genet. 37: 916-920, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11106354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11106354</a>] [<a href="https://doi.org/10.1136/jmg.37.12.916" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11106354">Wuyts et al. (2000)</a> identified a 1-bp deletion at position 504 (c.504delT) of the cDNA (adenosine of start codon +1) resulting in a premature stop codon after 179 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11106354" 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 PARIETAL FORAMINA 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> rs104894196 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894196;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/rs104894196?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=rs104894196" 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=rs104894196" 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=RCV000005320" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005320" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005320</a>
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<p>In affected members of a family segregating parietal foramina-2 (PFM2; <a href="/entry/609597">609597</a>), <a href="#14" class="mim-tip-reference" title="Wuyts, W., Cleiren, E., Homfray, T., Rasore-Quartino, A., Vanhoenacker, F., Van Hul, W. <strong>The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500).</strong> J. Med. Genet. 37: 916-920, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11106354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11106354</a>] [<a href="https://doi.org/10.1136/jmg.37.12.916" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11106354">Wuyts et al. (2000)</a> identified a G-to-C substitution at position 815 resulting in the replacement of an arginine by a proline residue (arg272 to pro; R272P). Arginine-272 is in a highly conserved region of the homeobox, and the authors concluded that this mutation was likely to disrupt DNA binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11106354" 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="0006" class="mim-anchor"></a>
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<strong>.0006 PARIETAL FORAMINA 2</strong>
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ALX4, SER207TER
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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> rs104894197 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894197;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/rs104894197?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=rs104894197" 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=rs104894197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005321" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005321" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005321</a>
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<p>In 5 affected members of a family with parietal foramina-2 (PFM2; <a href="/entry/609597">609597</a>), <a href="#8" class="mim-tip-reference" title="Mavrogiannis, L. A., Taylor, I. B., Davies, S. J., Ramos, F. J., Olivares, J. L., Wilkie, A. O. M. <strong>Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype.</strong> Europ. J. Hum. Genet. 14: 151-158, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16319823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16319823</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16319823[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/sj.ejhg.5201526" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16319823">Mavrogiannis et al. (2006)</a> identified a heterozygous c.620C-A transversion in the ALX4 gene, resulting in a ser207-to-ter (S207X) substitution. Three sibs also had mild dysmorphic facial features, high palate, and short, broad thumbs. The affected father and paternal grandfather had parietal foramina and broad thumbs. All had normal mental development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16319823" 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="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 PARIETAL FORAMINA 2</strong>
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ALX4, 10-BP DEL, NT385
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906325 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906325;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=rs387906325" 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=rs387906325" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005322" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005322" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005322</a>
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</span>
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<span class="mim-text-font">
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<p>In a female with parietal foramina-2 (PFM2; <a href="/entry/609597">609597</a>), <a href="#8" class="mim-tip-reference" title="Mavrogiannis, L. A., Taylor, I. B., Davies, S. J., Ramos, F. J., Olivares, J. L., Wilkie, A. O. M. <strong>Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype.</strong> Europ. J. Hum. Genet. 14: 151-158, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16319823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16319823</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16319823[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/sj.ejhg.5201526" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16319823">Mavrogiannis et al. (2006)</a> identified a heterozygous 10-bp deletion from nucleotides 385 to 394 in the ALX4 gene, resulting in a frameshift and premature termination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16319823" 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="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 FRONTONASAL DYSPLASIA 2</strong>
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</span>
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ALX4, ARG265TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606653 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606653;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=rs267606653" 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=rs267606653" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005323 OR RCV000623177 OR RCV001650830" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005323, RCV000623177, RCV001650830" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005323...</a>
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</span>
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<span class="mim-text-font">
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<p>In affected members of 2 consanguineous Turkish families segregating frontonasal dysplasia-2 (FND2; <a href="/entry/613451">613451</a>), <a href="#6" class="mim-tip-reference" title="Kayserili, H., Uz, E., Niessen, C., Vargel, I., Alanay, Y., Tuncbilek, G., Yigit, G., Uyguner, O., Candan, S., Okur, H., Kaygin, S., Balci, S., Mavili, E., Alikasifoglu, M., Haase, I., Wollnik, B., Akarsu, N. A. <strong>ALX4 dysfunction disrupts craniofacial and epidermal development.</strong> Hum. Molec. Genet. 18: 4357-4366, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19692347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19692347</a>] [<a href="https://doi.org/10.1093/hmg/ddp391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19692347">Kayserili et al. (2009)</a> identified homozygosity for a 793C-T transition in the ALX4 gene, which resulted in premature termination at codon 265 (R265X). Affected individuals exhibited a large skull defect, coronal craniosynostosis, hypertelorism, severely depressed nasal bridge and ridge, bifid nasal tip, cryptorchidism, agenesis of the corpus callosum, total alopecia, and mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19692347" 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="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 CRANIOSYNOSTOSIS 5, SUSCEPTIBILITY TO</strong>
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ALX4, VAL7PHE
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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> rs281865153 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281865153;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/rs281865153?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=rs281865153" 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=rs281865153" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000074434" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074434" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074434</a>
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<p>In a patient with isolated sagittal craniosynostosis (CRS5; <a href="/entry/615529">615529</a>), <a href="#16" class="mim-tip-reference" title="Yagnik, G., Ghuman, A., Kim, S., Stevens, C. G., Kimonis, V., Stoler, J., Sanchez-Lara, P. A., Bernstein, J. A., Naydenov, C., Drissi, H., Cunningham, M. L., Kim, J., Boyadjiev, S. A. <strong>ALX4 gain-of-function mutations in nonsyndromic craniosynostosis.</strong> Hum. Mutat. 33: 1626-1629, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22829454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22829454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22829454[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/10.1002/humu.22166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22829454">Yagnik et al. (2012)</a> identified heterozygosity for a c.19G-T transversion in the ALX4 gene, resulting in a val7-to-phe (V7F) substitution at a highly conserved residue. Dual-luciferase assay in transfected human calvarial osteoblasts demonstrated that the V7F mutant resulted in a 5.8-fold increase in luminescence compared to wildtype. Postsurgical evaluation of the proband confirmed age-appropriate development and the absence of associated anomalies. The mutation was also present in an unaffected parent; <a href="#16" class="mim-tip-reference" title="Yagnik, G., Ghuman, A., Kim, S., Stevens, C. G., Kimonis, V., Stoler, J., Sanchez-Lara, P. A., Bernstein, J. A., Naydenov, C., Drissi, H., Cunningham, M. L., Kim, J., Boyadjiev, S. A. <strong>ALX4 gain-of-function mutations in nonsyndromic craniosynostosis.</strong> Hum. Mutat. 33: 1626-1629, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22829454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22829454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22829454[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/10.1002/humu.22166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22829454">Yagnik et al. (2012)</a> concluded that the V7F variant represents a low-penetrance gain-of-function mutation that predisposes to CRS but is not causative by itself. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22829454" 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 CRANIOSYNOSTOSIS 5, SUSCEPTIBILITY TO</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">rs281865154 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281865154;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=rs281865154" 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=rs281865154" 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=RCV000074435" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074435" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074435</a>
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<p>In a patient with isolated craniosynostosis involving the metopic, right squamous, and sagittal sutures (CRS5; <a href="/entry/615529">615529</a>), <a href="#16" class="mim-tip-reference" title="Yagnik, G., Ghuman, A., Kim, S., Stevens, C. G., Kimonis, V., Stoler, J., Sanchez-Lara, P. A., Bernstein, J. A., Naydenov, C., Drissi, H., Cunningham, M. L., Kim, J., Boyadjiev, S. A. <strong>ALX4 gain-of-function mutations in nonsyndromic craniosynostosis.</strong> Hum. Mutat. 33: 1626-1629, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22829454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22829454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22829454[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/10.1002/humu.22166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22829454">Yagnik et al. (2012)</a> identified heterozygosity for a c.631A-G transition in the ALX4 gene, resulting in a lys211-to-glu (K211E) substitution at a highly conserved residue. Dual-luciferase assay in transfected human calvarial osteoblasts demonstrated that the K211E mutant resulted in a 5-fold increase in luminescence compared to wildtype. Postsurgical evaluation of the proband confirmed age-appropriate development and the absence of associated anomalies. The mutation was also present in an unaffected parent who had been evaluated by a clinical geneticist; <a href="#16" class="mim-tip-reference" title="Yagnik, G., Ghuman, A., Kim, S., Stevens, C. G., Kimonis, V., Stoler, J., Sanchez-Lara, P. A., Bernstein, J. A., Naydenov, C., Drissi, H., Cunningham, M. L., Kim, J., Boyadjiev, S. A. <strong>ALX4 gain-of-function mutations in nonsyndromic craniosynostosis.</strong> Hum. Mutat. 33: 1626-1629, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22829454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22829454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22829454[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/10.1002/humu.22166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22829454">Yagnik et al. (2012)</a> concluded that the K211E variant represents a low-penetrance gain-of-function mutation that predisposes to CRS but is not causative by itself. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22829454" 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">rs587777701 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777701;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=rs587777701" 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=rs587777701" 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=RCV000144037" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144037" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144037</a>
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<p>In a boy, born of consanguineous Turkish parents, with a mild form of frontonasal dysplasia-2 (FND2; <a href="/entry/613451">613451</a>), <a href="#5" class="mim-tip-reference" title="Kayserili, H., Altunoglu, U., Ozgur, H., Basaran, S., Uyguner, Z. O. <strong>Mild nasal malformations and parietal foramina caused by homozygous ALX4 mutations.</strong> Am. J. Med. Genet. 158A: 236-244, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22140057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22140057</a>] [<a href="https://doi.org/10.1002/ajmg.a.34390" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22140057">Kayserili et al. (2012)</a> identified a homozygous c.673C-G transversion in exon 2 of the ALX4 gene, resulting in a gln225-to-glu (Q225E) substitution at a highly conserved residue in the first helix motif of the homeodomain. The mutation was not detected in 100 ethnically matched control chromosomes; functional studies were not performed. The parents, who were heterozygous for the mutation, had uncovered bilateral parietal foramina of small size. The boy had hypertelorism, upslanting palpebral fissures, broad nasal bridge and ridge, bifid nasal tip, broad columella, cleft alae nasi, and an upper labiogingival sulcus. Skull and brain imaging showed bilateral parietal foramina and a mildly hypoplastic, kinked body of the corpus callosum and underdevelopment of the vermis. He had normal psychomotor development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22140057" 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>.0012 PARIETAL FORAMINA 2</strong>
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ALX4, 10-BP DEL/26-BP INS, NT1080
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777702 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777702;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=rs587777702" 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=rs587777702" 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=RCV000144038" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144038" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144038</a>
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<p>In a son and his mother with parietal foramina-2 (PFM2; <a href="/entry/609597">609597</a>) and frontonasal abnormalities, <a href="#2" class="mim-tip-reference" title="Bertola, D. R., Rodrigues, M. G., Quaio, C. R. D. C., Kim, C. A., Passos-Bueno, M. R. <strong>Vertical transmission of a frontonasal phenotype caused by a novel ALX4 mutation.</strong> Am. J. Med. Genet. 161A: 600-604, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23401352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23401352</a>] [<a href="https://doi.org/10.1002/ajmg.a.35762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23401352">Bertola et al. (2013)</a> identified a heterozygous deletion/insertion mutation in the last exon of the ALX4 gene (c.1080-1089del/ins), resulting in premature termination (Asp326fsTer21). The mutation was predicted to result in loss of the conserved OAR domain. <a href="#2" class="mim-tip-reference" title="Bertola, D. R., Rodrigues, M. G., Quaio, C. R. D. C., Kim, C. A., Passos-Bueno, M. R. <strong>Vertical transmission of a frontonasal phenotype caused by a novel ALX4 mutation.</strong> Am. J. Med. Genet. 161A: 600-604, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23401352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23401352</a>] [<a href="https://doi.org/10.1002/ajmg.a.35762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23401352">Bertola et al. (2013)</a> postulated that the mutation would escape nonsense-mediated mRNA decay and could interfere with the normal ALX4 allele in a dominant-negative manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23401352" 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"><span class="text-primary">●</span> rs587777700 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777700;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/rs587777700?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=rs587777700" 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=rs587777700" 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=RCV000144036" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144036" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144036</a>
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<p>In 4 members of a consanguineous Turkish family with parietal foramina-2 (PFM2; <a href="/entry/609597">609597</a>), <a href="#1" class="mim-tip-reference" title="Altunoglu, U., Satkin, B., Uyguner, Z. O., Kayserili, H. <strong>Mild nasal clefting may be predictive for ALX4 heterozygotes.</strong> Am. J. Med. Genet. 164A: 2054-2058, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24764194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24764194</a>] [<a href="https://doi.org/10.1002/ajmg.a.36578" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24764194">Altunoglu et al. (2014)</a> identified a heterozygous c.646C-G transversion in exon 2 of the ALX4 gene, resulting in an arg216-to-gly (R216G) substitution at a conserved residue in the homeodomain. The mutation was not found in publicly available SNP databases; functional studies were not performed. In addition to minute parietal foramina confirmed by imaging, the patients showed a phenotypic spectrum ranging from mild nasal clefting and broad columella to subtle changes in nasal configuration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24764194" 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 FRONTONASAL DYSPLASIA 2</strong>
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ALX4, 1-BP DEL, 503C
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs876657391 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs876657391;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=rs876657391" 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=rs876657391" 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=RCV000170519" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000170519" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000170519</a>
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<p>In a girl, born of consanguineous Iranian parents, with frontonasal dysplasia-2 (FND2; <a href="/entry/613451">613451</a>), <a href="#4" class="mim-tip-reference" title="Kariminejad, A., Bozorgmehr, B., Alizadeh, H., Ghaderi-Sohi, S., Toksoy, G., Uyguner, Z. O., Kayserili, H. <strong>Skull defects, alopecia, hypertelorism, and notched alae nasi caused by homozygous ALX4 gene mutation.</strong> Am. J. Med. Genet. 164A: 1322-1327, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24668755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24668755</a>] [<a href="https://doi.org/10.1002/ajmg.a.36008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24668755">Kariminejad et al. (2014)</a> identified a homozygous 1-bp deletion (c.503delC, NM_021926.3) in exon 2 of the ALX4 gene, resulting in a frameshift and premature termination (Pro168LeufsTer12). Each parent, who showed mild features, was heterozygous for the mutation, which was predicted to result in a complete loss of protein function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24668755" 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>REFERENCES</strong>
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<a id="Altunoglu2014" class="mim-anchor"></a>
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Altunoglu, U., Satkin, B., Uyguner, Z. O., Kayserili, H.
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<strong>Mild nasal clefting may be predictive for ALX4 heterozygotes.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24764194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24764194</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24764194" 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/10.1002/ajmg.a.36578" target="_blank">Full Text</a>]
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Bertola, D. R., Rodrigues, M. G., Quaio, C. R. D. C., Kim, C. A., Passos-Bueno, M. R.
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<strong>Vertical transmission of a frontonasal phenotype caused by a novel ALX4 mutation.</strong>
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[<a href="https://doi.org/10.1002/ajmg.a.35762" target="_blank">Full Text</a>]
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<a id="Boyadjiev2007" class="mim-anchor"></a>
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Boyadjiev, S. A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17651129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17651129</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17651129" 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/10.1111/j.1601-6343.2007.00393.x" target="_blank">Full Text</a>]
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<a id="Kariminejad2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Kariminejad, A., Bozorgmehr, B., Alizadeh, H., Ghaderi-Sohi, S., Toksoy, G., Uyguner, Z. O., Kayserili, H.
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<strong>Skull defects, alopecia, hypertelorism, and notched alae nasi caused by homozygous ALX4 gene mutation.</strong>
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Am. J. Med. Genet. 164A: 1322-1327, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24668755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24668755</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24668755" 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/10.1002/ajmg.a.36008" target="_blank">Full Text</a>]
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<a id="Kayserili2012" class="mim-anchor"></a>
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Kayserili, H., Altunoglu, U., Ozgur, H., Basaran, S., Uyguner, Z. O.
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<strong>Mild nasal malformations and parietal foramina caused by homozygous ALX4 mutations.</strong>
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Am. J. Med. Genet. 158A: 236-244, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22140057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22140057</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22140057" 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/10.1002/ajmg.a.34390" target="_blank">Full Text</a>]
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<a id="Kayserili2009" class="mim-anchor"></a>
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Kayserili, H., Uz, E., Niessen, C., Vargel, I., Alanay, Y., Tuncbilek, G., Yigit, G., Uyguner, O., Candan, S., Okur, H., Kaygin, S., Balci, S., Mavili, E., Alikasifoglu, M., Haase, I., Wollnik, B., Akarsu, N. A.
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<strong>ALX4 dysfunction disrupts craniofacial and epidermal development.</strong>
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Hum. Molec. Genet. 18: 4357-4366, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19692347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19692347</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19692347" 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/ddp391" target="_blank">Full Text</a>]
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<a id="Mavrogiannis2001" class="mim-anchor"></a>
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<div class="">
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Mavrogiannis, L. A., Antonopoulou, I., Baxova, A., Kutilek, S., Kim, C. A., Sugayama, S. M., Salamanca, A., Wall, S. A., Morriss-Kay, G. M., Wilkie, A. O. M.
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<strong>Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137991</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11137991" 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/10.1038/83703" target="_blank">Full Text</a>]
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<a id="Mavrogiannis2006" class="mim-anchor"></a>
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Mavrogiannis, L. A., Taylor, I. B., Davies, S. J., Ramos, F. J., Olivares, J. L., Wilkie, A. O. M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16319823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16319823</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16319823[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=16319823" 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/sj.ejhg.5201526" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.32.10.823" target="_blank">Full Text</a>]
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Qu, S., Niswender, K. D., Ji, Q., van der Meer, R., Keeney, D., Magnuson, M. A., Wisdom, R.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9374397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9374397</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9374397" 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/10.1242/dev.124.20.3999" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1242/dev.125.14.2711" target="_blank">Full Text</a>]
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<a id="Takahashi1998" class="mim-anchor"></a>
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Takahashi, M., Tamura, K., Buscher, D., Masuya, H., Yonei-Tamura, S., Matsumoto, K., Naitoh-Matsuo, M., Takeuchi, J., Ogura, K., Shiroishi, T., Ogura, T., Izpisua Belmonte, J. C.
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<strong>The role of Alx-4 in the establishment of anteroposterior polarity during vertebrate limb development.</strong>
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Development 125: 4417-4425, 1998. Note: Erratum: Development 125: preceding 4595, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9778501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9778501</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9778501" 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/10.1242/dev.125.22.4417" target="_blank">Full Text</a>]
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<a id="Wu2000" class="mim-anchor"></a>
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Wu, Y.-Q., Badano, J. L., McCaskill, C., Vogel, H., Potocki, L., Shaffer, L. G.
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<strong>Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11017806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11017806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11017806[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=11017806" 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/10.1016/S0002-9297(07)62963-2" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Wuyts2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wuyts, W., Cleiren, E., Homfray, T., Rasore-Quartino, A., Vanhoenacker, F., Van Hul, W.
|
|
<strong>The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500).</strong>
|
|
J. Med. Genet. 37: 916-920, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11106354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11106354</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11106354" 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/10.1136/jmg.37.12.916" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Wuyts1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wuyts, W., Van Hul, W., Wauters, J., Nemtsova, M., Reyniers, E., Van Hul, E. V., De Boulle, K., de Vries, B. B., Hendrickx, J., Herrygers, I., Bossuyt, P., Balemans, W., Fransen, E., Vits, L., Coucke, P., Nowak, N. J., Shows, T. B., Mallet, L., van den Ouweland, A. M., McGaughran, J., Halley, D. J., Willems, P. J.
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|
<strong>Positional cloning of a gene involved in hereditary multiple exostoses.</strong>
|
|
Hum. Molec. Genet. 5: 1547-1557, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8894688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8894688</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8894688" 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/5.10.1547" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Yagnik2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yagnik, G., Ghuman, A., Kim, S., Stevens, C. G., Kimonis, V., Stoler, J., Sanchez-Lara, P. A., Bernstein, J. A., Naydenov, C., Drissi, H., Cunningham, M. L., Kim, J., Boyadjiev, S. A.
|
|
<strong>ALX4 gain-of-function mutations in nonsyndromic craniosynostosis.</strong>
|
|
Hum. Mutat. 33: 1626-1629, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22829454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22829454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22829454[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=22829454" 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/10.1002/humu.22166" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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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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<a id="contributors" 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="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </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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Cassandra L. Kniffin - updated : 5/12/2015
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 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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Cassandra L. Kniffin - updated : 9/3/2014<br>Patricia A. Hartz - updated : 12/28/2010<br>George E. Tiller - updated : 6/16/2010<br>Cassandra L. Kniffin - updated : 2/17/2006<br>Michael J. Wright - updated : 2/9/2001<br>Victor A. McKusick - updated : 1/2/2001
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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 : 11/22/2000
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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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carol : 08/04/2020
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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 : 08/23/2019<br>carol : 01/02/2018<br>alopez : 05/18/2015<br>mcolton : 5/13/2015<br>ckniffin : 5/12/2015<br>carol : 9/8/2014<br>mcolton : 9/4/2014<br>mcolton : 9/4/2014<br>ckniffin : 9/3/2014<br>carol : 6/15/2014<br>carol : 11/19/2013<br>mcolton : 11/14/2013<br>carol : 10/12/2012<br>mgross : 1/7/2011<br>mgross : 1/7/2011<br>terry : 12/28/2010<br>terry : 6/17/2010<br>terry : 6/17/2010<br>carol : 6/16/2010<br>carol : 6/16/2010<br>wwang : 2/24/2006<br>ckniffin : 2/17/2006<br>ckniffin : 10/30/2003<br>terry : 3/21/2001<br>alopez : 2/9/2001<br>alopez : 2/9/2001<br>mgross : 1/2/2001<br>joanna : 11/30/2000<br>joanna : 11/29/2000<br>carol : 11/27/2000
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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> 605420
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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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|
|
ARISTALESS HOMEOBOX 4; ALX4
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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">
|
|
ARISTALESS-LIKE 4, MOUSE, HOMOLOG OF
|
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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: ALX4</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>
|
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<em>
|
|
Cytogenetic location: 11p11.2
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 11:44,260,440-44,310,139 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</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
|
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</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
11p11.2
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Craniosynostosis 5, susceptibility to}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
615529
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Frontonasal dysplasia 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613451
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Parietal foramina 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
609597
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
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|
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|
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</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
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<div>
|
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<br />
|
|
</div>
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|
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<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 ALX4 gene encodes a homeodomain transcription factor important for many developmental processes (summary by Bertola et al., 2013). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Wu et al. (2000) identified a human BAC clone mapping to chromosome 11p11.2 that contained a region homologous to the MSX2 gene (123101), which is mutated in parietal foramina-1 (PFM1; 168500). Further sequence analysis demonstrated that this region contained the human ortholog of the mouse Aristaless-like-4 gene (Alx4). Wu et al. (2000) assembled a full-length ALX4 cDNA encoding a deduced 410-amino acid protein that shares 80% sequence identity with the mouse Alx4 protein. Northern blot analysis demonstrated that expression of both the human and mouse genes is restricted to bone. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The ALX4 coding region comprises 4 exons (Wu et al., 2000; Wuyts et al., 2000). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Wu et al. (2000) identified the ALX4 gene within the critical region of Potocki-Shaffer syndrome (601224), also known as the proximal 11p deletion syndrome (P11pDS), which includes parietal foramina as a feature. </p><p>Qu et al. (1998) mapped the mouse Alx4 gene of a region of chromosome 2 that shares homology of synteny with human chromosome 11p12-q12. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cytogenetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>McGaughran et al. (1995) described a patient with the combination of multiple exostoses (133701), features of Potocki-Shaffer syndrome (601224), and WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation; 194072) associated with a del(11)(p14.2p11.2). The ALX4 gene contains 4 exons and maps centromeric to D11S2095 in reverse orientation to the EXT2 gene (608210); hence ALX4 lies just outside the P11pDS critical interval proposed by Wuyts et al. (1996). In the patient defining this centromeric boundary (McGaughran et al., 1995), ALX4 expression may have been abrogated by a position effect. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Parietal Foramina 2</em></strong></p><p>
|
|
Using FISH, Wu et al. (2000) tested for the presence or heterozygous deletion of the region corresponding to the BAC clone containing ALX4 on 11p in 2 patients with the Potocki-Shaffer syndrome and found that this region was deleted in these patients. The authors stated that the involvement of Alx4 in murine skull development (Qu et al., 1997), its bone-specific expression pattern, the finding that Alx4 is a dosage-sensitive gene in the mouse, and the localization of a human genomic clone containing ALX4 to 11p11.2, with hemizygosity in patients with deletion of 11p11.2 who have biparietal foramina, supported the contention that ALX4 is a candidate gene for parietal foramina in the Potocki-Shaffer syndrome. </p><p>Wuyts et al. (2000) identified heterozygous mutations in the ALX4 gene in affected members of 2 families segregating parietal foramina (PFM2; 609597). One mutation resulted in a premature stop codon (605420.0004) and the second was a missense mutation in a conserved region of the homeobox domain (R272P; 605420.0005), which Wuyts et al. (2000) concluded would disrupt DNA binding. Wuyts et al. (2000) did not find a mutation in either ALX4 or MSX2 in a third family with PFM. </p><p>In 4 families segregating PFM, Mavrogiannis et al. (2001) identified 3 distinct heterozygous ALX4 mutations in 19 affected individuals (605420.0001-605420.0003). The cranial phenotype associated with the ALX4 mutations ranged from severe deficiency in mineralization of the skull vault in infancy (cranium bifidum) to apparent nonpenetrance; most individuals had classic PFM. Mavrogiannis et al. (2001) found no significant difference in the size of PFM between ALX4 and MSX2 mutations, but cranium bifidum had not been described in association with mutations of MSX2. It remained to be determined whether MSX2 and ALX4 act hierarchically or in parallel developmental pathways. PFM and craniosynostosis (premature fusion of the cranial sutures) may result from opposite perturbations in osteogenic differentiation in the skull vault. Both occur with different mutations in the MSX2 gene, suggesting that ALX4 is a candidate gene for craniosynostosis as well as for PFM. </p><p>Bertola et al. (2013) and Altunoglu et al. (2014) independently identified heterozygous ALX4 mutations (605420.0012 and 605420.0013) in affected members of 2 unrelated families with autosomal dominant PFM associated with mild features of frontonasal dysplasia. The reports expanded the phenotype associated with ALX4 heterozygous mutations. The authors postulated that a dominant-negative effect may cause frontonasal abnormalities in addition to PFM, whereas haploinsufficiency may result in isolated PFM. Altunoglu et al. (2014) discussed the implications for genetic counseling. </p><p><strong><em>Frontonasal Dysplasia 2</em></strong></p><p>
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In affected members of 2 consanguineous Turkish families segregating frontonasal dysplasia mapping to chromosome 11p11.2-q12.3 (FND2; 613451), Kayserili et al. (2009) identified homozygosity for a nonsense mutation in the ALX4 gene (605420.0008). Affected individuals exhibited a large skull defect, coronal craniosynostosis, hypertelorism, severely depressed nasal bridge and ridge, bifid nasal tip, cryptorchidism, agenesis of the corpus callosum, total alopecia, and mental retardation. Skin from a biopsy of an affected individual demonstrated a hypomorphic interfollicular epidermis with reduced suprabasal layers associated with impaired interfollicular epidermal differentiation. Hair follicle-like structures were present but showed altered differentiation. Kayserili et al. (2009) concluded that ALX4 plays a critical role in craniofacial development as well as in skin and hair follicle development. </p><p>In a boy, born of consanguineous Turkish parents, with a mild form of FND2, Kayserili et al. (2012) identified a homozygous missense mutation in the ALX4 gene (Q225E; 605420.0011). Functional studies were not performed. The parents, who were heterozygous for the mutation, had uncovered bilateral parietal foramina of small size. The patient had mild nasal malformations, parietal foramina, and a hypoplastic and kinked corpus callosum, but normal psychomotor development. Kayserili et al. (2012) postulated that the less severe phenotype observed in this patient compared to the patients reported by Kayserili et al. (2009) was due to the missense mutation retaining some functionality. </p><p><strong><em>Susceptibility to Craniosynostosis 5</em></strong></p><p>
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Yagnik et al. (2012) studied 203 patients with nonsyndromic craniosynostosis (see CRS5, 615529), of whom 197 had single sagittal suture fusion and 6 had multiple-suture fusion with sagittal involvement. In 111 of the 203 probands with single-suture fusion and all 6 probands with multiple-suture fusion, Boyadjiev (2007) had previously excluded mutations in hotspot areas of the FGFR1 (136350), FGFR2 (176943), and FGFR3 (134934) genes, and the entire TWIST1 gene (601622). Yagnik et al. (2012) sequenced the entire coding region of the candidate gene ALX4 (605420) in the 203 CRS probands and identified heterozygous missense variants, V7F (605420.0009) and K211E (605420.0010), in 2 of the probands. Functional analysis showed a gain of function for both variants, which were also present in an unaffected parent from each family. Yagnik et al. (2012) concluded that the variants represent low-penetrance mutations that predispose to CRS but are not causative by themselves. </p>
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</span>
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<br />
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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>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The zone of polarizing activity (ZPA) is a group of mesenchymal cells localized to the posterior margin of the limb bud mesoderm that express Shh (600725) and function as a signaling center for patterning the anterior-posterior axis. Mice with the 'Strong luxoid' (lst) phenotype exhibit preaxial polydactyly that is preceded during development by formation of an ectopic ZPA and expression of Shh in the anterior mesenchyme of the limb bud. Qu et al. (1998) identified 3 inactivating mutations in the Alx4 gene in 3 independent strains of mice with the Strong luxoid phenotype, in addition to other strain-specific phenotypes. The 3 Alx4 mutations included a large deletion encompassing the Alx4 gene, a 16-bp deletion within the region encoding the paired-type homeodomain, resulting in a frameshift, and a missense mutation, arg206 to gln (R206Q), affecting a critical conserved arginine within the paired-type homeodomain. Qu et al. (1998) showed that wildtype Alx4 bound as a dimer to the high-affinity P3 palindromic DNA sequence, whereas the R206Q homeodomain failed to bind P3 as either a dimer or monomer. When expressed in human 293 cells, wildtype Alx4 efficiently activated transcription of a reporter construct containing the P3 sequence, but the R206Q mutant did not. Qu et al. (1998) concluded that the Alx4 mutations caused the polydactyly and abnormal ZPA signaling in the Strong luxoid mice, while the variable phenotypes present in heterozygous and homozygous mice, including hemimelia, ventral body wall defects, and alopecia, resulted from strain-specific rather than allele-specific effects. </p><p>Independently, Takahashi et al. (1998) identified the semidominant 16-bp deletion in the Alx4 gene in Strong luxoid mice. Using chicken embryos, they found that Alx4 expression originated from the anterior half of the apical ectodermal ridge. Alx4 acted downstream of early events that established anterior-posterior gene asymmetries, and Alx4 expression was downregulated prior to Shh upregulation. Local application of Shh and fibroblast growth factor (see 131220), or removal of the apical ectodermal ridge, suggested that Alx4 and Shh interact in a negative-feedback loop during limb outgrowth. The interaction of Alx4 and Shh in mice was independent of the negative Shh regulator Gli3 (165240). Takahashi et al. (1998) concluded that ALX4 is required for correct ZPA positioning. </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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<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>14 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 PARIETAL FORAMINA 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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ALX4, GLN140TER
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<br />
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SNP: rs104894191,
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ClinVar: RCV000005316
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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 segregating parietal foramina-2 (PFM2; 609597), Mavrogiannis et al. (2001) identified a heterozygous c.418C-T transition in the ALX4 gene, resulting in a gln140-to-ter (Q140X) substitution. The mutation was predicted to completely or partially eliminate the DNA-binding homeodomain. </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>.0002 PARIETAL FORAMINA 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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ALX4, GLN246TER
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<br />
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SNP: rs104894192,
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ClinVar: RCV000005317
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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 segregating parietal foramina-2 (PFM2; 609597), Mavrogiannis et al. (2001) identified a heterozygous c.736C-T transition in the ALX4 gene, resulting in a gln246-to-ter (Q246X) substitution. The mutation was predicted to completely or partially eliminate the DNA-binding homeodomain. </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>.0003 PARIETAL FORAMINA 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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ALX4, ARG218GLN
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<br />
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SNP: rs104894193,
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gnomAD: rs104894193,
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ClinVar: RCV000005318
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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 2 unrelated families with parietal foramina-2 (PFM2; 609597), Mavrogiannis et al. (2001) identified a heterozygous c.653G-A transition in the ALX4 gene, resulting in an arg218-to-gln (R218Q) substitution. The mutation substituted a highly conserved residue in the N-terminal arm of the homeodomain that contacts the minor groove of DNA. In mouse, the identical mutation underlies the Strong luxoid allele, Alx4(lst), and abolishes DNA binding and transcriptional activation in vitro, with no detectable dominant-negative effect. </p><p>In a review of 7 patients from 2 unrelated families with parietal foramina due to the R218Q mutation, Mavrogiannis et al. (2006) found that the patients had disproportionately wide defects compared to patients with other mutations. The authors postulated a dominant-negative effect. </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>.0004 PARIETAL FORAMINA 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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ALX4, 1-BP DEL, 504T
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<br />
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SNP: rs587776614,
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ClinVar: RCV000005319
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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 family segregating parietal foramina-2 (PFM2; 609597), Wuyts et al. (2000) identified a 1-bp deletion at position 504 (c.504delT) of the cDNA (adenosine of start codon +1) resulting in a premature stop codon after 179 amino acids. </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>.0005 PARIETAL FORAMINA 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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ALX4, ARG272PRO
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<br />
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SNP: rs104894196,
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gnomAD: rs104894196,
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ClinVar: RCV000005320
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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 segregating parietal foramina-2 (PFM2; 609597), Wuyts et al. (2000) identified a G-to-C substitution at position 815 resulting in the replacement of an arginine by a proline residue (arg272 to pro; R272P). Arginine-272 is in a highly conserved region of the homeobox, and the authors concluded that this mutation was likely to disrupt DNA binding. </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>.0006 PARIETAL FORAMINA 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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ALX4, SER207TER
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<br />
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SNP: rs104894197,
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gnomAD: rs104894197,
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ClinVar: RCV000005321
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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 5 affected members of a family with parietal foramina-2 (PFM2; 609597), Mavrogiannis et al. (2006) identified a heterozygous c.620C-A transversion in the ALX4 gene, resulting in a ser207-to-ter (S207X) substitution. Three sibs also had mild dysmorphic facial features, high palate, and short, broad thumbs. The affected father and paternal grandfather had parietal foramina and broad thumbs. All had normal mental development. </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>.0007 PARIETAL FORAMINA 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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ALX4, 10-BP DEL, NT385
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<br />
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SNP: rs387906325,
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ClinVar: RCV000005322
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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 female with parietal foramina-2 (PFM2; 609597), Mavrogiannis et al. (2006) identified a heterozygous 10-bp deletion from nucleotides 385 to 394 in the ALX4 gene, resulting in a frameshift and premature termination. </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>.0008 FRONTONASAL DYSPLASIA 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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ALX4, ARG265TER
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<br />
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SNP: rs267606653,
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ClinVar: RCV000005323, RCV000623177, RCV001650830
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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 2 consanguineous Turkish families segregating frontonasal dysplasia-2 (FND2; 613451), Kayserili et al. (2009) identified homozygosity for a 793C-T transition in the ALX4 gene, which resulted in premature termination at codon 265 (R265X). Affected individuals exhibited a large skull defect, coronal craniosynostosis, hypertelorism, severely depressed nasal bridge and ridge, bifid nasal tip, cryptorchidism, agenesis of the corpus callosum, total alopecia, and mental retardation. </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>.0009 CRANIOSYNOSTOSIS 5, SUSCEPTIBILITY TO</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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ALX4, VAL7PHE
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<br />
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SNP: rs281865153,
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gnomAD: rs281865153,
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ClinVar: RCV000074434
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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 patient with isolated sagittal craniosynostosis (CRS5; 615529), Yagnik et al. (2012) identified heterozygosity for a c.19G-T transversion in the ALX4 gene, resulting in a val7-to-phe (V7F) substitution at a highly conserved residue. Dual-luciferase assay in transfected human calvarial osteoblasts demonstrated that the V7F mutant resulted in a 5.8-fold increase in luminescence compared to wildtype. Postsurgical evaluation of the proband confirmed age-appropriate development and the absence of associated anomalies. The mutation was also present in an unaffected parent; Yagnik et al. (2012) concluded that the V7F variant represents a low-penetrance gain-of-function mutation that predisposes to CRS but is not causative by itself. </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>.0010 CRANIOSYNOSTOSIS 5, SUSCEPTIBILITY TO</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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ALX4, LYS211GLU
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<br />
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SNP: rs281865154,
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ClinVar: RCV000074435
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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 patient with isolated craniosynostosis involving the metopic, right squamous, and sagittal sutures (CRS5; 615529), Yagnik et al. (2012) identified heterozygosity for a c.631A-G transition in the ALX4 gene, resulting in a lys211-to-glu (K211E) substitution at a highly conserved residue. Dual-luciferase assay in transfected human calvarial osteoblasts demonstrated that the K211E mutant resulted in a 5-fold increase in luminescence compared to wildtype. Postsurgical evaluation of the proband confirmed age-appropriate development and the absence of associated anomalies. The mutation was also present in an unaffected parent who had been evaluated by a clinical geneticist; Yagnik et al. (2012) concluded that the K211E variant represents a low-penetrance gain-of-function mutation that predisposes to CRS but is not causative by itself. </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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<h4>
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<span class="mim-font">
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<strong>.0011 FRONTONASAL DYSPLASIA 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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ALX4, GLN225GLU
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<br />
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SNP: rs587777701,
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ClinVar: RCV000144037
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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 boy, born of consanguineous Turkish parents, with a mild form of frontonasal dysplasia-2 (FND2; 613451), Kayserili et al. (2012) identified a homozygous c.673C-G transversion in exon 2 of the ALX4 gene, resulting in a gln225-to-glu (Q225E) substitution at a highly conserved residue in the first helix motif of the homeodomain. The mutation was not detected in 100 ethnically matched control chromosomes; functional studies were not performed. The parents, who were heterozygous for the mutation, had uncovered bilateral parietal foramina of small size. The boy had hypertelorism, upslanting palpebral fissures, broad nasal bridge and ridge, bifid nasal tip, broad columella, cleft alae nasi, and an upper labiogingival sulcus. Skull and brain imaging showed bilateral parietal foramina and a mildly hypoplastic, kinked body of the corpus callosum and underdevelopment of the vermis. He had normal psychomotor development. </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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<h4>
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<span class="mim-font">
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<strong>.0012 PARIETAL FORAMINA 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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ALX4, 10-BP DEL/26-BP INS, NT1080
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<br />
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SNP: rs587777702,
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ClinVar: RCV000144038
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</div>
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<span class="mim-text-font">
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<p>In a son and his mother with parietal foramina-2 (PFM2; 609597) and frontonasal abnormalities, Bertola et al. (2013) identified a heterozygous deletion/insertion mutation in the last exon of the ALX4 gene (c.1080-1089del/ins), resulting in premature termination (Asp326fsTer21). The mutation was predicted to result in loss of the conserved OAR domain. Bertola et al. (2013) postulated that the mutation would escape nonsense-mediated mRNA decay and could interfere with the normal ALX4 allele in a dominant-negative manner. </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>.0013 PARIETAL FORAMINA 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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ALX4, ARG216GLY
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<br />
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SNP: rs587777700,
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gnomAD: rs587777700,
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ClinVar: RCV000144036
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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 4 members of a consanguineous Turkish family with parietal foramina-2 (PFM2; 609597), Altunoglu et al. (2014) identified a heterozygous c.646C-G transversion in exon 2 of the ALX4 gene, resulting in an arg216-to-gly (R216G) substitution at a conserved residue in the homeodomain. The mutation was not found in publicly available SNP databases; functional studies were not performed. In addition to minute parietal foramina confirmed by imaging, the patients showed a phenotypic spectrum ranging from mild nasal clefting and broad columella to subtle changes in nasal configuration. </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>.0014 FRONTONASAL DYSPLASIA 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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ALX4, 1-BP DEL, 503C
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<br />
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SNP: rs876657391,
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ClinVar: RCV000170519
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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 girl, born of consanguineous Iranian parents, with frontonasal dysplasia-2 (FND2; 613451), Kariminejad et al. (2014) identified a homozygous 1-bp deletion (c.503delC, NM_021926.3) in exon 2 of the ALX4 gene, resulting in a frameshift and premature termination (Pro168LeufsTer12). Each parent, who showed mild features, was heterozygous for the mutation, which was predicted to result in a complete loss of protein function. </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>REFERENCES</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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<ol>
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<li>
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<p class="mim-text-font">
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Altunoglu, U., Satkin, B., Uyguner, Z. O., Kayserili, H.
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<strong>Mild nasal clefting may be predictive for ALX4 heterozygotes.</strong>
|
|
Am. J. Med. Genet. 164A: 2054-2058, 2014.
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[PubMed: 24764194]
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[Full Text: https://doi.org/10.1002/ajmg.a.36578]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bertola, D. R., Rodrigues, M. G., Quaio, C. R. D. C., Kim, C. A., Passos-Bueno, M. R.
|
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<strong>Vertical transmission of a frontonasal phenotype caused by a novel ALX4 mutation.</strong>
|
|
Am. J. Med. Genet. 161A: 600-604, 2013.
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[PubMed: 23401352]
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[Full Text: https://doi.org/10.1002/ajmg.a.35762]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Boyadjiev, S. A.
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<strong>Genetic analysis of non-syndromic craniosynostosis.</strong>
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Orthod. Craniofac. Res. 10: 129-137, 2007.
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[PubMed: 17651129]
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[Full Text: https://doi.org/10.1111/j.1601-6343.2007.00393.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kariminejad, A., Bozorgmehr, B., Alizadeh, H., Ghaderi-Sohi, S., Toksoy, G., Uyguner, Z. O., Kayserili, H.
|
|
<strong>Skull defects, alopecia, hypertelorism, and notched alae nasi caused by homozygous ALX4 gene mutation.</strong>
|
|
Am. J. Med. Genet. 164A: 1322-1327, 2014.
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[PubMed: 24668755]
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[Full Text: https://doi.org/10.1002/ajmg.a.36008]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Kayserili, H., Altunoglu, U., Ozgur, H., Basaran, S., Uyguner, Z. O.
|
|
<strong>Mild nasal malformations and parietal foramina caused by homozygous ALX4 mutations.</strong>
|
|
Am. J. Med. Genet. 158A: 236-244, 2012.
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[PubMed: 22140057]
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[Full Text: https://doi.org/10.1002/ajmg.a.34390]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kayserili, H., Uz, E., Niessen, C., Vargel, I., Alanay, Y., Tuncbilek, G., Yigit, G., Uyguner, O., Candan, S., Okur, H., Kaygin, S., Balci, S., Mavili, E., Alikasifoglu, M., Haase, I., Wollnik, B., Akarsu, N. A.
|
|
<strong>ALX4 dysfunction disrupts craniofacial and epidermal development.</strong>
|
|
Hum. Molec. Genet. 18: 4357-4366, 2009.
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[PubMed: 19692347]
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[Full Text: https://doi.org/10.1093/hmg/ddp391]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Mavrogiannis, L. A., Antonopoulou, I., Baxova, A., Kutilek, S., Kim, C. A., Sugayama, S. M., Salamanca, A., Wall, S. A., Morriss-Kay, G. M., Wilkie, A. O. M.
|
|
<strong>Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects.</strong>
|
|
Nature Genet. 27: 17-18, 2001.
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[PubMed: 11137991]
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[Full Text: https://doi.org/10.1038/83703]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Mavrogiannis, L. A., Taylor, I. B., Davies, S. J., Ramos, F. J., Olivares, J. L., Wilkie, A. O. M.
|
|
<strong>Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype.</strong>
|
|
Europ. J. Hum. Genet. 14: 151-158, 2006.
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[PubMed: 16319823]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5201526]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
McGaughran, J. M., Ward, H. B., Evans, D. G.
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<strong>WAGR syndrome and multiple exostoses in a patient with del(11)(p11.2p14.2).</strong>
|
|
J. Med. Genet. 32: 823-824, 1995.
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[PubMed: 8558565]
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[Full Text: https://doi.org/10.1136/jmg.32.10.823]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Qu, S., Niswender, K. D., Ji, Q., van der Meer, R., Keeney, D., Magnuson, M. A., Wisdom, R.
|
|
<strong>Polydactyly and ectopic ZPA formation in Alx-4 mutant mice.</strong>
|
|
Development 124: 3999-4008, 1997.
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[PubMed: 9374397]
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[Full Text: https://doi.org/10.1242/dev.124.20.3999]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Qu, S., Tucker, S. C., Ehrlich, J. S., Levorse, J. M., Flaherty, L. A., Wisdom, R., Vogt, T. F.
|
|
<strong>Mutations in mouse Aristaless-like4 cause Strong's luxoid polydactyly.</strong>
|
|
Development 125: 2711-2721, 1998.
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[PubMed: 9636085]
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[Full Text: https://doi.org/10.1242/dev.125.14.2711]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Takahashi, M., Tamura, K., Buscher, D., Masuya, H., Yonei-Tamura, S., Matsumoto, K., Naitoh-Matsuo, M., Takeuchi, J., Ogura, K., Shiroishi, T., Ogura, T., Izpisua Belmonte, J. C.
|
|
<strong>The role of Alx-4 in the establishment of anteroposterior polarity during vertebrate limb development.</strong>
|
|
Development 125: 4417-4425, 1998. Note: Erratum: Development 125: preceding 4595, 1998.
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[PubMed: 9778501]
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[Full Text: https://doi.org/10.1242/dev.125.22.4417]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Wu, Y.-Q., Badano, J. L., McCaskill, C., Vogel, H., Potocki, L., Shaffer, L. G.
|
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<strong>Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome.</strong>
|
|
Am. J. Hum. Genet. 67: 1327-1332, 2000.
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[PubMed: 11017806]
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[Full Text: https://doi.org/10.1016/S0002-9297(07)62963-2]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Wuyts, W., Cleiren, E., Homfray, T., Rasore-Quartino, A., Vanhoenacker, F., Van Hul, W.
|
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<strong>The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500).</strong>
|
|
J. Med. Genet. 37: 916-920, 2000.
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[PubMed: 11106354]
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[Full Text: https://doi.org/10.1136/jmg.37.12.916]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Wuyts, W., Van Hul, W., Wauters, J., Nemtsova, M., Reyniers, E., Van Hul, E. V., De Boulle, K., de Vries, B. B., Hendrickx, J., Herrygers, I., Bossuyt, P., Balemans, W., Fransen, E., Vits, L., Coucke, P., Nowak, N. J., Shows, T. B., Mallet, L., van den Ouweland, A. M., McGaughran, J., Halley, D. J., Willems, P. J.
|
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<strong>Positional cloning of a gene involved in hereditary multiple exostoses.</strong>
|
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Hum. Molec. Genet. 5: 1547-1557, 1996.
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[PubMed: 8894688]
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[Full Text: https://doi.org/10.1093/hmg/5.10.1547]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Yagnik, G., Ghuman, A., Kim, S., Stevens, C. G., Kimonis, V., Stoler, J., Sanchez-Lara, P. A., Bernstein, J. A., Naydenov, C., Drissi, H., Cunningham, M. L., Kim, J., Boyadjiev, S. A.
|
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<strong>ALX4 gain-of-function mutations in nonsyndromic craniosynostosis.</strong>
|
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Hum. Mutat. 33: 1626-1629, 2012.
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[PubMed: 22829454]
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[Full Text: https://doi.org/10.1002/humu.22166]
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</p>
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</li>
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</ol>
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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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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
|
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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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Cassandra L. Kniffin - updated : 5/12/2015<br>Cassandra L. Kniffin - updated : 9/3/2014<br>Patricia A. Hartz - updated : 12/28/2010<br>George E. Tiller - updated : 6/16/2010<br>Cassandra L. Kniffin - updated : 2/17/2006<br>Michael J. Wright - updated : 2/9/2001<br>Victor A. McKusick - updated : 1/2/2001
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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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<br />
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</div>
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<div>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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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 : 11/22/2000
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</span>
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</div>
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</div>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Edit History:
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</span>
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</div>
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carol : 08/04/2020<br>carol : 08/23/2019<br>carol : 01/02/2018<br>alopez : 05/18/2015<br>mcolton : 5/13/2015<br>ckniffin : 5/12/2015<br>carol : 9/8/2014<br>mcolton : 9/4/2014<br>mcolton : 9/4/2014<br>ckniffin : 9/3/2014<br>carol : 6/15/2014<br>carol : 11/19/2013<br>mcolton : 11/14/2013<br>carol : 10/12/2012<br>mgross : 1/7/2011<br>mgross : 1/7/2011<br>terry : 12/28/2010<br>terry : 6/17/2010<br>terry : 6/17/2010<br>carol : 6/16/2010<br>carol : 6/16/2010<br>wwang : 2/24/2006<br>ckniffin : 2/17/2006<br>ckniffin : 10/30/2003<br>terry : 3/21/2001<br>alopez : 2/9/2001<br>alopez : 2/9/2001<br>mgross : 1/2/2001<br>joanna : 11/30/2000<br>joanna : 11/29/2000<br>carol : 11/27/2000
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