2596 lines
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Entry
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- *601513 - FIBROBLAST GROWTH FACTOR 12; FGF12
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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">*601513</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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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneFamily">Gene Family</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601513">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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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div id="mimFloatingLinksMenu">
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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 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=ENSG00000114279;t=ENST00000445105" 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=2257" 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=601513" 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=ENSG00000114279;t=ENST00000445105" 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_001377292,NM_001377293,NM_001377294,NM_004113,NM_021032,XM_005247227,XM_006713538" 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_004113" 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=601513" 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=03303&isoform_id=03303_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/FGF12" 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/1563885,1749791,5442453,11136630,18490696,21614511,47117683,88687000,119598490,119598491,119598492,189053916,189069076,193785028,530374148,578807162,1788703464,1788703471,1788703484,2462588029,2462588032" 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/P61328" 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=2257" 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=ENSG00000114279;t=ENST00000445105" 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=FGF12" 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=FGF12" 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+2257" 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/FGF12" 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:2257" 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/2257" 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=chr3&hgg_gene=ENST00000445105.7&hgg_start=192139390&hgg_end=192727541&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:3668" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3668" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601513[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>
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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=601513[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/FGF12/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/ENSG00000114279" 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=FGF12" 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=FGF12" 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=FGF12" 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=FGF12&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/PA28108" 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:3668" 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/FBgn0014135.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:109183" 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/FGF12#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:109183" 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/2257/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2257" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00002881;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-050221-6" 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=FGF12&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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601513
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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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FIBROBLAST GROWTH FACTOR 12; FGF12
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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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FIBROBLAST GROWTH FACTOR HOMOLOGOUS FACTOR 1; FHF1
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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=FGF12" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FGF12</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/3/968?start=-3&limit=10&highlight=968">3q28-q29</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:192139390-192727541&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'})">3:192,139,390-192,727,541</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>
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<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>
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Phenotype
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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>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
|
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<a href="/geneMap/3/968?start=-3&limit=10&highlight=968">
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3q28-q29
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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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Developmental and epileptic encephalopathy 47
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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/617166"> 617166 </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 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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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/601513" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/601513" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
|
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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<p>The FGF12 gene encodes a member of the fibroblast growth factor homologous factor (FHF) family, which are small cytosolic proteins that interact with the cytoplasmic tails of voltage-gated sodium channels and elevate the voltage dependence of neuronal sodium channel fast inactivation (summary by <a href="#4" class="mim-tip-reference" title="Siekierska, A., Isrie, M., Liu, Y., Scheldeman, C., Vanthillo, N., Lagae, L., de Witte, P. A. M., Van Esch, H., Goldfarb, M., Buyse, G. M. <strong>Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy.</strong> Neurology 86: 2162-2170, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27164707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27164707</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27164707[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/10.1212/WNL.0000000000002752" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27164707">Siekierska et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27164707" 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="#5" class="mim-tip-reference" title="Smallwood, P. M., Munoz-Sanjuan, I., Tong, P., Macke, J. P., Hendry, S. H. C., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., Nathans, J. <strong>Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development.</strong> Proc. Nat. Acad. Sci. 93: 9850-9857, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8790420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8790420</a>] [<a href="https://doi.org/10.1073/pnas.93.18.9850" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8790420">Smallwood et al. (1996)</a> identified and characterized 4 novel members of the fibroblast growth factor (FGF) family, including FGF12, which they referred to as fibroblast growth factor homologous factors (FHFs). The genes were identified by a combination of random cDNA sequencing, database searches, and degenerate PCR. Pairwise comparisons between the 4 FHFs show between 58% and 71% amino acid sequence identity, but each FHF shows less than 30% identity when compared with other FGFs. Like FGF1 (<a href="/entry/131220">131220</a>) and FGF2 (<a href="/entry/134920">134920</a>), the FHFs lack a classic signal sequence and contain clusters of basic residues that can act as nuclear localization signals. In transiently transfected 293 cells, FHF1 accumulates in the nucleus and is not secreted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8790420" 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>Fibroblast growth factors comprise a family of related polypeptides with broad mitogenic and cell survival activities. <a href="#5" class="mim-tip-reference" title="Smallwood, P. M., Munoz-Sanjuan, I., Tong, P., Macke, J. P., Hendry, S. H. C., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., Nathans, J. <strong>Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development.</strong> Proc. Nat. Acad. Sci. 93: 9850-9857, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8790420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8790420</a>] [<a href="https://doi.org/10.1073/pnas.93.18.9850" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8790420">Smallwood et al. (1996)</a> noted that FGF1, or acidic FGF, and FGF2, or basic FGF, were the first 2 family members to be identified, purified, and sequenced, and are widely expressed as a potent mitogen for a variety of cell types. FGF3 (<a href="/entry/164950">164950</a>) is a common target for activation by the mouse mammary tumor virus. The genes encoding FGF4 (<a href="/entry/164980">164980</a>), FGF5 (<a href="/entry/165190">165190</a>), and FGF6 (<a href="/entry/134921">134921</a>) have transforming activity when introduced into NIH 3T3 cells. FGF7 (<a href="/entry/148180">148180</a>), FGF8 (<a href="/entry/600483">600483</a>), and FGF9 (<a href="/entry/600921">600921</a>) are mitogens for keratinocytes, mammary carcinoma cells, and astrocytes, respectively. Several FGFs have been found to have additional bioactivities that were not evident during their initial identification. The FGFs are between 150 and 268 amino acid residues in length and share a conserved central region of approximately 140 amino acids. FGF signaling is generally assumed to occur by activation of transmembrane tyrosine kinase receptors. Four FGF receptors, FGFR1 (<a href="/entry/136350">136350</a>) through FGFR4 (<a href="/entry/134935">134935</a>), had been identified, and activating or inactivating receptor mutations have been described for a subset of these genes in both mice and humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8790420" 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>By Southern blot hybridization of genomic DNA from rodent/human hybrid cell lines containing individual human chromosomes, <a href="#5" class="mim-tip-reference" title="Smallwood, P. M., Munoz-Sanjuan, I., Tong, P., Macke, J. P., Hendry, S. H. C., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., Nathans, J. <strong>Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development.</strong> Proc. Nat. Acad. Sci. 93: 9850-9857, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8790420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8790420</a>] [<a href="https://doi.org/10.1073/pnas.93.18.9850" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8790420">Smallwood et al. (1996)</a> demonstrated that the human FHF1 (also symbolized FGF12), FHF2 (<a href="/entry/300070">300070</a>), FHF3 (<a href="/entry/601514">601514</a>), and FHF4 (<a href="/entry/601515">601515</a>) genes are located on chromosomes 3, X, 17, and 13, respectively. They found that a sequence tagged site (STS) that encompassed 1 exon of FHF3 was derived from human chromosome 17 and mapped near the BRCA1 gene (<a href="/entry/113705">113705</a>), which is located at 17q21. The chromosomal locations of Fhf1, Fhf2, and Fhf4 in the mouse were determined using an interspecific mapping panel. Fhf1 mapped to the proximal region of mouse chromosome 16, 1.6 cM distal to somatostatin (<a href="/entry/182450">182450</a>) and 5.1 cM proximal to ApoD (<a href="/entry/107740">107740</a>). Fhf2 mapped to the mouse X chromosome and did not recombine with the CD40 ligand gene (<a href="/entry/300386">300386</a>) in 168 mice typed, suggesting that the 2 loci are within 1.8 cM of each other. Fhf4 mapped to the distal region of chromosome 14 and did not recombine with Rap2a (<a href="/entry/179540">179540</a>) in 142 mice typed in common. The Fhf3 gene was not mapped with the backcross panel because it failed to demonstrate an informative RFLP when tested with 14 restriction enzymes. The proximity of the human FHF3 gene to BRCA1 suggested to <a href="#5" class="mim-tip-reference" title="Smallwood, P. M., Munoz-Sanjuan, I., Tong, P., Macke, J. P., Hendry, S. H. C., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., Nathans, J. <strong>Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development.</strong> Proc. Nat. Acad. Sci. 93: 9850-9857, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8790420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8790420</a>] [<a href="https://doi.org/10.1073/pnas.93.18.9850" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8790420">Smallwood et al. (1996)</a> that the mouse homolog resides on chromosome 11 in the region that is syntenic with the BRCA1 region of human chromosome 17. From the location of the Fhf1 gene in the mouse one can infer that the human gene is located on 3q28. <a href="#5" class="mim-tip-reference" title="Smallwood, P. M., Munoz-Sanjuan, I., Tong, P., Macke, J. P., Hendry, S. H. C., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., Nathans, J. <strong>Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development.</strong> Proc. Nat. Acad. Sci. 93: 9850-9857, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8790420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8790420</a>] [<a href="https://doi.org/10.1073/pnas.93.18.9850" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8790420">Smallwood et al. (1996)</a> showed that FHFs are expressed principally in the nervous system and are therefore likely to play a role in nervous system development and/or function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8790420" 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="#3" class="mim-tip-reference" title="Liu, Y., Chiu, I.-M. <strong>Assignment of FGF12, the human FGF homologous factor 1 gene, to chromosome 3q29-3qter by fluorescence in situ hybridization.</strong> Cytogenet. Cell Genet. 78: 48-49, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9345906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9345906</a>] [<a href="https://doi.org/10.1159/000134625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9345906">Liu and Chiu (1997)</a> mapped the FGF12 gene to 3q29-qter by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9345906" 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>In 2 sibs with developmental and epileptic encephalopathy-47 (DEE47; <a href="/entry/617166">617166</a>), <a href="#4" class="mim-tip-reference" title="Siekierska, A., Isrie, M., Liu, Y., Scheldeman, C., Vanthillo, N., Lagae, L., de Witte, P. A. M., Van Esch, H., Goldfarb, M., Buyse, G. M. <strong>Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy.</strong> Neurology 86: 2162-2170, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27164707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27164707</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27164707[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/10.1212/WNL.0000000000002752" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27164707">Siekierska et al. (2016)</a> identified a de novo heterozygous missense mutation in the FGF12 gene (R114H; R52H in the B isoform; <a href="#0001">601513.0001</a>). The mutation, which was found by exome sequencing, was not present in either parent, suggesting germline mosaicism. In vitro functional expression studies in neuronal cells and in zebrafish showed that the mutation resulted in a gain-of-function effect with increased neuronal excitability and epileptiform activity in zebrafish. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27164707" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Al-Mehmadi, S., Splitt, M., Ramesh, V., DeBrosse, S., Dessoffy, K., Xia, F., Yang, Y., Rosenfeld, J. A., Cossette, P., Michaud, J. L., Hamdan, F. F., Campeau, P. M., Minassian, B. A. <strong>FHF1 (FGF12) epileptic encephalopathy.</strong> Neurol. Genet. 2: e115, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27830185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27830185</a>] [<a href="https://doi.org/10.1212/NXG.0000000000000115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27830185">Al-Mehmadi et al. (2016)</a> identified a de novo heterozygous R52H mutation in the FGF12 gene in 3 unrelated patients with DEE47. The mutations were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that their findings, combined with the report of <a href="#4" class="mim-tip-reference" title="Siekierska, A., Isrie, M., Liu, Y., Scheldeman, C., Vanthillo, N., Lagae, L., de Witte, P. A. M., Van Esch, H., Goldfarb, M., Buyse, G. M. <strong>Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy.</strong> Neurology 86: 2162-2170, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27164707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27164707</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27164707[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/10.1212/WNL.0000000000002752" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27164707">Siekierska et al. (2016)</a>, suggested that DEE47 is an FGF12 R52H mutation-specific disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27830185+27164707" 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="Guella, I., Huh, L., McKenzie, M. B., Toyota, E. B., Bebin, E. M., Thompson, M. L., Cooper, G. M., Evans, D. M., Buerki, S. E., Adam, S., Van Allen, M. I., Nelson, T. N., Connolly, M. B., Farrer, M. J., Demos, M. <strong>De novo FGF12 mutation in 2 patients with neonatal-onset epilepsy.</strong> Neurol. Genet. 2: e120, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27872899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27872899</a>] [<a href="https://doi.org/10.1212/NXG.0000000000000120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27872899">Guella et al. (2016)</a> identified a de novo heterozygous R52H mutation in 2 unrelated patients with DEE47. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies and studies of patient cells were not performed. <a href="#2" class="mim-tip-reference" title="Guella, I., Huh, L., McKenzie, M. B., Toyota, E. B., Bebin, E. M., Thompson, M. L., Cooper, G. M., Evans, D. M., Buerki, S. E., Adam, S., Van Allen, M. I., Nelson, T. N., Connolly, M. B., Farrer, M. J., Demos, M. <strong>De novo FGF12 mutation in 2 patients with neonatal-onset epilepsy.</strong> Neurol. Genet. 2: e120, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27872899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27872899</a>] [<a href="https://doi.org/10.1212/NXG.0000000000000120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27872899">Guella et al. (2016)</a> noted that 1 of the patients had normal development and neurologic examination at age 11 months, which may have resulted from early successful treatment with phenytoin at 20 days of age. The findings significantly expanded the phenotype associated with this specific mutation, suggesting that other genetic and/or environmental factors may be involved. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27872899" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By whole-exome sequencing in 2 unrelated Japanese patients with DEE47, <a href="#6" class="mim-tip-reference" title="Takeguchi, R., Haginoya, K., Uchiyama, Y., Fujita, A., Nagura, M., takeshita, E., Inui, T., Okubo, Y., Sato, R., Miyabayashi, T., Togashi, N., Saito, T., Nakagawa, E., Sugai, K., Nakashima, M., Saitsu, H., Matsumoto, N., Sasaki, M. <strong>Two Japanese cases of epileptic encephalopathy associated with an FGF12 mutation.</strong> Brain Dev. 40: 728-732, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29699863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29699863</a>] [<a href="https://doi.org/10.1016/j.braindev.2018.04.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29699863">Takeguchi et al. (2018)</a> identified heterozygosity for the R114H mutation in the FGF12 gene. Both patients started having seizures a few days after birth; patient 1 was diagnosed with early infantile epileptic encephalopathy, and patient 2 was diagnosed with epilepsy of infancy with migrating focal seizures, which responded well to phenytoin and high-dose phenobarbital. The phenotypically normal mother of patient 1 was found to be mosaic for the mutation. The authors noted that DEE47 is associated with diverse phenotypes and may respond to sodium channel blocker or high-dose phenobarbital. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29699863" 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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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601513[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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<strong>.0001 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 47</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">rs886039903 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886039903;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=rs886039903" 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=rs886039903" 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=RCV000258032 OR RCV000522341 OR RCV001249217 OR RCV002294210" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000258032, RCV000522341, RCV001249217, RCV002294210" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000258032...</a>
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<p>In 2 sibs with developmental and epileptic encephalopathy-47 (DEE47; <a href="/entry/617166">617166</a>), <a href="#4" class="mim-tip-reference" title="Siekierska, A., Isrie, M., Liu, Y., Scheldeman, C., Vanthillo, N., Lagae, L., de Witte, P. A. M., Van Esch, H., Goldfarb, M., Buyse, G. M. <strong>Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy.</strong> Neurology 86: 2162-2170, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27164707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27164707</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27164707[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/10.1212/WNL.0000000000002752" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27164707">Siekierska et al. (2016)</a> identified a de novo heterozygous C-to-T transition (chr3.192,053,223C-T, GRCh37) in the FGF12 gene, resulting in an arg114-to-his (R114H) substitution in the A-isoform and an arg52-to-his (R52H) substitution in the B-isoform. The mutation, which was found by exome sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. It was also not present in either parent, suggesting germline mosaicism. The substitution occurs at a highly conserved residue that binds the cytoplasmic tail of voltage-gated sodium channels necessary for modulation of fast inactivation. In vitro functional expression studies in neuronal cells showed that both the R114H and R52H variants strongly changed the voltage dependence of inactivation gating, resulting in a gain-of-function effect and increased neuronal excitability. Additional experiments with different substitutions of the arg114 residue indicated that the loss of arginine side-chain interactions with the channel likely causes impaired function. Transfection of the orthologous mutation in zebrafish caused epileptiform activity in larval optic tecta. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27164707" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Al-Mehmadi, S., Splitt, M., Ramesh, V., DeBrosse, S., Dessoffy, K., Xia, F., Yang, Y., Rosenfeld, J. A., Cossette, P., Michaud, J. L., Hamdan, F. F., Campeau, P. M., Minassian, B. A. <strong>FHF1 (FGF12) epileptic encephalopathy.</strong> Neurol. Genet. 2: e115, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27830185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27830185</a>] [<a href="https://doi.org/10.1212/NXG.0000000000000115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27830185">Al-Mehmadi et al. (2016)</a> identified a de novo heterozygous R52H mutation in the FGF12 gene in 3 unrelated patients with DEE47. Whole-exome or whole-genome sequencing in these patients detected a c.155G-A transition (c.155G-A, NM_004113.5); the mutation was confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that their findings, combined with the report of <a href="#4" class="mim-tip-reference" title="Siekierska, A., Isrie, M., Liu, Y., Scheldeman, C., Vanthillo, N., Lagae, L., de Witte, P. A. M., Van Esch, H., Goldfarb, M., Buyse, G. M. <strong>Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy.</strong> Neurology 86: 2162-2170, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27164707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27164707</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27164707[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/10.1212/WNL.0000000000002752" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27164707">Siekierska et al. (2016)</a>, suggested that DEE47 is an FGF12 R52H mutation-specific disease. The patients had onset of seizures in the first days to weeks of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27830185+27164707" 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="Guella, I., Huh, L., McKenzie, M. B., Toyota, E. B., Bebin, E. M., Thompson, M. L., Cooper, G. M., Evans, D. M., Buerki, S. E., Adam, S., Van Allen, M. I., Nelson, T. N., Connolly, M. B., Farrer, M. J., Demos, M. <strong>De novo FGF12 mutation in 2 patients with neonatal-onset epilepsy.</strong> Neurol. Genet. 2: e120, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27872899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27872899</a>] [<a href="https://doi.org/10.1212/NXG.0000000000000120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27872899">Guella et al. (2016)</a> identified a de novo heterozygous c.155G-A transition in the FGF12 gene, resulting in an R52H substitution, in 2 unrelated patients with DEE47. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies and studies of patient cells were not performed. <a href="#2" class="mim-tip-reference" title="Guella, I., Huh, L., McKenzie, M. B., Toyota, E. B., Bebin, E. M., Thompson, M. L., Cooper, G. M., Evans, D. M., Buerki, S. E., Adam, S., Van Allen, M. I., Nelson, T. N., Connolly, M. B., Farrer, M. J., Demos, M. <strong>De novo FGF12 mutation in 2 patients with neonatal-onset epilepsy.</strong> Neurol. Genet. 2: e120, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27872899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27872899</a>] [<a href="https://doi.org/10.1212/NXG.0000000000000120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27872899">Guella et al. (2016)</a> noted that 1 of the patients had normal development and neurologic examination at age 11 months, which may have resulted from early successful treatment with phenytoin at 20 days of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27872899" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By whole-exome sequencing in 2 unrelated Japanese patients with DEE47 (<a href="/entry/617166">617166</a>), <a href="#6" class="mim-tip-reference" title="Takeguchi, R., Haginoya, K., Uchiyama, Y., Fujita, A., Nagura, M., takeshita, E., Inui, T., Okubo, Y., Sato, R., Miyabayashi, T., Togashi, N., Saito, T., Nakagawa, E., Sugai, K., Nakashima, M., Saitsu, H., Matsumoto, N., Sasaki, M. <strong>Two Japanese cases of epileptic encephalopathy associated with an FGF12 mutation.</strong> Brain Dev. 40: 728-732, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29699863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29699863</a>] [<a href="https://doi.org/10.1016/j.braindev.2018.04.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29699863">Takeguchi et al. (2018)</a> identified a heterozygous c.341G-A transition (c.341G-A, NM_021032.4) in the FGF12 gene, resulting in an R114H substitution. In patient 1, the mutation was inherited from a phenotypically normal mother who was mosaic for the mutation; in patient 2, the mutation occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29699863" 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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Al-Mehmadi, S., Splitt, M., Ramesh, V., DeBrosse, S., Dessoffy, K., Xia, F., Yang, Y., Rosenfeld, J. A., Cossette, P., Michaud, J. L., Hamdan, F. F., Campeau, P. M., Minassian, B. A.
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<strong>FHF1 (FGF12) epileptic encephalopathy.</strong>
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Neurol. Genet. 2: e115, 2016. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27830185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27830185</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27830185" 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/10.1212/NXG.0000000000000115" target="_blank">Full Text</a>]
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Guella, I., Huh, L., McKenzie, M. B., Toyota, E. B., Bebin, E. M., Thompson, M. L., Cooper, G. M., Evans, D. M., Buerki, S. E., Adam, S., Van Allen, M. I., Nelson, T. N., Connolly, M. B., Farrer, M. J., Demos, M.
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<strong>De novo FGF12 mutation in 2 patients with neonatal-onset epilepsy.</strong>
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Neurol. Genet. 2: e120, 2016. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27872899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27872899</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27872899" 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/10.1212/NXG.0000000000000120" target="_blank">Full Text</a>]
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Liu, Y., Chiu, I.-M.
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<strong>Assignment of FGF12, the human FGF homologous factor 1 gene, to chromosome 3q29-3qter by fluorescence in situ hybridization.</strong>
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Cytogenet. Cell Genet. 78: 48-49, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9345906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9345906</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9345906" 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/10.1159/000134625" target="_blank">Full Text</a>]
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Siekierska, A., Isrie, M., Liu, Y., Scheldeman, C., Vanthillo, N., Lagae, L., de Witte, P. A. M., Van Esch, H., Goldfarb, M., Buyse, G. M.
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<strong>Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy.</strong>
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Neurology 86: 2162-2170, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27164707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27164707</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27164707[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=27164707" 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/10.1212/WNL.0000000000002752" target="_blank">Full Text</a>]
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Smallwood, P. M., Munoz-Sanjuan, I., Tong, P., Macke, J. P., Hendry, S. H. C., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., Nathans, J.
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<strong>Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development.</strong>
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Proc. Nat. Acad. Sci. 93: 9850-9857, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8790420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8790420</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8790420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Takeguchi, R., Haginoya, K., Uchiyama, Y., Fujita, A., Nagura, M., takeshita, E., Inui, T., Okubo, Y., Sato, R., Miyabayashi, T., Togashi, N., Saito, T., Nakagawa, E., Sugai, K., Nakashima, M., Saitsu, H., Matsumoto, N., Sasaki, M.
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<strong>Two Japanese cases of epileptic encephalopathy associated with an FGF12 mutation.</strong>
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Brain Dev. 40: 728-732, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29699863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29699863</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29699863" 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/j.braindev.2018.04.002" target="_blank">Full Text</a>]
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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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Sonja A. Rasmussen - updated : 11/24/2021
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</span>
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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 : 04/18/2017<br>Cassandra L. Kniffin - updated : 10/20/2016<br>Victor A. McKusick - updated : 12/2/1997
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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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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<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 : 11/18/1996
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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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 : 11/29/2021
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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carol : 11/24/2021<br>alopez : 11/19/2020<br>alopez : 11/10/2020<br>joanna : 10/19/2020<br>carol : 04/26/2017<br>ckniffin : 04/18/2017<br>carol : 10/24/2016<br>ckniffin : 10/20/2016<br>wwang : 02/03/2010<br>alopez : 4/13/2009<br>alopez : 4/13/2009<br>carol : 4/8/2002<br>psherman : 4/12/1999<br>carol : 4/6/1999<br>alopez : 12/15/1997<br>alopez : 12/15/1997<br>dholmes : 12/4/1997<br>mark : 2/23/1997<br>terry : 11/20/1996<br>mark : 11/18/1996<br>mark : 11/18/1996
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 601513
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</h3>
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<h3>
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<span class="mim-font">
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FIBROBLAST GROWTH FACTOR 12; FGF12
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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FIBROBLAST GROWTH FACTOR HOMOLOGOUS FACTOR 1; FHF1
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: FGF12</em></strong>
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</span>
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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: 3q28-q29
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:192,139,390-192,727,541 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<th>
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Location
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Phenotype
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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>
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<td rowspan="1">
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<span class="mim-font">
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3q28-q29
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</td>
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<td>
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<span class="mim-font">
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Developmental and epileptic encephalopathy 47
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</td>
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<td>
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<span class="mim-font">
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617166
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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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Autosomal dominant
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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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3
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</span>
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</td>
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</tbody>
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</table>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The FGF12 gene encodes a member of the fibroblast growth factor homologous factor (FHF) family, which are small cytosolic proteins that interact with the cytoplasmic tails of voltage-gated sodium channels and elevate the voltage dependence of neuronal sodium channel fast inactivation (summary by Siekierska et al., 2016). </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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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Smallwood et al. (1996) identified and characterized 4 novel members of the fibroblast growth factor (FGF) family, including FGF12, which they referred to as fibroblast growth factor homologous factors (FHFs). The genes were identified by a combination of random cDNA sequencing, database searches, and degenerate PCR. Pairwise comparisons between the 4 FHFs show between 58% and 71% amino acid sequence identity, but each FHF shows less than 30% identity when compared with other FGFs. Like FGF1 (131220) and FGF2 (134920), the FHFs lack a classic signal sequence and contain clusters of basic residues that can act as nuclear localization signals. In transiently transfected 293 cells, FHF1 accumulates in the nucleus and is not secreted. </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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<h4>
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<span class="mim-font">
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<strong>Gene Family</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>Fibroblast growth factors comprise a family of related polypeptides with broad mitogenic and cell survival activities. Smallwood et al. (1996) noted that FGF1, or acidic FGF, and FGF2, or basic FGF, were the first 2 family members to be identified, purified, and sequenced, and are widely expressed as a potent mitogen for a variety of cell types. FGF3 (164950) is a common target for activation by the mouse mammary tumor virus. The genes encoding FGF4 (164980), FGF5 (165190), and FGF6 (134921) have transforming activity when introduced into NIH 3T3 cells. FGF7 (148180), FGF8 (600483), and FGF9 (600921) are mitogens for keratinocytes, mammary carcinoma cells, and astrocytes, respectively. Several FGFs have been found to have additional bioactivities that were not evident during their initial identification. The FGFs are between 150 and 268 amino acid residues in length and share a conserved central region of approximately 140 amino acids. FGF signaling is generally assumed to occur by activation of transmembrane tyrosine kinase receptors. Four FGF receptors, FGFR1 (136350) through FGFR4 (134935), had been identified, and activating or inactivating receptor mutations have been described for a subset of these genes in both mice and humans. </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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<h4>
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<span class="mim-font">
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<strong>Mapping</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>By Southern blot hybridization of genomic DNA from rodent/human hybrid cell lines containing individual human chromosomes, Smallwood et al. (1996) demonstrated that the human FHF1 (also symbolized FGF12), FHF2 (300070), FHF3 (601514), and FHF4 (601515) genes are located on chromosomes 3, X, 17, and 13, respectively. They found that a sequence tagged site (STS) that encompassed 1 exon of FHF3 was derived from human chromosome 17 and mapped near the BRCA1 gene (113705), which is located at 17q21. The chromosomal locations of Fhf1, Fhf2, and Fhf4 in the mouse were determined using an interspecific mapping panel. Fhf1 mapped to the proximal region of mouse chromosome 16, 1.6 cM distal to somatostatin (182450) and 5.1 cM proximal to ApoD (107740). Fhf2 mapped to the mouse X chromosome and did not recombine with the CD40 ligand gene (300386) in 168 mice typed, suggesting that the 2 loci are within 1.8 cM of each other. Fhf4 mapped to the distal region of chromosome 14 and did not recombine with Rap2a (179540) in 142 mice typed in common. The Fhf3 gene was not mapped with the backcross panel because it failed to demonstrate an informative RFLP when tested with 14 restriction enzymes. The proximity of the human FHF3 gene to BRCA1 suggested to Smallwood et al. (1996) that the mouse homolog resides on chromosome 11 in the region that is syntenic with the BRCA1 region of human chromosome 17. From the location of the Fhf1 gene in the mouse one can infer that the human gene is located on 3q28. Smallwood et al. (1996) showed that FHFs are expressed principally in the nervous system and are therefore likely to play a role in nervous system development and/or function. </p><p>Liu and Chiu (1997) mapped the FGF12 gene to 3q29-qter by fluorescence in situ hybridization. </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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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</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>In 2 sibs with developmental and epileptic encephalopathy-47 (DEE47; 617166), Siekierska et al. (2016) identified a de novo heterozygous missense mutation in the FGF12 gene (R114H; R52H in the B isoform; 601513.0001). The mutation, which was found by exome sequencing, was not present in either parent, suggesting germline mosaicism. In vitro functional expression studies in neuronal cells and in zebrafish showed that the mutation resulted in a gain-of-function effect with increased neuronal excitability and epileptiform activity in zebrafish. </p><p>Al-Mehmadi et al. (2016) identified a de novo heterozygous R52H mutation in the FGF12 gene in 3 unrelated patients with DEE47. The mutations were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that their findings, combined with the report of Siekierska et al. (2016), suggested that DEE47 is an FGF12 R52H mutation-specific disease. </p><p>Guella et al. (2016) identified a de novo heterozygous R52H mutation in 2 unrelated patients with DEE47. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies and studies of patient cells were not performed. Guella et al. (2016) noted that 1 of the patients had normal development and neurologic examination at age 11 months, which may have resulted from early successful treatment with phenytoin at 20 days of age. The findings significantly expanded the phenotype associated with this specific mutation, suggesting that other genetic and/or environmental factors may be involved. </p><p>By whole-exome sequencing in 2 unrelated Japanese patients with DEE47, Takeguchi et al. (2018) identified heterozygosity for the R114H mutation in the FGF12 gene. Both patients started having seizures a few days after birth; patient 1 was diagnosed with early infantile epileptic encephalopathy, and patient 2 was diagnosed with epilepsy of infancy with migrating focal seizures, which responded well to phenytoin and high-dose phenobarbital. The phenotypically normal mother of patient 1 was found to be mosaic for the mutation. The authors noted that DEE47 is associated with diverse phenotypes and may respond to sodium channel blocker or high-dose phenobarbital. </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>1 Selected Example):</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 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 47</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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FGF12, ARG114HIS
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<br />
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SNP: rs886039903,
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ClinVar: RCV000258032, RCV000522341, RCV001249217, RCV002294210
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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 2 sibs with developmental and epileptic encephalopathy-47 (DEE47; 617166), Siekierska et al. (2016) identified a de novo heterozygous C-to-T transition (chr3.192,053,223C-T, GRCh37) in the FGF12 gene, resulting in an arg114-to-his (R114H) substitution in the A-isoform and an arg52-to-his (R52H) substitution in the B-isoform. The mutation, which was found by exome sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. It was also not present in either parent, suggesting germline mosaicism. The substitution occurs at a highly conserved residue that binds the cytoplasmic tail of voltage-gated sodium channels necessary for modulation of fast inactivation. In vitro functional expression studies in neuronal cells showed that both the R114H and R52H variants strongly changed the voltage dependence of inactivation gating, resulting in a gain-of-function effect and increased neuronal excitability. Additional experiments with different substitutions of the arg114 residue indicated that the loss of arginine side-chain interactions with the channel likely causes impaired function. Transfection of the orthologous mutation in zebrafish caused epileptiform activity in larval optic tecta. </p><p>Al-Mehmadi et al. (2016) identified a de novo heterozygous R52H mutation in the FGF12 gene in 3 unrelated patients with DEE47. Whole-exome or whole-genome sequencing in these patients detected a c.155G-A transition (c.155G-A, NM_004113.5); the mutation was confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that their findings, combined with the report of Siekierska et al. (2016), suggested that DEE47 is an FGF12 R52H mutation-specific disease. The patients had onset of seizures in the first days to weeks of life. </p><p>Guella et al. (2016) identified a de novo heterozygous c.155G-A transition in the FGF12 gene, resulting in an R52H substitution, in 2 unrelated patients with DEE47. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies and studies of patient cells were not performed. Guella et al. (2016) noted that 1 of the patients had normal development and neurologic examination at age 11 months, which may have resulted from early successful treatment with phenytoin at 20 days of age. </p><p>By whole-exome sequencing in 2 unrelated Japanese patients with DEE47 (617166), Takeguchi et al. (2018) identified a heterozygous c.341G-A transition (c.341G-A, NM_021032.4) in the FGF12 gene, resulting in an R114H substitution. In patient 1, the mutation was inherited from a phenotypically normal mother who was mosaic for the mutation; in patient 2, the mutation occurred de novo. </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>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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Al-Mehmadi, S., Splitt, M., Ramesh, V., DeBrosse, S., Dessoffy, K., Xia, F., Yang, Y., Rosenfeld, J. A., Cossette, P., Michaud, J. L., Hamdan, F. F., Campeau, P. M., Minassian, B. A.
|
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<strong>FHF1 (FGF12) epileptic encephalopathy.</strong>
|
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Neurol. Genet. 2: e115, 2016. Note: Electronic Article.
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[PubMed: 27830185]
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[Full Text: https://doi.org/10.1212/NXG.0000000000000115]
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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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Guella, I., Huh, L., McKenzie, M. B., Toyota, E. B., Bebin, E. M., Thompson, M. L., Cooper, G. M., Evans, D. M., Buerki, S. E., Adam, S., Van Allen, M. I., Nelson, T. N., Connolly, M. B., Farrer, M. J., Demos, M.
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<strong>De novo FGF12 mutation in 2 patients with neonatal-onset epilepsy.</strong>
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Neurol. Genet. 2: e120, 2016. Note: Electronic Article.
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[PubMed: 27872899]
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[Full Text: https://doi.org/10.1212/NXG.0000000000000120]
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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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Liu, Y., Chiu, I.-M.
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<strong>Assignment of FGF12, the human FGF homologous factor 1 gene, to chromosome 3q29-3qter by fluorescence in situ hybridization.</strong>
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Cytogenet. Cell Genet. 78: 48-49, 1997.
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[PubMed: 9345906]
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[Full Text: https://doi.org/10.1159/000134625]
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Siekierska, A., Isrie, M., Liu, Y., Scheldeman, C., Vanthillo, N., Lagae, L., de Witte, P. A. M., Van Esch, H., Goldfarb, M., Buyse, G. M.
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<strong>Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy.</strong>
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Neurology 86: 2162-2170, 2016.
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[PubMed: 27164707]
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[Full Text: https://doi.org/10.1212/WNL.0000000000002752]
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Smallwood, P. M., Munoz-Sanjuan, I., Tong, P., Macke, J. P., Hendry, S. H. C., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., Nathans, J.
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<strong>Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development.</strong>
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Proc. Nat. Acad. Sci. 93: 9850-9857, 1996.
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[PubMed: 8790420]
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[Full Text: https://doi.org/10.1073/pnas.93.18.9850]
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Takeguchi, R., Haginoya, K., Uchiyama, Y., Fujita, A., Nagura, M., takeshita, E., Inui, T., Okubo, Y., Sato, R., Miyabayashi, T., Togashi, N., Saito, T., Nakagawa, E., Sugai, K., Nakashima, M., Saitsu, H., Matsumoto, N., Sasaki, M.
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<strong>Two Japanese cases of epileptic encephalopathy associated with an FGF12 mutation.</strong>
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Brain Dev. 40: 728-732, 2018.
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[PubMed: 29699863]
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[Full Text: https://doi.org/10.1016/j.braindev.2018.04.002]
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Sonja A. Rasmussen - updated : 11/24/2021<br>Cassandra L. Kniffin - updated : 04/18/2017<br>Cassandra L. Kniffin - updated : 10/20/2016<br>Victor A. McKusick - updated : 12/2/1997
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Victor A. McKusick : 11/18/1996
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