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Entry
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- *182389 - SODIUM VOLTAGE-GATED CHANNEL, ALPHA SUBUNIT 1; SCN1A
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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">*182389</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/182389">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000144285;t=ENST00000674923" 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=6323" 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=182389" 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=ENSG00000144285;t=ENST00000674923" 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_001165963,NM_001165964,NM_001202435,NM_001353948,NM_001353949,NM_001353950,NM_001353951,NM_001353952,NM_001353954,NM_001353955,NM_001353957,NM_001353958,NM_001353960,NM_001353961,NM_006920,NR_148667,XM_047445392,XM_047445393" 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_001165963" 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=182389" 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=01669&isoform_id=01669_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/SCN1A" 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/36418,560666,12642270,12644229,15421162,23978418,23978422,27263190,62420265,115583677,119631723,119631724,165975065,194374565,194378876,260166633,260166635,320461722,338808472,338808474,338808476,338808478,338808480,1227045122,1227045125,1227045127,1227045129,1227045131,1227045133,1227045135,1227045137,1227045139,1227045141,1227045143,1245697901,1245697903,1245697905,1245697907,1245697909,1245697911,1245697913,1245697915,1245697917,1245697919,1245697921,1245697923,1245697925,1245697927,1245697929,1245697931,1245697933,1245697935,1245697937,1245697939,1245697941,1245697943,1245697945,1245697947,1245697949,1245697951,1245697953,1245697955,1245697957,1245697959,1245697961,1245697963,1245697965,1245697967,1245697969,1245697971,1245697973,1245697975,1245697977,1245697979,1245697981,1245697983,1245697985,1245697987,1245697989,1245697991,1245697993,1245697995,1245697997,1245697999,1245698001,1245698003,1245698005,1245698007,1245698009,1245698011,1245698013,1245698015,1245698017,1245698019,1245698021,1245698023,1245698025,1245698027,1245698029,1245698031,1245698033,1245698035,1245698037,1245698039,1359216210,1359216212,1359216214,1359216216,1359216218,1359216220,1359216222,1359216224,1359216226,1359216228,1359216230,1359216232,1359216234,1359216236,1359216238,1359216240,1359216242,1359216244,1359216246,1359216248,1359216250,1359216252,1359216254,1359216256,1359216258,1359216260,1359216262,1359216264,1359216266,1359216268,1359216270,1359216272,1359216274,1359216276,1359216278,1359216280,1359216282,1359216284,1359216286,1359216288,1359216290,1359216292,1359216294,1359216296,1359216298,1359216300,1359216302,1359216304,1359216306,1359216308,1359216310,1359216312,1359216314,1359216316,1359216318,1359216320,1359216322,1359216324,1359216326,1359216328,1359216330,1359216332,1359216334,1359216336,1359216338,1359216340,1359216342,1359216344,1359216346,1359216348,1359216350,1359216352,1359216354,1359216356,1359216358,1375621705,1375621707,1375621709,1375621711,1375621713,1375621715,1375621717,1375621719,1375621721,1375621723,1375621725,1375621727,1375621729,1375621731,1375621733,1375621735,1375621737,1375621739,1375621741,1375621743,1375621745,1375621747,1375621749,1375621751,1375621753,1375621755,1375621757,1375621759,1375621761,1375621763,1375621765,1375621767,1375621769,1375621771,1375621773,1375621775,1375621777,1375621779,1375621781,1375621783,1375621785,1375621787,1375621789,1375621791,1375621793,1375621795,1375621797,1375621799,1375621801,1375621803,1375621805,1375621807,1375621809,1375621811,1375621813,1375621815,1375621817,1375621819,1375621821,1375621823,1375621825,1375621827,1375621829,1375621831,1375621833,1375621835,1375621837,1375621839,1375621841,1375621843,1391207425,1391207427,1391207429,1391207431,1391207433,1391207435,1391207437,1391207439,1391207441,1391207443,1391207445,1391207447,1391207449,1391207451,1391207453,1391207455,1391207457,1391207459,1391207461,1391207463,1391207465,1391207467,1391207469,1391207471,1391207473,1391207475,1391207477,1391207479,1391207481,1391207483,1391207485,1391207487,1391207489,1391207491,1391207493,1391207495,1391207497,1391207499,1391207501,1391207503,1391207505,1391207507,1391207509,1391207511,1391207513,1391207515,1391207517,1391207519,1391207521,1391207523,1391207525,1391207527,1391207529,1391207531,1391207533,1391207535,1391207537,1391207539,1391207541,1391207543,1391207545,1391207547,1391207549,1391207551,1391207553,1391207555,1391207557,1391207559,1391207561,1391207563,1391207565,1391207567,1391207569,2217330067,2217330069,2239584681,2239584683,2239584685,2239584687,2239584689,2239584691,2239584693,2239584695,2239584697,2239584700,2239584702,2239584704,2239584706,2239584708,2239584710,2239584712,2239584714,2239584716,2239584718,2239584720,2239584722,2462575875,2462575877" 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/P35498" 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=6323" 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=ENSG00000144285;t=ENST00000674923" 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=SCN1A" 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=SCN1A" 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+6323" 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/SCN1A" 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:6323" 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/6323" 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=chr2&hgg_gene=ENST00000674923.1&hgg_start=165984641&hgg_end=166149161&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:10585" 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:10585" 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=182389[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=182389[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/SCN1A/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/ENSG00000144285" 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=SCN1A" 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=SCN1A" 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=SCN1A" 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=SCN1A&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/PA301" 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:10585" 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/FBgn0285944.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:98246" 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/SCN1A#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:98246" 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/6323/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=6323" 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://zfin.org/ZDB-GENE-040426-751" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:6323" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=SCN1A&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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<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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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 230437002<br />
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<strong>ICD10CM:</strong> G40.83, G40.834<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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182389
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</span>
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</span>
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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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SODIUM VOLTAGE-GATED CHANNEL, ALPHA SUBUNIT 1; SCN1A
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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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<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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SODIUM CHANNEL, NEURONAL TYPE I, ALPHA SUBUNIT<br />
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SODIUM CHANNEL, BRAIN TYPE I, ALPHA SUBUNIT; NAC1<br />
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NAV1.1
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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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<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=SCN1A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SCN1A</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/2/740?start=-3&limit=10&highlight=740">2q24.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:165984641-166149161&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'})">2:165,984,641-166,149,161</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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<span class="hidden-sm hidden-xs pull-right">
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<a href="/clinicalSynopsis/table?mimNumber=619317,607208,604403,604403,609634" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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View Clinical Synopses
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</a>
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</span>
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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="5">
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<span class="mim-font">
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<a href="/geneMap/2/740?start=-3&limit=10&highlight=740">
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2q24.3
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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 6B, non-Dravet
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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/619317"> 619317 </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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<tr>
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<td>
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<span class="mim-font">
|
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Dravet syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/607208"> 607208 </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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<tr>
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<td>
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<span class="mim-font">
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Febrile seizures, familial, 3A
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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/604403"> 604403 </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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<tr>
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<td>
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<span class="mim-font">
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Generalized epilepsy with febrile seizures plus, type 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/604403"> 604403 </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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<tr>
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<td>
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<span class="mim-font">
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Migraine, familial hemiplegic, 3
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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/609634"> 609634 </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">
|
|
PheneGene Graphics <span class="caret"></span>
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/182389" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/182389" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>The vertebrate sodium channel is a voltage-gated ion channel essential for the generation and propagation of action potentials, chiefly in nerve and muscle. Voltage-sensitive sodium channels are heteromeric complexes consisting of a large central pore-forming glycosylated alpha subunit and 2 smaller auxiliary beta subunits. Functional studies have indicated that the transmembrane alpha subunit of the brain sodium channels is sufficient for expression of functional sodium channels (<a href="#15" class="mim-tip-reference" title="Goldin, A. L., Snutch, T., Lubbert, H., Dowsett, A., Marshall, J., Auld, V., Downey, W., Fritz, L. C., Lester, H. A., Dunn, R., Catterall, W. A., Davidson, N. <strong>Messenger RNA coding for only the alpha subunit of the rat brain Na channel is sufficient for expression of functional channels in Xenopus oocytes.</strong> Proc. Nat. Acad. Sci. 83: 7503-7507, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2429308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2429308</a>] [<a href="https://doi.org/10.1073/pnas.83.19.7503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2429308">Goldin et al., 1986</a>; <a href="#19" class="mim-tip-reference" title="Isom, L. L. <strong>The role of sodium channels in cell adhesion.</strong> Front. Biosci. 7: 12-23, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11779698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11779698</a>] [<a href="https://doi.org/10.2741/isom" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11779698">Isom, 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2429308+11779698" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#12" class="mim-tip-reference" title="Escayg, A., MacDonald, B. T., Meisler, M. H., Baulac, S., Huberfeld, G., An-Gourfinkel, I., Brice, A., LeGuern, E., Moulard, B., Chaigne, D., Buresi, C., Malafosse, A. <strong>Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2.</strong> Nature Genet. 24: 343-345, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742094</a>] [<a href="https://doi.org/10.1038/74159" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742094">Escayg et al. (2000)</a> determined the coding sequence of the human SCN1A gene by aligning the rat cDNA sequence with genomic sequence. The deduced amino acid sequence of the 2,009-residue human SCN1A protein was determined. Human SCN1A is highly conserved, with 98% amino acid sequence identity to the corresponding rat sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10742094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<br />
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<div>
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<a id="geneStructure" class="mim-anchor"></a>
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<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimGeneStructureToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</h4>
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</div>
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<div id="mimGeneStructureFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#12" class="mim-tip-reference" title="Escayg, A., MacDonald, B. T., Meisler, M. H., Baulac, S., Huberfeld, G., An-Gourfinkel, I., Brice, A., LeGuern, E., Moulard, B., Chaigne, D., Buresi, C., Malafosse, A. <strong>Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2.</strong> Nature Genet. 24: 343-345, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742094</a>] [<a href="https://doi.org/10.1038/74159" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742094">Escayg et al. (2000)</a> determined that the SCN1A gene has 26 exons. Its intron-exon organization is identical to that of SCN8A (<a href="/entry/600702">600702</a>) at chromosome 12q13 and probably corresponds to that of the ancestral gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10742094" 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 the mouse, <a href="#25" class="mim-tip-reference" title="Malo, D., Schurr, E., Dorfman, J., Canfield, V., Levenson, R., Gros, P. <strong>Three brain sodium channel alpha-subunit genes are clustered on the proximal segment of mouse chromosome 2.</strong> Genomics 10: 666-672, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1679748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1679748</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90450-s" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1679748">Malo et al. (1991)</a> showed that Scn1a and Scn2a are tightly linked and separated by a distance of 0.7 cM. The latter gene (SCN2A; <a href="/entry/182390">182390</a>) had been mapped to chromosome 2 in both man and mouse; by homology, SCN1A would be located on human chromosome 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1679748" 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 fluorescence in situ hybridization, Malo et al. (<a href="#26" class="mim-tip-reference" title="Malo, M. S., Blanchard, B. J., Andresen, J. M., Srivastava, K., Chen, X.-N., Li, X., Jabs, E. W., Korenberg, J. R., Ingram, V. M. <strong>Localization of a putative human brain sodium channel gene (SCN1A) to chromosome band 2q24.</strong> Cytogenet. Cell Genet. 67: 178-186, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8062593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8062593</a>] [<a href="https://doi.org/10.1159/000133818" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8062593">1994</a>, <a href="#27" class="mim-tip-reference" title="Malo, M. S., Srivastava, K., Andresen, J. M., Chen, X.-N., Korenberg, J. R., Ingram, V. M. <strong>Targeted gene walking by low stringency polymerase chain reaction: assignment of a putative human brain sodium channel gene (SCN3A) to chromosome 2q24-31.</strong> Proc. Nat. Acad. Sci. 91: 2975-2979, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8159690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8159690</a>] [<a href="https://doi.org/10.1073/pnas.91.8.2975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8159690">1994</a>) mapped the SCN1A gene to chromosome 2q24. <a href="#12" class="mim-tip-reference" title="Escayg, A., MacDonald, B. T., Meisler, M. H., Baulac, S., Huberfeld, G., An-Gourfinkel, I., Brice, A., LeGuern, E., Moulard, B., Chaigne, D., Buresi, C., Malafosse, A. <strong>Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2.</strong> Nature Genet. 24: 343-345, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742094</a>] [<a href="https://doi.org/10.1038/74159" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742094">Escayg et al. (2000)</a> confirmed the location of SCN1A within the candidate region for generalized epilepsy with febrile seizures plus, type 2 (GEFSP2; <a href="/entry/604403">604403</a>) by typing the GB4 radiation hybrid panel with primers for intron 21, further localizing the SCN1A gene to the 4-cM interval between D2S156 and D2S399. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10742094+8062593+8159690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The axon initial segment (AIS) is the site at which neural signals arise, and should be the most efficient site to regulate neural activity. <a href="#22" class="mim-tip-reference" title="Kuba, H., Oichi, Y., Ohmori, H. <strong>Presynaptic activity regulates Na+ channel distribution at the axon initial segment.</strong> Nature 465: 1075-1078, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20543825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20543825</a>] [<a href="https://doi.org/10.1038/nature09087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20543825">Kuba et al. (2010)</a> reported that deprivation of auditory input in an avian brainstem auditory neuron leads to an increase in AIS length, thus augmenting the excitability of the neuron. The length of the AIS, defined by the distribution of voltage-gated sodium channels and the AIS anchoring protein, ankyrin G (<a href="/entry/106410">106410</a>), increased by 1.7 times in 7 days after auditory input deprivation. This was accompanied by an increase in the whole-cell sodium current, membrane excitability, and spontaneous firing. <a href="#22" class="mim-tip-reference" title="Kuba, H., Oichi, Y., Ohmori, H. <strong>Presynaptic activity regulates Na+ channel distribution at the axon initial segment.</strong> Nature 465: 1075-1078, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20543825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20543825</a>] [<a href="https://doi.org/10.1038/nature09087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20543825">Kuba et al. (2010)</a> concluded that their work demonstrated homeostatic regulations of the AIS, which may contribute to the maintenance of the auditory pathway after hearing loss. Furthermore, plasticity at the spike initiation site suggests a powerful pathway for refining neuronal computation in the face of strong sensory deprivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20543825" 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="#40" class="mim-tip-reference" title="Osteen, J. D., Herzig, V., Gilchrist, J., Emrick, J. J., Zhang, C., Wang, X., Castro, J., Garcia-Caraballo, S., Grundy, L., Rychkov, G. Y., Weyer, A. D., Dekan, Z., Undheim, E. A. B., Alewood, P., Stucky, C. L., Brierley, S. M., Basbaum, A. I., Bosmans, F., King, G. F., Julius, D. <strong>Selective spider toxins reveal a role for the Na(V)1.1 channel in mechanical pain.</strong> Nature 534: 494-499, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27281198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27281198</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27281198[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature17976" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27281198">Osteen et al. (2016)</a> identified and characterized tarantula toxins that selectively activated human and rodent NAV1.1. Using the spider toxin probes in mice, they showed that activated Nav1.1-expressing fibers elicited robust pain behavior without neurogenic inflammation and produced profound hypersensitivity to mechanical, but not thermal, stimuli. Mechanosensitive fibers expressing Nav1.1 were also present in gut and showed enhanced toxin sensitivity in a mouse model of irritable bowel syndrome. <a href="#40" class="mim-tip-reference" title="Osteen, J. D., Herzig, V., Gilchrist, J., Emrick, J. J., Zhang, C., Wang, X., Castro, J., Garcia-Caraballo, S., Grundy, L., Rychkov, G. Y., Weyer, A. D., Dekan, Z., Undheim, E. A. B., Alewood, P., Stucky, C. L., Brierley, S. M., Basbaum, A. I., Bosmans, F., King, G. F., Julius, D. <strong>Selective spider toxins reveal a role for the Na(V)1.1 channel in mechanical pain.</strong> Nature 534: 494-499, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27281198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27281198</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27281198[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature17976" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27281198">Osteen et al. (2016)</a> concluded that NAV1.1 contributes to peripheral pain signaling, by both acute and repetitive mechanical stimulation, through myelinated afferent fibers expressing the receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27281198" 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="#34" class="mim-tip-reference" title="Mulley, J. C., Scheffer, I. E., Petrou, S., Dibbens, L. M., Berkovic, S. F., Harkin, L. A. <strong>SCN1A mutations and epilepsy.</strong> Hum. Mutat. 25: 535-542, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15880351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15880351</a>] [<a href="https://doi.org/10.1002/humu.20178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15880351">Mulley et al. (2005)</a> stated that of all the known epilepsy genes, SCN1A was the most clinically relevant, with the largest number of epilepsy-related mutations characterized to that time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15880351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Generalized Epilepsy with Febrile Seizures Plus, Type 2</em></strong></p><p>
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<a href="#2" class="mim-tip-reference" title="Baulac, S., Gourfinkel-An, I., Picard, F., Rosenberg-Bourgin, M., Prud'homme, J.-F., Baulac, M., Brice, A., LeGuern, E. <strong>A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21-q33.</strong> Am. J. Hum. Genet. 65: 1078-1085, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10486327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10486327</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10486327[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10486327">Baulac et al. (1999)</a> and <a href="#32" class="mim-tip-reference" title="Moulard, B., Guipponi, M., Chaigne, D., Mouthon, D., Buresi, C., Malafosse, A. <strong>Identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+) on chromosome 2q24-q33.</strong> Am. J. Hum. Genet. 65: 1396-1400, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10521305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10521305</a>] [<a href="https://doi.org/10.1086/302621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10521305">Moulard et al. (1999)</a> reported 2 unrelated families with generalized epilepsy with febrile seizures plus who showed linkage to a locus on chromosome 2q21-q33, consistent with GEFS+ type 2 (GEFSP2; <a href="/entry/604403">604403</a>). Using conformation-sensitive gel electrophoresis to scan the 26 exons of the SCN1A gene from 1 affected and 1 unaffected individual from each of these families, <a href="#12" class="mim-tip-reference" title="Escayg, A., MacDonald, B. T., Meisler, M. H., Baulac, S., Huberfeld, G., An-Gourfinkel, I., Brice, A., LeGuern, E., Moulard, B., Chaigne, D., Buresi, C., Malafosse, A. <strong>Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2.</strong> Nature Genet. 24: 343-345, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742094</a>] [<a href="https://doi.org/10.1038/74159" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742094">Escayg et al. (2000)</a> identified 2 missense mutations. The mutant residues thr875 (see <a href="#0002">182389.0002</a>) and arg1648 (see <a href="#0001">182389.0001</a>) are located in the S4 transmembrane segments of the sodium channel alpha-subunit, which is composed of 4 homologous domains (D1-D4), each containing 6 transmembrane segments. The functional importance of the mutations was supported by the evolutionary conservation in other mammalian gene family members and in lower vertebrates and invertebrates. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10742094+10486327+10521305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Escayg, A., Heils, A., MacDonald, B. T., Haug, K., Sander, T., Meisler, M. H. <strong>A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy.</strong> Am. J. Hum. Genet. 68: 866-873, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254445[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/319524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254445">Escayg et al. (2001)</a> identified an additional SCN1A mutation (W1204R; <a href="#0006">182389.0006</a>) in a family with GEFS+2, but concluded that SCN1A is not a major contributor to idiopathic generalized epilepsy (EIG; <a href="/entry/600669">600669</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11254445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 3 unrelated families with GEFS+2, <a href="#53" class="mim-tip-reference" title="Wallace, R. H., Scheffer, I. E., Barnett, S., Richards, M., Dibbens, L., Desai, R. R., Lerman-Sagie, T., Lev, D., Mazarib, A., Brand, N., Ben-Zeev, B., Goikhman, I., Singh, R., Kremmidiotis, G., Gardner, A., Sutherland, G. R., George, A. L., Jr., Mulley, J. C., Berkovic, S. F. <strong>Neuronal sodium-channel alpha-1-subunit mutations in generalized epilepsy with febrile seizures plus.</strong> Am. J. Hum. Genet. 68: 859-865, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254444</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254444[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/319516" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254444">Wallace et al. (2001)</a> identified heterozygous missense mutations in the SCN1A gene: family A, the Australian family originally reported by <a href="#43" class="mim-tip-reference" title="Scheffer, I. E., Berkovic, S. F. <strong>Generalized epilepsy with febrile seizures plus: a genetic disorder with heterogeneous clinical phenotypes.</strong> Brain 120: 479-490, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9126059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9126059</a>] [<a href="https://doi.org/10.1093/brain/120.3.479" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9126059">Scheffer and Berkovic (1997)</a>, had a D188V mutation (<a href="#0003">182389.0003</a>); family B, of Ashkenazi Jewish descent, had a V1353L mutation (<a href="#0004">182389.0004</a>); and family C, of Druze origin, carried an I1656M mutation (<a href="#0005">182389.0005</a>). Functional studies of the variants and studies of patient cells were not performed, but the authors noted that all occurred in functional domains and may result in neuronal hyperexcitability. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11254444+9126059" 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="#39" class="mim-tip-reference" title="Orrico, A., Galli, L., Grosso, S., Buoni, S., Pianigiani, R., Balestri, P., Sorrentino, V. <strong>Mutational analysis of the SCN1A, SCN1B and GABRG2 genes in 150 Italian patients with idiopathic childhood epilepsies. (Letter)</strong> Clin. Genet. 75: 579-581, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19522081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19522081</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01155.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19522081">Orrico et al. (2009)</a> identified 21 mutations, including 14 novel mutations, in the SCN1A gene in 22 (14.66%) of 150 Italian pediatric probands with epilepsy. SCN1A mutations were found in 21.2% of patients with GEFS+ and in 75% of patients with Dravet syndrome from the overall patient cohort. Only 1 potentially pathogenic mutation was identified in the SCN1B gene (<a href="/entry/600235">600235</a>), and no mutations were found in the GABRG2 gene (<a href="/entry/137164">137164</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19522081" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Dravet Syndrome</em></strong></p><p>
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Mutation in the SCN1A gene can cause a spectrum of early-onset epileptic encephalopathies, with the most common designation being Dravet syndrome (DRVT; <a href="/entry/607208">607208</a>) (summary by <a href="#5" class="mim-tip-reference" title="Carranza Rojo, D., Hamiwka, L., McMahon, J. M., Dibbens, L. M., Arsov, T., Suls, A., Stodberg, T., Kelley, K., Wirrell, E., Appleton, B., Mackay, M., Freeman, J. L., and 8 others. <strong>De novo SCN1A mutations in migrating partial seizures of infancy.</strong> Neurology 77: 380-383, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21753172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21753172</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318227046d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21753172">Carranza Rojo et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21753172" 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>Because both GEFS+ and Dravet syndrome, also known as severe myoclonic epilepsy of infancy (SMEI), involve fever-associated seizures, and because GEFS+ is associated with mutations in the SCN1A gene, <a href="#7" class="mim-tip-reference" title="Claes, L., Del-Favero, J., Ceulemans, B., Lagae, L., Van Broeckhoven, C., De Jonghe, P. <strong>De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.</strong> Am. J. Hum. Genet. 68: 1327-1332, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11359211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11359211</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11359211[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320609" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11359211">Claes et al. (2001)</a> screened 7 unrelated Belgian patients with SMEI for mutations in SCN1A. They identified de novo heterozygous mutations in each patient (see, e.g., <a href="#0007">182389.0007</a>-<a href="#0009">182389.0009</a>). The mutations included 4 frameshifts, 1 nonsense, 1 splice site, and 1 missense. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11359211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 14 patients, including a pair of monozygotic twins, with classic symptoms of SMEI, <a href="#47" class="mim-tip-reference" title="Sugawara, T., Mazaki-Miyazaki, E., Fukushima, K., Shimomura, J., Fujiwara, T., Hamano, S., Inoue, Y., Yamakawa, K. <strong>Frequent mutations of SCN1A in severe myoclonic epilepsy in infancy.</strong> Neurology 58: 1122-1124, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11940708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11940708</a>] [<a href="https://doi.org/10.1212/wnl.58.7.1122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11940708">Sugawara et al. (2002)</a> identified 10 heterozygous mutations in the SCN1A gene. There were 3 frameshift mutations that resulted in intragenic stop codons and truncated channels, and 7 nonsense mutations which also resulted in truncated channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11940708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 29 patients with severe myoclonic epilepsy of infancy and 11 patients with other types of epilepsy, <a href="#38" class="mim-tip-reference" title="Ohmori, I., Ouchida, M., Ohtsuka, Y., Oka, E., Shimizu, K. <strong>Significant correlation of the SCN1A mutations and severe myoclonic epilepsy in infancy.</strong> Biochem. Biophys. Res. Commun. 295: 17-23, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12083760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12083760</a>] [<a href="https://doi.org/10.1016/s0006-291x(02)00617-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12083760">Ohmori et al. (2002)</a> performed a mutation search of the SCN1A gene. They detected de novo heterozygous mutations in 24 of the 29 patients with SMEI, but in none of the patients with other types of epilepsy. The mutations included deletions, insertions, missense changes, and nonsense changes. The authors found no mutations in the SCN1B or GABRG2 (<a href="/entry/137164">137164</a>) genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12083760" 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="#6" class="mim-tip-reference" title="Claes, L., Ceulemans, B., Audenaert, D., Smets, K., Lofgren, A., Del-Favero, J., Ala-Mello, S., Basel-Vanagaite, L., Plecko, B., Raskin, S., Thiry, P., Wolf, N. I., Van Broeckhoven, C., De Jonghe, P. <strong>De novo SCN1A mutations are a major cause of severe myoclonic epilepsy of infancy.</strong> Hum. Mutat. 21: 615-621, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12754708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12754708</a>] [<a href="https://doi.org/10.1002/humu.10217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12754708">Claes et al. (2003)</a> investigated 9 patients with Dravet syndrome and observed 8 coding and 1 noncoding mutation in the SCN1A gene. In contrast to a previous study of 7 isolated patients (<a href="#7" class="mim-tip-reference" title="Claes, L., Del-Favero, J., Ceulemans, B., Lagae, L., Van Broeckhoven, C., De Jonghe, P. <strong>De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.</strong> Am. J. Hum. Genet. 68: 1327-1332, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11359211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11359211</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11359211[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320609" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11359211">Claes et al., 2001</a>), most mutations were found to be missense mutations clustering in the S4-S6 region of SCN1A. These findings demonstrated that de novo mutations in SCN1A are a major cause of isolated Dravet syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12754708+11359211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 7 of 10 unrelated patients with intractable childhood epilepsy with generalized tonic-clonic seizures, a variant of Dravet syndrome without myoclonus, <a href="#14" class="mim-tip-reference" title="Fujiwara, T., Sugawara, T., Mazaki-Miyazaki, E., Takahashi, Y., Fukushima, K., Watanabe, M., Hara, K., Morikawa, T., Yagi, K., Yamakawa, K., Inoue, Y. <strong>Mutations of sodium channel alpha-subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures.</strong> Brain 126: 531-546, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566275</a>] [<a href="https://doi.org/10.1093/brain/awg053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566275">Fujiwara et al. (2003)</a> identified heterozygous mutations in the SCN1A gene (see, e.g., <a href="#0013">182389.0013</a>; <a href="#0014">182389.0014</a>). All of the mutations were missense mutations. The findings extended the phenotypic spectrum associated with mutations in the SCN1A gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12566275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using multiplex ligation-dependent probe amplification (MLPA), <a href="#33" class="mim-tip-reference" title="Mulley, J. C., Nelson, P., Guerrero, S., Dibbens, L., Iona, X., McMahon, J. M., Harkin, L., Schouten, J., Yu, S., Berkovic, S. F., Scheffer, I. E. <strong>A new molecular mechanism for severe myoclonic epilepsy of infancy: exonic deletions in SCN1A.</strong> Neurology 67: 1094-1095, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17000989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17000989</a>] [<a href="https://doi.org/10.1212/01.wnl.0000237322.04338.2b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17000989">Mulley et al. (2006)</a> identified exon deletions in the SCN1A gene (<a href="#0018">182389.0018</a> and <a href="#0019">182389.0019</a>) in 2 (15%) of 13 unrelated SMEI patients who did not have point or splice site mutations in the SCN1A gene. The findings provided a new molecular mechanism for the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17000989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#55" class="mim-tip-reference" title="Zucca, C., Redaelli, F., Epifanio, R., Zanotta, N., Romeo, A., Lodi, M., Veggiotti, P., Airoldi, G., Panzeri, C., Romaniello, R., De Polo, G., Bonanni, P., Cardinali, S., Baschirotto, C., Martorell, L., Borgatti, R., Bresolin, N., Bassi, M. T. <strong>Cryptogenic epileptic syndromes related to SCN1A: twelve novel mutations identified.</strong> Arch. Neurol. 65: 489-494, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18413471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18413471</a>] [<a href="https://doi.org/10.1001/archneur.65.4.489" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18413471">Zucca et al. (2008)</a> identified 13 mutations, including 12 novel mutations, in the SCN1A gene in 12 (20%) of 60 unrelated patients with cryptogenic epilepsy beginning in the first 2 years of life. Ten patients had SMEI, and 1 had GEFS+. The twelfth patient had severe mental retardation and generalized tonic-clonic seizures, which evolved to hemiclonic seizures suggestive of focal epilepsy; this phenotype was considered to be a variable expression of SMEI. No large deletions in the SCN1A gene were identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18413471" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Depienne, C., Trouillard, O., Saint-Martin, C., Gourfinkel-An, I., Bouteiller, D., Carpentier, W., Keren, B., Abert, B., Gautier, A., Baulac, S., Arzimanoglou, A., Cazeneuve, C., Nabbout, R., LeGuern, E. <strong>Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. (Letter)</strong> J. Med. Genet. 46: 183-191, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18930999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18930999</a>] [<a href="https://doi.org/10.1136/jmg.2008.062323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18930999">Depienne et al. (2009)</a> identified pathogenic mutations or deletions, including 161 novel point mutations, in the SCN1A gene in 242 (73%) of 333 patients with Dravet syndrome. The most common mutations were missense (42%), and 14 patients had microrearrangements in or deletions of the gene. Thus, the disease mechanism appeared to be haploinsufficiency of the SCN1A gene. Mutations were scattered throughout the gene, and there were no apparent genotype/phenotype correlations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18930999" 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="#39" class="mim-tip-reference" title="Orrico, A., Galli, L., Grosso, S., Buoni, S., Pianigiani, R., Balestri, P., Sorrentino, V. <strong>Mutational analysis of the SCN1A, SCN1B and GABRG2 genes in 150 Italian patients with idiopathic childhood epilepsies. (Letter)</strong> Clin. Genet. 75: 579-581, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19522081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19522081</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01155.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19522081">Orrico et al. (2009)</a> identified 21 mutations, including 14 novel mutations, in the SCN1A gene in 22 (14.66%) of 150 Italian pediatric probands with epilepsy. SCN1A mutations were found in 21.2% of patients with GEFS+ and in 75% of patients with Dravet syndrome from the overall patient cohort. Only 1 potentially pathogenic mutation was identified in the SCN1B gene (<a href="/entry/600235">600235</a>), and no mutations were found in the GABRG2 gene (<a href="/entry/137164">137164</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19522081" 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="#45" class="mim-tip-reference" title="Singh, N. A., Pappas, C., Dahle, E. J., Claes, L. R. F., Pruess, T. H., De Jonghe, P., Thompson, J., Dixon, M., Gurnett, C., Peiffer, A., White, H. S., Filloux, F., Leppert, M. F. <strong>A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.</strong> PLoS Genet. 5: e1000649, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19763161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19763161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19763161[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/10.1371/journal.pgen.1000649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19763161">Singh et al. (2009)</a> presented preliminary evidence that mutations in the SCN9A gene (<a href="/entry/603415">603415</a>) may act as a genetic modifier of Dravet syndrome when found in conjunction with an SCN1A mutation. They identified mutations in the SCN9A gene in 9 (8%) of 109 patients with Dravet syndrome, including 6 with SCN1A mutation and 3 without SCN1A mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19763161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using Western blot analysis and ELISA, <a href="#51" class="mim-tip-reference" title="Thompson, C. H., Porter, J. C., Kahling, K. M., Daniels, M. A., George, A. L., Jr. <strong>Nontruncating SCN1A mutations associated with severe myoclonic epilepsy of infancy impair cell surface expression.</strong> J. Biol. Chem. 287: 42001-42008, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23086956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23086956</a>] [<a href="https://doi.org/10.1074/jbc.M112.421883" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23086956">Thompson et al. (2012)</a> showed that 7 different nontruncating SCN1A mutations associated with SMEI, including R1648C, impaired trafficking of SCN1A and reduced its cell surface expression. Treatment with the antiepileptic drugs phenytoin or lamotrigine increased the cell surface expression of R1648C and restored its voltage-gated sodium channel function. However, lamotrigine also increased persistent sodium current mediated by R1648C. Phenytoin increased surface expression of another mutant channel but did not restore its channel function, suggesting that some SCN1A mutations also cause intrinsic loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23086956" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Familial Hemiplegic Migraine 3</em></strong></p><p>
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In affected members of 3 European families with familial hemiplegic migraine-3 (FHM3; <a href="/entry/609634">609634</a>), <a href="#10" class="mim-tip-reference" title="Dichgans, M., Freilinger, T., Eckstein, G., Babini, E., Lorenz-Depiereux, B., Biskup, S., Ferrari, M. D., Herzog, J., van den Maagdenberg, A. M. J. M., Pusch, M., Strom, T. M. <strong>Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine.</strong> Lancet 366: 371-377, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16054936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16054936</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)66786-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16054936">Dichgans et al. (2005)</a> identified a heterozygous mutation in the SCN1A gene (<a href="#0012">182389.0012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16054936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Familial Febrile Seizures 3A</em></strong></p><p>
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In affected members of an Italian family with familial febrile convulsions-3A (FEB3A; see <a href="/entry/604403">604403</a>), <a href="#29" class="mim-tip-reference" title="Mantegazza, M., Gambardella, A., Rusconi, R., Schiavon, E., Annesi, F., Cassulini, R. R., Labate, A., Carrideo, S., Chifari, R., Canevini, M. P., Canger, R., Franceschetti, S., Annesi, G., Wanke, E., Quattrone, A. <strong>Identification of an Na(v)1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures.</strong> Proc. Nat. Acad. Sci. 102: 18177-18182, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16326807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16326807</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16326807[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0506818102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16326807">Mantegazza et al. (2005)</a> identified heterozygosity for a mutation in the SCN1A gene (<a href="#0015">182389.0015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16326807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Developmental and Epileptic Encephalopathy 6B</em></strong></p><p>
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In a 6-year-old Japanese girl with developmental and epileptic encephalopathy-6B (DEE6B; <a href="/entry/619317">619317</a>), <a href="#37" class="mim-tip-reference" title="Ohashi, T., Akasaka, N., Kobayashi, Y., Magara, S., Kawashima, H., Matsumoto, N., Saitsu, H., Tohyama, J. <strong>Infantile epileptic encephalopathy with a hyperkinetic movement disorder and hand stereotypies associated with a novel SCN1A mutation.</strong> Epileptic Disord. 16: 208-212, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24776920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24776920</a>] [<a href="https://doi.org/10.1684/epd.2014.0649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24776920">Ohashi et al. (2014)</a> identified a de novo heterozygous missense mutation in the SCN1A gene (V422L; <a href="#0025">182389.0025</a>). The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or in 408 in-house Japanese controls. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24776920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 8 unrelated patients with DEE6B, <a href="#42" class="mim-tip-reference" title="Sadleir, L. G., Mountier, E. I., Gill, D., Davis, S., Joshi, C., DeVile, C., Kurian, M. A., Mandelstam, S., Wirrell, E., Nickels, K. C., Murali, H. R., Carvill, G., Myers, C. T., Mefford, H. C., Scheffer, I. E. <strong>Not all SCN1A epileptic encephalopathies are Dravet syndrome: early profound thr226met phenotype.</strong> Neurology 89: 1035-1042, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28794249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28794249</a>] [<a href="https://doi.org/10.1212/WNL.0000000000004331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28794249">Sadleir et al. (2017)</a> identified a de novo recurrent heterozygous missense mutation in the SCN1A gene (T226M; <a href="#0026">182389.0026</a>). Another patient (patient 9) carried a different de novo heterozygous missense mutation (P1345S; <a href="#0027">182389.0027</a>). Functional studies of the variants were not performed, but the authors speculated a gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28794249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Studies of SCN1A Protein Variants</em></strong></p><p>
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<a href="#24" class="mim-tip-reference" title="Lossin, C., Wang, D. W., Rhodes, T. H., Vanoye, C. G., George, A. L., Jr. <strong>Molecular basis of an inherited epilepsy.</strong> Neuron 34: 877-884, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12086636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12086636</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00714-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12086636">Lossin et al. (2002)</a> characterized the functional effects of 3 mutations in SCN1A by heterologous expression with its accessory subunits, SCN1B and SCN2B (<a href="/entry/601327">601327</a>), in cultured mammalian cells. SCN1A mutations altered channel inactivation, resulting in persistent inward sodium current. This gain-of-function abnormality was expected to enhance excitability of neuronal membranes by causing prolonged membrane depolarization, a plausible underlying biophysical mechanism responsible for autosomal dominant generalized epilepsy with febrile seizures plus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12086636" 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="#49" class="mim-tip-reference" title="Tate, S. K., Depondt, C., Sisodiya, S. M., Cavalleri, G. L., Schorge, S., Soranzo, N., Thom, M., Sen, A., Shorvon, S. D., Sander, J. W., Wood, N. W., Goldstein, D. B. <strong>Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin.</strong> Proc. Nat. Acad. Sci. 102: 5507-5512, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15805193[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0407346102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805193">Tate et al. (2005)</a> identified a G-to-A polymorphism in the SCN1A gene (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3812718;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3812718</a>; <a href="#0016">182389.0016</a>) that affects alternative splicing of exon 5. The major A allele disrupts the consensus sequence of the fetal/neonatal exon 5N, reducing the expression of this exon relative to the adult exon 5A. Two antiepileptic drugs, carbamazepine and phenytoin, act by binding to the alpha-subunit of neuronal sodium channels encoded by SCN1A. Among 425 and 281 epileptic patients treated with carbamazepine and phenytoin, respectively, <a href="#49" class="mim-tip-reference" title="Tate, S. K., Depondt, C., Sisodiya, S. M., Cavalleri, G. L., Schorge, S., Soranzo, N., Thom, M., Sen, A., Shorvon, S. D., Sander, J. W., Wood, N. W., Goldstein, D. B. <strong>Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin.</strong> Proc. Nat. Acad. Sci. 102: 5507-5512, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15805193[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0407346102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805193">Tate et al. (2005)</a> found a significant association with the <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3812718;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3812718</a> polymorphism and maximum dose needed to control symptoms; those with the G allele (and the neonatal SCN1A isoform) needed less medication. Maximum doses of carbamazepine averaged 1,313, 1,225, and 1,083 mg for AA, AG, and GG individuals, respectively; maximum doses of phenytoin averaged 373, 340, and 326 mg, for AA, AG, and GG individuals, respectively, suggesting a trend of reduction in maximum dose required according to genotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15805193" 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="#18" class="mim-tip-reference" title="Heinzen, E. L., Yoon, W., Tate, S. K., Sen, A., Wood, N. W., Sisodiya, S. M., Goldstein, D. B. <strong>Nova2 interacts with a Cis-acting polymorphism to influence the proportions of drug-responsive splice variants of SCN1A.</strong> Am. J. Hum. Genet. 80: 876-883, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436242</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436242[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/516650" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436242">Heinzen et al. (2007)</a> found that individuals with the G allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3812718;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3812718</a> had significantly increased levels of SCN1A transcripts containing exon 5N, consistent with the neonatal isoform, compared to those with the A allele. In addition, the G allele exhibited a dominant effect. These results were confirmed in a minigene expression system. Further studies in the minigene expression system suggested a role for NOVA2 (<a href="/entry/601991">601991</a>) in the regulation of splicing, with higher NOVA2 expression increasing the proportion of the neonate isoform including exon 5N; this effect was seen particularly with the AA genotype. <a href="#18" class="mim-tip-reference" title="Heinzen, E. L., Yoon, W., Tate, S. K., Sen, A., Wood, N. W., Sisodiya, S. M., Goldstein, D. B. <strong>Nova2 interacts with a Cis-acting polymorphism to influence the proportions of drug-responsive splice variants of SCN1A.</strong> Am. J. Hum. Genet. 80: 876-883, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436242</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436242[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/516650" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436242">Heinzen et al. (2007)</a> noted that individuals with the AA genotype require increased doses of antiepileptic drugs compared to those with the GG genotype, suggesting that patients with the AA genotype have a more severe form of epilepsy. Alternatively, the different splice forms may cause alterations in pharmacology, since the drugs act on the SCN1A gene. The findings emphasized an emerging role of genetic polymorphisms in modulation of drug effect, and illustrated the importance of considering the activity of compounds at alternative splice forms of drug targets. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17436242" 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="#41" class="mim-tip-reference" title="Petrovski, S., Scheffer, I. E., Sisodiya, S. M., O'Brien, T. J., Berkovic, S. F. <strong>Lack of replication of association between SCN1A SNP and febrile seizures.</strong> Neurology 73: 1928-1930, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19949041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19949041</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181c3fd6f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19949041">Petrovski et al. (2009)</a> was unable to replicate the association between <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3812718;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3812718</a> and febrile seizures in a study of 558 Australian patients with seizures, including 76 (14%) with febrile seizures and 482 (86%) without febrile seizures. Only 10 (2%) had isolated febrile seizures. The association was also not replicated in a second cohort of 1,589 European patients with focal epilepsy, consisting of 232 with febrile seizures and 1,357 without febrile seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19949041" 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 an analysis of 14 GEFS+ and 60 SMEI SCN1A missense mutations previously reported, <a href="#20" class="mim-tip-reference" title="Kanai, K., Hirose, S., Oguni, H., Fukuma, G., Shirasaka, Y., Miyajima, T., Wada, K., Iwasa, H., Yasumoto, S., Matsuo, M., Ito, M., Mitsudome, A., Kaneko, S. <strong>Effect of localization of missense mutations in SCN1A on epilepsy phenotype severity.</strong> Neurology 63: 329-334, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15277629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15277629</a>] [<a href="https://doi.org/10.1212/01.wnl.0000129829.31179.5b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15277629">Kanai et al. (2004)</a> found that mutations in SMEI occurred more frequently in the 'pore' regions of SCN1A than did those in GEFS+. The SMEI pore region mutations were more strongly associated with the presence of ataxia and slightly earlier onset compared to mutations in other regions of the gene. Although the genotype-phenotype correlation was statistically significant, SMEI mutations also occurred outside the pore region and GEFS+ mutations occurred inside the pore region. Three SCN1A mutations were identified in both groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15277629" 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="#34" class="mim-tip-reference" title="Mulley, J. C., Scheffer, I. E., Petrou, S., Dibbens, L. M., Berkovic, S. F., Harkin, L. A. <strong>SCN1A mutations and epilepsy.</strong> Hum. Mutat. 25: 535-542, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15880351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15880351</a>] [<a href="https://doi.org/10.1002/humu.20178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15880351">Mulley et al. (2005)</a> found that the more than 100 epilepsy-associated mutations reported in the SCN1A gene to that time were spread throughout the gene. Some clustering of mutations was observed in the C terminus and the loops between segments 5 and 6 of the first 3 domains of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15880351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Kanai, K., Yoshida, S., Hirose, S., Oguni, H., Kuwabara, S., Sawai, S., Hiraga, A., Fukuma, G., Iwasa, H., Kojima, T., Kaneko, S. <strong>Physicochemical property changes of amino acid residues that accompany missense mutations in SCN1A affect epilepsy phenotype severity.</strong> J. Med. Genet. 46: 671-679, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19586930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19586930</a>] [<a href="https://doi.org/10.1136/jmg.2008.060897" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19586930">Kanai et al. (2009)</a> performed a metaanalysis of the physiochemical effects of amino acid substitutions resulting from missense mutations in the SCN1A gene and their phenotypes in order to assess genotype/phenotype correlations. From 33 articles, they studied 155 missense mutations, including 22 associated with GEFS+, 14 associated with an intermediate phenotype (e.g., T1709I; <a href="#0013">182389.0013</a>), and 119 associated with a severe phenotype, including SMEI. Changes that resulted in decreased hydrophobicity in the S1-S4 transmembrane region outside of the pore region were significantly associated with a more severe phenotype. These changes may affect the stability of the transmembrane domains, which lie within the hydrophobic lipid layer. In addition, mutations that resulted in large changes in the isoelectric point within the pore region were associated with a more severe phenotype. Changes in charge on the surface of the pore may affect the function of the pore of the ion channel. However, patch-clamp studies were unable to find significant associations between changes in physicochemical properties and functional characteristics of mutated channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19586930" 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 polymerase chain reaction (PCR), <a href="#3" class="mim-tip-reference" title="Blanchard, B. J., Ingram, V. M. <strong>The gene for the sodium channel I-alpha subunit is located on chromosome 21. (Abstract)</strong> Cytogenet. Cell Genet. 58: 2034 only, 1991."None>Blanchard and Ingram (1991)</a> isolated the SCN1A gene from a library of EcoRI fragments from flow-sorted chromosome 21. Primers were selected from a highly conserved region in the rat brain sodium channel I-alpha cDNA sequence. The assignment to chromosome 21 was subsequently found to be an error, presumably due to contamination of the chromosome 21 library by material from chromosome 2 (<a href="#28" class="mim-tip-reference" title="Malo, M. <strong>Personal Communication.</strong> Pearl River, N. Y. 12/6/1993."None>Malo, 1993</a>).</p>
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<p><a href="#54" class="mim-tip-reference" title="Yu, F. H., Mantegazza, M., Westenbroek, R. E., Robbins, C. A., Kalume, F., Burton, K. A., Spain, W. J., McKnight, G. S., Scheuer, T., Catterall, W. A. <strong>Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy.</strong> Nature Neurosci. 9: 1142-1149, 2006. Note: Erratum: Nature Neurosci. 10: 134 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16921370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16921370</a>] [<a href="https://doi.org/10.1038/nn1754" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16921370">Yu et al. (2006)</a> found that Scn1a -/- mice developed severe ataxia and seizures and died on postnatal day 15. Scn1a +/- mice had spontaneous seizures and sporadic deaths beginning after postnatal day 21, with a notable dependence on genetic background. Loss of Scn1a did not change voltage-dependent activation or inactivation of sodium channels in hippocampal neurons. However, the sodium current density was substantially reduced in inhibitory interneurons of Scn1a -/- and +/- mice. The findings suggested that reduced sodium currents in GABAergic inhibitory interneurons resulting from heterozygous SCN1A mutations may cause the hyperexcitability that leads to epilepsy in patients with SMEI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16921370" 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="#36" class="mim-tip-reference" title="Ogiwara, I., Miyamoto, H., Morita, N., Atapour, N., Mazaki, E., Inoue, I., Takeuchi, T., Itohara, S., Yanegawa, Y., Obata, K., Furuichi, T., Hensch, T. K., Yamakawa, K. <strong>Na(v)1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation.</strong> J. Neurosci. 27: 5903-5914, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17537961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17537961</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17537961[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/10.1523/JNEUROSCI.5270-06.2007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17537961">Ogiwara et al. (2007)</a> generated a knockin mouse line with a loss-of-function mutation in the Scn1a gene. Both homozygous and heterozygous mutant mice developed seizures within the first postnatal month. Homozygous mice also showed gait instability, and both groups showed early death. Immunohistochemical studies on wildtype mice showed relatively intense Scn1a expression in caudal brain parts, including the thalamus, superior colliculus, inferior colliculus, pons, medulla, deep cerebellar nuclei, and spinal cord, with lower expression in the hippocampus, cerebral cortex, and cerebellum. In the developing neocortex, Scn1a expression was clustered predominantly in axon initial segments of parvalbumin-positive interneurons and in nodes of Ranvier in the cerebellar white matter. Pyramidal neurons in the hippocampus showed low levels of Scn1a. Scn1a expression was absent in homozygous knockin mutant mice. In heterozygous mice, trains of evoked action potentials in fast-spiking inhibitory cells showed pronounced spike amplitude decrements late in the burst, suggesting that Scn1a is necessary to maintain but not initiate fast spiking. <a href="#36" class="mim-tip-reference" title="Ogiwara, I., Miyamoto, H., Morita, N., Atapour, N., Mazaki, E., Inoue, I., Takeuchi, T., Itohara, S., Yanegawa, Y., Obata, K., Furuichi, T., Hensch, T. K., Yamakawa, K. <strong>Na(v)1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation.</strong> J. Neurosci. 27: 5903-5914, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17537961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17537961</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17537961[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/10.1523/JNEUROSCI.5270-06.2007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17537961">Ogiwara et al. (2007)</a> concluded that haploinsufficiency of the Scn1a gene underlies seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17537961" 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="#30" class="mim-tip-reference" title="Martin, M. S., Tang, B., Papale, L. A., Yu, F. H., Catterall, W. A., Escayg, A. <strong>The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy.</strong> Hum. Molec. Genet. 16: 2892-2899, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17881658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17881658</a>] [<a href="https://doi.org/10.1093/hmg/ddm248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17881658">Martin et al. (2007)</a> showed that the seizure severity of heterozygous Scn1a +/- mice (see <a href="#54" class="mim-tip-reference" title="Yu, F. H., Mantegazza, M., Westenbroek, R. E., Robbins, C. A., Kalume, F., Burton, K. A., Spain, W. J., McKnight, G. S., Scheuer, T., Catterall, W. A. <strong>Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy.</strong> Nature Neurosci. 9: 1142-1149, 2006. Note: Erratum: Nature Neurosci. 10: 134 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16921370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16921370</a>] [<a href="https://doi.org/10.1038/nn1754" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16921370">Yu et al., 2006</a>), which is a mouse model for SMEI, was ameliorated by a heterozygous point mutation (med-jo) in the Scn8a gene (<a href="/entry/600702">600702</a>). Double-heterozygous Scn1a +/- and Scn8a +/(med-jo) mice had seizure thresholds that were comparable to wildtype littermates, and the Scn8a(med-jo) allele was also able to rescue the premature lethality of Scn1a +/- mice and extended the life span of Scn1a -/- mice. The authors hypothesized that the opposing effects of Scn1a and Scn8a dysfunction on seizure thresholds result from differences in the cell types that are influenced by the respective sodium channel subtypes. Scn1a mutants result in reduced sodium currents in inhibitory GABAergic interneurons of the hippocampus and cortex, whereas Scn8a mutants affect excitatory pyramidal cells of the hippocampus and cortex, suggesting that reduced excitability of these cells may underlie the elevated seizure resistance of Scn8a-mutant mice. <a href="#30" class="mim-tip-reference" title="Martin, M. S., Tang, B., Papale, L. A., Yu, F. H., Catterall, W. A., Escayg, A. <strong>The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy.</strong> Hum. Molec. Genet. 16: 2892-2899, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17881658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17881658</a>] [<a href="https://doi.org/10.1093/hmg/ddm248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17881658">Martin et al. (2007)</a> suggested that their results demonstrated that genetic interactions can alter seizure severity, and supported the hypothesis that genetic modifiers, including the SCN8A gene, contribute to the clinical variability observed in SMEI and GEFS+. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17881658+16921370" 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="#35" class="mim-tip-reference" title="Oakley, J. C., Kalume, F., Yu, F. H., Scheuer, T., Catterall, W. A. <strong>Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy.</strong> Proc. Nat. Acad. Sci. 106: 3994-3999, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19234123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19234123</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19234123[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0813330106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19234123">Oakley et al. (2009)</a> generated a mouse model of SMEI by targeted heterozygous deletion of the Scn1a gene. Mutant mice developed seizures induced by elevated core body temperature, whereas wildtype mice were unaffected. In 3 age groups studied, none of postnatal day (P) 17 to 18 mutant mice had temperature-induced seizures, but nearly all P20 to P22 and P30 to P46 mutant mice developed myoclonic seizures followed by generalized seizures caused by elevated core body temperature. There was an age-related susceptibility to seizures at lower temperatures as well as a general increase in severity of seizures with increasing age. Spontaneous seizures were only observed in mice older than P32, suggesting that mutant mice become susceptible to temperature-induced seizures before spontaneous seizures. Interictal EEG spike activity was seen at normal body temperature in most P30 to P46 mutant mice, but not in P20 to P22 or P17 to P18 mutant mice, indicating that interictal epileptic activity correlates with seizure susceptibility. Most P20 to P22 mutant mice had interictal spike activity with elevated body temperature. <a href="#35" class="mim-tip-reference" title="Oakley, J. C., Kalume, F., Yu, F. H., Scheuer, T., Catterall, W. A. <strong>Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy.</strong> Proc. Nat. Acad. Sci. 106: 3994-3999, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19234123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19234123</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19234123[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0813330106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19234123">Oakley et al. (2009)</a> concluded that their results defined a critical developmental transition for susceptibility to seizures in SMEI, demonstrated that body temperature elevation alone is sufficient to induce seizures in mutation carriers, and revealed a close correspondence between human and mouse SMEI in the temperature and age dependence of seizure frequency and severity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19234123" 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="#16" class="mim-tip-reference" title="Han, S., Tai, C., Westenbroek, R. E., Yu, F. H., Cheah, C. S., Potter, G. B., Rubenstein, J. L., Scheuer, T., de la Iglesia, H. O., Catterall, W. A. <strong>Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission.</strong> Nature 489: 385-390, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22914087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22914087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22914087[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22914087">Han et al. (2012)</a> reported that mice with Scn1a haploinsufficiency exhibit hyperactivity, stereotyped behaviors, social interaction deficits, and impaired context-dependent spatial memory. Olfactory sensitivity is retained, but novel food odors and social odors are aversive to Scn1a +/- mice. GABAergic neurotransmission is specifically impaired by this mutation, and selective deletion of Na(v)1.1 channels in forebrain interneurons is sufficient to cause these behavioral and cognitive impairments. Remarkably, treatment with low-dose clonazepam, a positive allosteric modulator of GABA(A) receptors, completely rescued the abnormal social behaviors and deficits in fear memory in the mouse model of Dravet syndrome (<a href="/entry/607208">607208</a>), demonstrating that they are caused by impaired GABAergic neurotransmission and not by neuronal damage from recurrent seizures. <a href="#16" class="mim-tip-reference" title="Han, S., Tai, C., Westenbroek, R. E., Yu, F. H., Cheah, C. S., Potter, G. B., Rubenstein, J. L., Scheuer, T., de la Iglesia, H. O., Catterall, W. A. <strong>Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission.</strong> Nature 489: 385-390, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22914087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22914087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22914087[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22914087">Han et al. (2012)</a> concluded that their results demonstrated a critical role for Na(v)1.1 channels in neuropsychiatric functions and provided a potential therapeutic strategy for cognitive deficit and autism spectrum behaviors in Dravet syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22914087" 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="#46" class="mim-tip-reference" title="Stein, R. E., Kaplan, J. S., Li, J., Catterall, W. A. <strong>Hippocampal deletion of Nav1.1 channels in mice causes thermal seizures and cognitive deficit characteristic of Dravet syndrome.</strong> Proc. Nat. Acad. Sci. 116: 16571-16576, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31346088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31346088</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31346088[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1906833116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31346088">Stein et al. (2019)</a> found that hippocampus-specific deletion of Scn1a in mice resulted in selective reduction in excitability of inhibitory neurons. It also induced thermally evoked seizures, as well as spatial learning and memory defects, as seen in mice with global deletion of Scn1a. However, unlike global deletion of Scn1a, hippocampal deletion of Scn1a did not cause hyperactivity or defects in cognitive abilities, social interaction, and context-dependent fear conditioning. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31346088" 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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<p>In a 3-generation pedigree segregating autosomal dominant generalized epilepsy with febrile seizures plus, type 2 (GEFSP2; <a href="/entry/604403">604403</a>) previously reported by <a href="#2" class="mim-tip-reference" title="Baulac, S., Gourfinkel-An, I., Picard, F., Rosenberg-Bourgin, M., Prud'homme, J.-F., Baulac, M., Brice, A., LeGuern, E. <strong>A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21-q33.</strong> Am. J. Hum. Genet. 65: 1078-1085, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10486327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10486327</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10486327[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10486327">Baulac et al. (1999)</a>, <a href="#12" class="mim-tip-reference" title="Escayg, A., MacDonald, B. T., Meisler, M. H., Baulac, S., Huberfeld, G., An-Gourfinkel, I., Brice, A., LeGuern, E., Moulard, B., Chaigne, D., Buresi, C., Malafosse, A. <strong>Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2.</strong> Nature Genet. 24: 343-345, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742094</a>] [<a href="https://doi.org/10.1038/74159" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742094">Escayg et al. (2000)</a> identified a G-to-A transition at nucleotide 4943 in exon 26 of the SCN1A gene that resulted in an amino acid substitution, arg1648 to his. This mutation causes loss of the MaeII site and cosegregated with GEFS+2 in this family. The mutation was identified in 1 asymptomatic individual and was interpreted as an example of incomplete penetrance. One seemingly affected individual did not carry the mutation, suggesting it as a phenocopy; this was previously suggested by haplotype reconstruction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10742094+10486327" 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>.0002 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918623 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918623;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=rs121918623" 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=rs121918623" 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=RCV000013743 OR RCV000059471 OR RCV000686817 OR RCV001253103 OR RCV001311218 OR RCV002316193 OR RCV004554602 OR RCV004724740" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013743, RCV000059471, RCV000686817, RCV001253103, RCV001311218, RCV002316193, RCV004554602, RCV004724740" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013743...</a>
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<p>In a family previously reported by <a href="#32" class="mim-tip-reference" title="Moulard, B., Guipponi, M., Chaigne, D., Mouthon, D., Buresi, C., Malafosse, A. <strong>Identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+) on chromosome 2q24-q33.</strong> Am. J. Hum. Genet. 65: 1396-1400, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10521305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10521305</a>] [<a href="https://doi.org/10.1086/302621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10521305">Moulard et al. (1999)</a> with GEFS+2 (GEFSP2; <a href="/entry/604403">604403</a>), <a href="#12" class="mim-tip-reference" title="Escayg, A., MacDonald, B. T., Meisler, M. H., Baulac, S., Huberfeld, G., An-Gourfinkel, I., Brice, A., LeGuern, E., Moulard, B., Chaigne, D., Buresi, C., Malafosse, A. <strong>Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2.</strong> Nature Genet. 24: 343-345, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742094/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742094</a>] [<a href="https://doi.org/10.1038/74159" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742094">Escayg et al. (2000)</a> identified a C-to-T transition at nucleotide 2624 of the SCN1A gene, resulting in an amino acid substitution thr875 to met. This mutation results from the loss of an Acl1 site. Eleven affected individuals and an obligate carrier were heterozygous for the mutation, whereas 4 unaffected relatives carried 2 normal alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10742094+10521305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121917953 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917953;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=rs121917953" 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=rs121917953" 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=RCV000013744 OR RCV000059448 OR RCV000636336" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013744, RCV000059448, RCV000636336" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013744...</a>
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<p>In affected members of a large multigenerational Australian family (family A) with GEFS+2 (GEFSP2; <a href="/entry/604403">604403</a>), <a href="#53" class="mim-tip-reference" title="Wallace, R. H., Scheffer, I. E., Barnett, S., Richards, M., Dibbens, L., Desai, R. R., Lerman-Sagie, T., Lev, D., Mazarib, A., Brand, N., Ben-Zeev, B., Goikhman, I., Singh, R., Kremmidiotis, G., Gardner, A., Sutherland, G. R., George, A. L., Jr., Mulley, J. C., Berkovic, S. F. <strong>Neuronal sodium-channel alpha-1-subunit mutations in generalized epilepsy with febrile seizures plus.</strong> Am. J. Hum. Genet. 68: 859-865, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254444</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254444[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/319516" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254444">Wallace et al. (2001)</a> identified a heterozygous c.563A-T transversion in exon 4 of the SCN1A gene, resulting in an asp188-to-val (D188V) substitution at a conserved residue. The family had previously been reported by <a href="#43" class="mim-tip-reference" title="Scheffer, I. E., Berkovic, S. F. <strong>Generalized epilepsy with febrile seizures plus: a genetic disorder with heterogeneous clinical phenotypes.</strong> Brain 120: 479-490, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9126059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9126059</a>] [<a href="https://doi.org/10.1093/brain/120.3.479" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9126059">Scheffer and Berkovic (1997)</a>. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11254444+9126059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span class="mim-font">
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<strong>.0004 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
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SCN1A, VAL1353LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121917954 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917954;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=rs121917954" 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=rs121917954" 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=RCV000013745 OR RCV000059409 OR RCV003992150" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013745, RCV000059409, RCV003992150" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013745...</a>
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<p>In affected members of an Ashkenazi Jewish family (family B) with GEFS+2 (GEFSP2; <a href="/entry/604403">604403</a>), <a href="#53" class="mim-tip-reference" title="Wallace, R. H., Scheffer, I. E., Barnett, S., Richards, M., Dibbens, L., Desai, R. R., Lerman-Sagie, T., Lev, D., Mazarib, A., Brand, N., Ben-Zeev, B., Goikhman, I., Singh, R., Kremmidiotis, G., Gardner, A., Sutherland, G. R., George, A. L., Jr., Mulley, J. C., Berkovic, S. F. <strong>Neuronal sodium-channel alpha-1-subunit mutations in generalized epilepsy with febrile seizures plus.</strong> Am. J. Hum. Genet. 68: 859-865, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254444</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254444[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/319516" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254444">Wallace et al. (2001)</a> used single-strand conformation analysis (SSCA) to identify a heterozygous c.4057G-C transversion in exon 21 of the SCN1A gene, resulting in a val1353-to-leu (V1353L) substitution at a highly conserved residue in the S5 segment of domain III. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11254444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121917955 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917955;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=rs121917955" 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=rs121917955" 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=RCV000013746 OR RCV000059433 OR RCV001385324 OR RCV003992151" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013746, RCV000059433, RCV001385324, RCV003992151" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013746...</a>
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<p>In affected members of a Druze family (family C) with GEFS+2 (GEFSP2; <a href="/entry/604403">604403</a>), <a href="#53" class="mim-tip-reference" title="Wallace, R. H., Scheffer, I. E., Barnett, S., Richards, M., Dibbens, L., Desai, R. R., Lerman-Sagie, T., Lev, D., Mazarib, A., Brand, N., Ben-Zeev, B., Goikhman, I., Singh, R., Kremmidiotis, G., Gardner, A., Sutherland, G. R., George, A. L., Jr., Mulley, J. C., Berkovic, S. F. <strong>Neuronal sodium-channel alpha-1-subunit mutations in generalized epilepsy with febrile seizures plus.</strong> Am. J. Hum. Genet. 68: 859-865, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254444</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254444[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/319516" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254444">Wallace et al. (2001)</a> identified a heterozygous c.4968C-G transversion in the SCN1A gene, resulting in an ile1656-to-met (I1656M) substitution in the S4 segment of domain IV. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11254444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121917930 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917930;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=rs121917930" 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=rs121917930" 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=RCV000013747 OR RCV000059402 OR RCV001091670" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013747, RCV000059402, RCV001091670" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013747...</a>
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<p><a href="#11" class="mim-tip-reference" title="Escayg, A., Heils, A., MacDonald, B. T., Haug, K., Sander, T., Meisler, M. H. <strong>A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy.</strong> Am. J. Hum. Genet. 68: 866-873, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254445[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/319524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254445">Escayg et al. (2001)</a> identified a T-to-C transition in exon 18 of the SCN1A gene, resulting in a trp1204-to-arg (W1204R) missense mutation, as the cause of GEFS+2 (GEFSP2; <a href="/entry/604403">604403</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11254445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1574272192 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1574272192;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=rs1574272192" 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=rs1574272192" 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=RCV000032603" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032603" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032603</a>
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<p>In a 4-year-old boy (EP153) with Dravet syndrome (DRVT; <a href="/entry/607208">607208</a>), <a href="#7" class="mim-tip-reference" title="Claes, L., Del-Favero, J., Ceulemans, B., Lagae, L., Van Broeckhoven, C., De Jonghe, P. <strong>De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.</strong> Am. J. Hum. Genet. 68: 1327-1332, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11359211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11359211</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11359211[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320609" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11359211">Claes et al. (2001)</a> identified a de novo heterozygous 2-bp deletion (c.657_658delAG) in exon 5 of the SCN1A gene, predicted to result in a frameshift and premature termination (Ser219fsTer275). Functional studies of the variant and studies of patient cells were not performed. The patient presented with seizures at 3 months of age; he died at 4 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11359211" 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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SCN1A, ARG222TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918624 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918624;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=rs121918624" 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=rs121918624" 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=RCV000032604 OR RCV000188841 OR RCV000763461 OR RCV001037392 OR RCV001257707 OR RCV002316194 OR RCV003388823" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032604, RCV000188841, RCV000763461, RCV001037392, RCV001257707, RCV002316194, RCV003388823" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032604...</a>
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<p>In a 6-year-old boy (EP78) with Dravet syndrome (DRVT; <a href="/entry/607208">607208</a>), <a href="#7" class="mim-tip-reference" title="Claes, L., Del-Favero, J., Ceulemans, B., Lagae, L., Van Broeckhoven, C., De Jonghe, P. <strong>De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.</strong> Am. J. Hum. Genet. 68: 1327-1332, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11359211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11359211</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11359211[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320609" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11359211">Claes et al. (2001)</a> identified a de novo heterozygous c.664C-T transition in exon 5 of the SCN1A gene, resulting in an arg222-to-ter (R222X) substitution. Functional studies of the variant and studies of patient cells were not performed. The patient developed seizures at 6 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11359211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0009" class="mim-anchor"></a>
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<strong>.0009 DRAVET SYNDROME</strong>
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SCN1A, LEU986PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918625 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918625;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=rs121918625" 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=rs121918625" 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=RCV000032605 OR RCV000794577" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032605, RCV000794577" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032605...</a>
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<p>In a 2-year-old girl (EP147) with Dravet syndrome (DRVT; <a href="/entry/607208">607208</a>), <a href="#7" class="mim-tip-reference" title="Claes, L., Del-Favero, J., Ceulemans, B., Lagae, L., Van Broeckhoven, C., De Jonghe, P. <strong>De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.</strong> Am. J. Hum. Genet. 68: 1327-1332, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11359211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11359211</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11359211[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/320609" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11359211">Claes et al. (2001)</a> identified a de novo heterozygous c.2956C-T transition in exon 16 of the SCN1A gene, resulting in a leu986-to-phe (L986F) substitution in the S6 region of domain II. Functional studies of the variant and studies of patient cells were not performed. She had onset of seizures at 4 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11359211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0010 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
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SCN1A, LYS1270THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918626 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918626;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=rs121918626" 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=rs121918626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013751 OR RCV000059501 OR RCV002513023" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013751, RCV000059501, RCV002513023" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013751...</a>
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<p>In a large family in which 27 members (18 still living) had febrile seizures accompanied in some by partial as well as generalized seizures (GEFSP2; <a href="/entry/604403">604403</a>), <a href="#1" class="mim-tip-reference" title="Abou-Khalil, B., Ge, Q., Desai, R., Ryther, R., Bazyk, A., Bailey, R., Haines, J. L., Sutcliffe, J. S., George, A. L., Jr. <strong>Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation.</strong> Neurology 57: 2265-2272, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11756608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11756608</a>] [<a href="https://doi.org/10.1212/wnl.57.12.2265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11756608">Abou-Khalil et al. (2001)</a> identified an A-to-C transversion at nucleotide 3809 of the SCN1A gene, resulting in a lys1270-to-thr (K1270T) substitution, in all affected members. The mutation was also present in 1 asymptomatic member, which was explained by the authors as incomplete penetrance. Pedigree analysis revealed autosomal dominant transmission. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11756608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0011 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
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SCN1A, VAL1428ALA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918627 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918627;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=rs121918627" 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=rs121918627" 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=RCV000013752 OR RCV000059508" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013752, RCV000059508" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013752...</a>
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<p>In a Japanese patient with GEFS+2 (GEFSP2; <a href="/entry/604403">604403</a>) associated with the development of partial epilepsy, <a href="#48" class="mim-tip-reference" title="Sugawara, T., Mazaki-Miyazaki, E., Ito, M., Nagafuji, H., Fukuma, G., Mitsudome, A., Wada, K., Kaneko, S., Hirose, S., Yamakawa, K. <strong>Na-v-1.1 mutations cause febrile seizures associated with afebrile partial seizures.</strong> Neurology 57: 703-705, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11524484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11524484</a>] [<a href="https://doi.org/10.1212/wnl.57.4.703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11524484">Sugawara et al. (2001)</a> identified a 4283T-C missense mutation in the SCN1A gene, resulting in a val1428-to-ala substitution. The mutation occurred in the pore-forming region of the sodium channel, which the authors hypothesized may affect ion selectivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11524484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<strong>.0012 MIGRAINE, FAMILIAL HEMIPLEGIC, 3</strong>
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SCN1A, GLN1489LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918628 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918628;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=rs121918628" 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=rs121918628" 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=RCV000013753 OR RCV003992152" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013753, RCV003992152" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013753...</a>
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<p>In affected members of 3 European families with familial hemiplegic migraine-3 (<a href="/entry/609634">609634</a>), <a href="#10" class="mim-tip-reference" title="Dichgans, M., Freilinger, T., Eckstein, G., Babini, E., Lorenz-Depiereux, B., Biskup, S., Ferrari, M. D., Herzog, J., van den Maagdenberg, A. M. J. M., Pusch, M., Strom, T. M. <strong>Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine.</strong> Lancet 366: 371-377, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16054936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16054936</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)66786-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16054936">Dichgans et al. (2005)</a> identified a heterozygous 4465C-A transversion in exon 23 of the SCN1A gene, resulting in a gln1489-to-lys (Q1489K) substitution in the cytoplasmic linker between domains III and IV, which is critical for fast inactivation. The mutation occurs in a highly conserved residue of the protein and was not identified in 1400 control chromosomes. Functional expression studies showed that the Q1489K substitution resulted in a 2- to 4-fold faster recovery from fast inactivation. The mutation was predicted to allow higher neuronal firing rates and enhanced excitability. <a href="#10" class="mim-tip-reference" title="Dichgans, M., Freilinger, T., Eckstein, G., Babini, E., Lorenz-Depiereux, B., Biskup, S., Ferrari, M. D., Herzog, J., van den Maagdenberg, A. M. J. M., Pusch, M., Strom, T. M. <strong>Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine.</strong> Lancet 366: 371-377, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16054936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16054936</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)66786-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16054936">Dichgans et al. (2005)</a> suggested that the mutation may facilitate initiation and propagation of cortical spreading depression, which is thought to be related to migraine aura. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16054936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0013" class="mim-anchor"></a>
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<strong>.0013 DRAVET SYNDROME</strong>
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GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2, INCLUDED
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SCN1A, THR1709ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918629 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918629;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=rs121918629" 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=rs121918629" 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=RCV000013754 OR RCV000013755 OR RCV001296128" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013754, RCV000013755, RCV001296128" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013754...</a>
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<p>In a patient with Dravet syndrome (DRVT; <a href="/entry/607208">607208</a>), <a href="#14" class="mim-tip-reference" title="Fujiwara, T., Sugawara, T., Mazaki-Miyazaki, E., Takahashi, Y., Fukushima, K., Watanabe, M., Hara, K., Morikawa, T., Yagi, K., Yamakawa, K., Inoue, Y. <strong>Mutations of sodium channel alpha-subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures.</strong> Brain 126: 531-546, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566275</a>] [<a href="https://doi.org/10.1093/brain/awg053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566275">Fujiwara et al. (2003)</a> identified a heterozygous c.5126C-T transition in the SCN1A gene, resulting in a thr1709-to-ile (T1709I) substitution in domain IV of the protein. The patient's mother, who also carried the mutation, had a history of febrile seizures consistent with GEFS+ (GEFSP2; <a href="/entry/604403">604403</a>). The T1709I substitution was not identified in 109 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12566275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0014" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0014 DRAVET SYNDROME</strong>
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</h4>
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<span class="mim-text-font">
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GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2, INCLUDED
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SCN1A, VAL1611PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918630 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918630;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121918630?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918630" 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=rs121918630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013756 OR RCV000013757" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013756, RCV000013757" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013756...</a>
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<span class="mim-text-font">
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<p>In a patient with a Dravet syndrome (DRVT; <a href="/entry/607208">607208</a>), <a href="#14" class="mim-tip-reference" title="Fujiwara, T., Sugawara, T., Mazaki-Miyazaki, E., Takahashi, Y., Fukushima, K., Watanabe, M., Hara, K., Morikawa, T., Yagi, K., Yamakawa, K., Inoue, Y. <strong>Mutations of sodium channel alpha-subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures.</strong> Brain 126: 531-546, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12566275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12566275</a>] [<a href="https://doi.org/10.1093/brain/awg053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12566275">Fujiwara et al. (2003)</a> identified a heterozygous c.4831G-T transversion in the SCN1A gene, resulting in a val1611-to-phe (V1611F) substitution in domain IV of the protein. The patient's mother, who also had the mutation, had a history of febrile seizures consistent with GEFS+ (GEFSP2; <a href="/entry/604403">604403</a>). The V1611F substitution was not identified in 93 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12566275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0015" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0015 FEBRILE SEIZURES, FAMILIAL, 3A</strong>
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</h4>
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SCN1A, MET145THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918631 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918631;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=rs121918631" 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=rs121918631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013758 OR RCV000255880 OR RCV000993711 OR RCV003595856 OR RCV003992153" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013758, RCV000255880, RCV000993711, RCV003595856, RCV003992153" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013758...</a>
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<p>In 12 affected members of an Italian family with simple febrile seizures-3 (FEB3A; see <a href="/entry/604403">604403</a>), <a href="#29" class="mim-tip-reference" title="Mantegazza, M., Gambardella, A., Rusconi, R., Schiavon, E., Annesi, F., Cassulini, R. R., Labate, A., Carrideo, S., Chifari, R., Canevini, M. P., Canger, R., Franceschetti, S., Annesi, G., Wanke, E., Quattrone, A. <strong>Identification of an Na(v)1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures.</strong> Proc. Nat. Acad. Sci. 102: 18177-18182, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16326807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16326807</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16326807[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0506818102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16326807">Mantegazza et al. (2005)</a> identified a heterozygous 434T-C transition in exon 3 of the SCN1A gene, resulting in a met145-to-thr (M145T) substitution of a highly conserved residue in the first transmembrane segment (S1) of domain I. The mutation was not identified in unaffected family members or in 50 control individuals. Functional expression studies showed that the M145T mutation resulted in a 60% reduction of current density and a 10-mV positive shift of the activation curve. <a href="#29" class="mim-tip-reference" title="Mantegazza, M., Gambardella, A., Rusconi, R., Schiavon, E., Annesi, F., Cassulini, R. R., Labate, A., Carrideo, S., Chifari, R., Canevini, M. P., Canger, R., Franceschetti, S., Annesi, G., Wanke, E., Quattrone, A. <strong>Identification of an Na(v)1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures.</strong> Proc. Nat. Acad. Sci. 102: 18177-18182, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16326807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16326807</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16326807[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0506818102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16326807">Mantegazza et al. (2005)</a> considered the findings consistent with a loss-of-function mutation. Three affected individuals later developed mesial temporal lobe epilepsy, 2 of whom had associated mesial temporal sclerosis on MRI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16326807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0016" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0016 FEBRILE SEIZURES, FAMILIAL, 3A, SUSCEPTIBILITY TO</strong>
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SCN1A, IVS5N+5G-A (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3812718;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3812718</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs3812718 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3812718;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs3812718?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs3812718" 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=rs3812718" 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=RCV000013759 OR RCV000211149 OR RCV001510181" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013759, RCV000211149, RCV001510181" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013759...</a>
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<p>In a 2-stage case-control study including a total of 234 patients with febrile seizures (FEB3A; see <a href="/entry/604403">604403</a>), <a href="#44" class="mim-tip-reference" title="Schlachter, K., Gruber-Sedlmayr, U., Stogmann, E., Lausecker, M., Hotzy, C., Balzar, J., Schuh, E., Baumgartner, C., Mueller, J. C., Illig, T., Wichmann, H. E., Lichtner, P., Meitinger, T., Strom, T. M., Zimprich, A., Zimprich, F. <strong>A splice site variant in the sodium channel gene SCN1A confers risk of febrile seizures.</strong> Neurology 72: 974-978, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19289736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19289736</a>] [<a href="https://doi.org/10.1212/01.wnl.0000344401.02915.00" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19289736">Schlachter et al. (2009)</a> found a significant association between the major A allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3812718;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3812718</a> and febrile seizures (first stage p value of 0.000017; replication p value of 0.00069). The data suggested that homozygosity for the A allele confers a 3-fold increased relative risk of febrile seizures and may account for a population attributable risk factor of up to 50%. The data were consistent with the hypothesis that low-risk variants with a high population frequency contribute to the risk of common and genetically complex diseases such as epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19289736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The SCN1A IVS5N+5G-A polymorphism, formerly SCN1A IVS5-91G-A (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3812718;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3812718</a>), was shown by <a href="#49" class="mim-tip-reference" title="Tate, S. K., Depondt, C., Sisodiya, S. M., Cavalleri, G. L., Schorge, S., Soranzo, N., Thom, M., Sen, A., Shorvon, S. D., Sander, J. W., Wood, N. W., Goldstein, D. B. <strong>Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin.</strong> Proc. Nat. Acad. Sci. 102: 5507-5512, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15805193[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0407346102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805193">Tate et al. (2005)</a> to affect the alternative splicing of exon 5. The major allele, A, disrupts the consensus sequence of fetal exon 5N, resulting in decreased expression of the fetal SCN1A isoform compared to the adult isoform. Among a total of 706 patients with epilepsy, <a href="#49" class="mim-tip-reference" title="Tate, S. K., Depondt, C., Sisodiya, S. M., Cavalleri, G. L., Schorge, S., Soranzo, N., Thom, M., Sen, A., Shorvon, S. D., Sander, J. W., Wood, N. W., Goldstein, D. B. <strong>Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin.</strong> Proc. Nat. Acad. Sci. 102: 5507-5512, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15805193[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0407346102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805193">Tate et al. (2005)</a> found maximum required antiepileptic drug dose to be lowest in patients with a GG genotype, intermediate in those with the GA genotype, and highest in those with the AA genotype. <a href="#49" class="mim-tip-reference" title="Tate, S. K., Depondt, C., Sisodiya, S. M., Cavalleri, G. L., Schorge, S., Soranzo, N., Thom, M., Sen, A., Shorvon, S. D., Sander, J. W., Wood, N. W., Goldstein, D. B. <strong>Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin.</strong> Proc. Nat. Acad. Sci. 102: 5507-5512, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15805193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15805193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15805193[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0407346102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15805193">Tate et al. (2005)</a> emphasized that their findings required replication. In a separate study by <a href="#50" class="mim-tip-reference" title="Tate, S. K., Singh, R., Hung, C.-C., Tai, J. J., Depondt, C., Cavalleri, G. L., Sisodiya, S. M., Goldstein, D. B., Liou, H.-H. <strong>A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose.</strong> Pharmacogenet. Genomics 16: 721-726, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17001291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17001291</a>] [<a href="https://doi.org/10.1097/01.fpc.0000230114.41828.73" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17001291">Tate et al. (2006)</a> that involved patients of Chinese ancestry, an association was found between SCN1A IVS5N+5G-A and phenytoin serum concentrations at maintenance dose; presence of the A allele was associated with higher doses. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15805193+17001291" 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="#18" class="mim-tip-reference" title="Heinzen, E. L., Yoon, W., Tate, S. K., Sen, A., Wood, N. W., Sisodiya, S. M., Goldstein, D. B. <strong>Nova2 interacts with a Cis-acting polymorphism to influence the proportions of drug-responsive splice variants of SCN1A.</strong> Am. J. Hum. Genet. 80: 876-883, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436242</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436242[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/516650" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436242">Heinzen et al. (2007)</a> found that in human brain tissue, the SCN1A IVS5N+5G-A polymorphism has a substantial effect on the percentage of transcripts containing exon 5N (neonatal form) of SCN1A. Individuals with the AA genotype had a mean of 0.7% of SCN1A transcripts in the neonatal form, whereas subjects with the GG genotype had 41% of transcripts containing exon 5N. The G allele elicited a dominant effect, with those with the AG genotype having 28% of transcripts in the neonatal form. <a href="#18" class="mim-tip-reference" title="Heinzen, E. L., Yoon, W., Tate, S. K., Sen, A., Wood, N. W., Sisodiya, S. M., Goldstein, D. B. <strong>Nova2 interacts with a Cis-acting polymorphism to influence the proportions of drug-responsive splice variants of SCN1A.</strong> Am. J. Hum. Genet. 80: 876-883, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436242</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436242[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/516650" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436242">Heinzen et al. (2007)</a> noted that individuals with the AA genotype require increased doses of antiepileptic drugs compared to those with the GG genotype, suggesting that patients with the AA genotype have a more severe form of epilepsy. Alternatively, the different splice forms may cause alterations in pharmacology, since the drugs act on the SCN1A gene. The authors noted that future work was required to elucidate the functional differences between the transcripts containing exons 5A and 5N. The findings emphasized an emerging role of genetic polymorphisms in modulation of drug effect, and illustrated the importance of considering the activity of compounds at alternative splice forms of drug targets. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17436242" 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="#41" class="mim-tip-reference" title="Petrovski, S., Scheffer, I. E., Sisodiya, S. M., O'Brien, T. J., Berkovic, S. F. <strong>Lack of replication of association between SCN1A SNP and febrile seizures.</strong> Neurology 73: 1928-1930, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19949041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19949041</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181c3fd6f" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19949041">Petrovski et al. (2009)</a> was unable to replicate the association between <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3812718;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3812718</a> and febrile seizures in a study of 558 Australian patients with seizures, including 76 (14%) with febrile seizures and 482 (86%) without febrile seizures. Only 10 (2%) had isolated febrile seizures. The association was also not replicated in a second cohort of 1,589 European patients with focal epilepsy, consisting of 232 with febrile seizures and 1,357 without febrile seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19949041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2105816922 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2105816922;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=rs2105816922" 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=rs2105816922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#4" class="mim-tip-reference" title="Buoni, S., Orrico, A., Galli, L., Zannolli, R., Burroni, L., Hayek, J., Fois, A., Sorrentino, V. <strong>SCN1A (2528delG) novel truncating mutation with benign outcome of severe myoclonic epilepsy of infancy.</strong> Neurology 66: 606-607, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16505326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16505326</a>] [<a href="https://doi.org/10.1212/01.WNL.0000198504.41315.B1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16505326">Buoni et al. (2006)</a> identified a de novo heterozygous 1-bp deletion (c.2528delG) in exon 14 of the SCN1A gene in a 13-year-old boy with generalized epilepsy with febrile seizures plus, type 2 (GEFSP2; <a href="/entry/604403">604403</a>). The mutation was predicted to result in a frameshift and premature termination of the protein at codon 853. The patient had prolonged febrile seizures at ages 6, 10, and 13 months, afebrile complex partial seizures with secondary generalization beginning at age 18 months, and 2 episodes of status epilepticus at age 2 years. He also had abnormal EEG findings and myoclonic jerks. Antiepileptic medication was unsuccessful. At age 4 years, the seizure frequency decreased in response to medication, and by age 9, he had complex partial seizures with secondary generalization. By age 13, he was treated with valproate and had a febrile seizure. He did not have intellectual disability. <a href="#4" class="mim-tip-reference" title="Buoni, S., Orrico, A., Galli, L., Zannolli, R., Burroni, L., Hayek, J., Fois, A., Sorrentino, V. <strong>SCN1A (2528delG) novel truncating mutation with benign outcome of severe myoclonic epilepsy of infancy.</strong> Neurology 66: 606-607, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16505326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16505326</a>] [<a href="https://doi.org/10.1212/01.WNL.0000198504.41315.B1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16505326">Buoni et al. (2006)</a> emphasized the relatively benign outcome in this patient despite a truncating mutation in the SCN1A gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16505326" 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 a patient with Dravet syndrome (DRVT; <a href="/entry/607208">607208</a>) manifest as severe myoclonic epilepsy of infancy (SMEI), <a href="#33" class="mim-tip-reference" title="Mulley, J. C., Nelson, P., Guerrero, S., Dibbens, L., Iona, X., McMahon, J. M., Harkin, L., Schouten, J., Yu, S., Berkovic, S. F., Scheffer, I. E. <strong>A new molecular mechanism for severe myoclonic epilepsy of infancy: exonic deletions in SCN1A.</strong> Neurology 67: 1094-1095, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17000989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17000989</a>] [<a href="https://doi.org/10.1212/01.wnl.0000237322.04338.2b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17000989">Mulley et al. (2006)</a> used multiplex ligation-dependent probe amplification (MLPA) to identify a de novo heterozygous deletion of exons 21 through 26 of the SCN1A gene. The phenotype was similar to SMEI patients with coding or splicing SCN1A mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17000989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000032608" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032608" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032608</a>
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<p>In a patient with Dravet syndrome (DRVT; <a href="/entry/607208">607208</a>) manifest as severe myoclonic epilepsy of infancy (SMEI), <a href="#33" class="mim-tip-reference" title="Mulley, J. C., Nelson, P., Guerrero, S., Dibbens, L., Iona, X., McMahon, J. M., Harkin, L., Schouten, J., Yu, S., Berkovic, S. F., Scheffer, I. E. <strong>A new molecular mechanism for severe myoclonic epilepsy of infancy: exonic deletions in SCN1A.</strong> Neurology 67: 1094-1095, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17000989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17000989</a>] [<a href="https://doi.org/10.1212/01.wnl.0000237322.04338.2b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17000989">Mulley et al. (2006)</a> used multiplex ligation-dependent probe amplification (MLPA) to identify a de novo heterozygous deletion of exon 21 of the SCN1A gene. Sequence analysis showed that the deletion was 6,499 bp in size and encompassed part of intron 20, all of exon 21, and part of intron 21. The phenotype was similar to SMEI patients with coding or splicing SCN1A mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17000989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1574061044 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1574061044;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=rs1574061044" 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=rs1574061044" 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=RCV000032609" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032609" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032609</a>
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<p>In a female patient with Dravet syndrome (DRVT; <a href="/entry/607208">607208</a>), <a href="#31" class="mim-tip-reference" title="McArdle, E. J., Kunic, J. D., George, A. L., Jr. <strong>Novel SCN1A frameshift mutation with absence of truncated Na(v)1.1 protein in severe myoclonic epilepsy of infancy. (Letter)</strong> Am. J. Med. Genet. 146A: 2421-2423, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18680191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18680191</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18680191[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.32448" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18680191">McArdle et al. (2008)</a> identified a heterozygous 1-bp deletion (c.3608delA) in the SCN1A gene, predicted to result in a frameshift and premature termination in the intracellular cytoplasmic linker region between domains D2 and D3. She died at age 5 years. Postmortem Western blot analysis of cerebellar tissue did not detect the truncated protein but only the full-length protein. However, RT-PCR analysis found expression of both alleles in cerebellar tissue from the patient, with slightly greater expression of the wildtype transcript. The findings indicated that nonsense-mediated mRNA decay could not explain the lack of mutant protein expression. <a href="#31" class="mim-tip-reference" title="McArdle, E. J., Kunic, J. D., George, A. L., Jr. <strong>Novel SCN1A frameshift mutation with absence of truncated Na(v)1.1 protein in severe myoclonic epilepsy of infancy. (Letter)</strong> Am. J. Med. Genet. 146A: 2421-2423, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18680191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18680191</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18680191[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.32448" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18680191">McArdle et al. (2008)</a> speculated that the mutant truncated protein may have been misfolded in the endoplasmic reticulum and then been targeted for ER-associated protein degradation, suggesting haploinsufficiency as the disease mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18680191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918632 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918632;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=rs121918632" 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=rs121918632" 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=RCV000013765 OR RCV001090363 OR RCV001857344 OR RCV003992154" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013765, RCV001090363, RCV001857344, RCV003992154" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013765...</a>
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<p>In affected members of a 3-generation French family with familial hemiplegic migraine (FHM3; <a href="/entry/609634">609634</a>), <a href="#52" class="mim-tip-reference" title="Vahedi, K., Depienne, C., Le Fort, D., Riant, F., Chaine, P., Trouillard, O., Gaudric, A., Morris, M. A., LeGuern, E., Tournier-Lasserve, E., Bousser, M.-G. <strong>Elicited repetitive daily blindness: a new phenotype associated with hemiplegic migraine and SCN1A mutations.</strong> Neurology 72: 1178-1183, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19332696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19332696</a>] [<a href="https://doi.org/10.1212/01.wnl.0000345393.53132.8c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19332696">Vahedi et al. (2009)</a> identified a heterozygous 4495T-C transition in exon 24 of the SCN1A gene, resulting in a phe1499-to-leu (F1499L) substitution in a highly conserved residue in an intracellular loop. The proband was an 18-year-old woman who also had episodes of elicited repetitive daily blindness (ERDB) that was temporally unrelated to the FHM episodes; her affected mother, sister, and maternal grandfather did not have episodic blindness. <a href="#52" class="mim-tip-reference" title="Vahedi, K., Depienne, C., Le Fort, D., Riant, F., Chaine, P., Trouillard, O., Gaudric, A., Morris, M. A., LeGuern, E., Tournier-Lasserve, E., Bousser, M.-G. <strong>Elicited repetitive daily blindness: a new phenotype associated with hemiplegic migraine and SCN1A mutations.</strong> Neurology 72: 1178-1183, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19332696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19332696</a>] [<a href="https://doi.org/10.1212/01.wnl.0000345393.53132.8c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19332696">Vahedi et al. (2009)</a> noted that ERDB has features of spreading depression in the retina, with propagation of the darkness from the periphery to the center and a refractory period. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19332696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918633 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918633;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=rs121918633" 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=rs121918633" 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=RCV000013766" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013766" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013766</a>
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<p>In 4 affected members of a Swiss family with familial hemiplegic migraine (FHM3; <a href="/entry/609634">609634</a>), previously reported by <a href="#23" class="mim-tip-reference" title="Le Fort, D., Safran, A. B., Picard, F., Bochardy, I., Morris, M. A. <strong>Elicited repetitive daily blindness: a new familial disorder related to migraine and epilepsy.</strong> Neurology 63: 348-350, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15277634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15277634</a>] [<a href="https://doi.org/10.1212/01.wnl.0000130251.59422.b4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15277634">Le Fort et al. (2004)</a>, <a href="#52" class="mim-tip-reference" title="Vahedi, K., Depienne, C., Le Fort, D., Riant, F., Chaine, P., Trouillard, O., Gaudric, A., Morris, M. A., LeGuern, E., Tournier-Lasserve, E., Bousser, M.-G. <strong>Elicited repetitive daily blindness: a new phenotype associated with hemiplegic migraine and SCN1A mutations.</strong> Neurology 72: 1178-1183, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19332696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19332696</a>] [<a href="https://doi.org/10.1212/01.wnl.0000345393.53132.8c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19332696">Vahedi et al. (2009)</a> identified a heterozygous 4467G-C transversion in exon 23 of the SCN1A gene, resulting in a gln1489-to-his (Q1489H) substitution in a highly conserved residue in an intracellular loop. All 4 affected family members also had episodes of elicited repetitive daily blindness (ERDB) that was temporally unrelated to the FHM episodes. <a href="#52" class="mim-tip-reference" title="Vahedi, K., Depienne, C., Le Fort, D., Riant, F., Chaine, P., Trouillard, O., Gaudric, A., Morris, M. A., LeGuern, E., Tournier-Lasserve, E., Bousser, M.-G. <strong>Elicited repetitive daily blindness: a new phenotype associated with hemiplegic migraine and SCN1A mutations.</strong> Neurology 72: 1178-1183, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19332696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19332696</a>] [<a href="https://doi.org/10.1212/01.wnl.0000345393.53132.8c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19332696">Vahedi et al. (2009)</a> noted that ERDB has features of spreading depression, with propagation of the darkness from the periphery to the center and a refractory period. A different mutation in this same codon has also been associated with FHM3 (Q1489K; <a href="#0012">182389.0012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19332696+15277634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514458 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514458;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=rs397514458" 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=rs397514458" 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=RCV000022764 OR RCV001379443" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022764, RCV001379443" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022764...</a>
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<p>In a female infant with Dravet syndrome (DRVT; <a href="/entry/607208">607208</a>) manifest clinically as 'malignant migrating partial seizures of infancy' (MPSI, MMPSI), <a href="#13" class="mim-tip-reference" title="Freilich, E. R., Jones, J. M., Gaillard, W. D., Conry, J. A., Tsuchida, T. N., Reyes, C., Dib-Hajj, S., Waxman, S. G., Meisler, M. H., Pearl, P. L. <strong>Novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy.</strong> Arch. Neurol. 68: 665-671, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21555645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21555645</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21555645[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/10.1001/archneurol.2011.98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21555645">Freilich et al. (2011)</a> identified a heterozygous c.5006C-A transversion in the SCN1A gene, resulting in an ala1669-to-glu (A1669E) substitution in a highly conserved residue in a cytoplasmic linker region between transmembrane segments 4 and 5 of domain 4. The mutation was predicted to be deleterious; functional studies were not performed. RT-PCR studies of the patient's brain matter showed that the mutant transcript was expressed similar to wildtype (ratio of 40:60). The patient was born by in vitro fertilization from a donor ovum and paternal sperm; the father did not carry the mutation, and DNA was not available from the ovum donor. The patient had a severe phenotype, with onset of seizures at age 10 weeks, progression to refractory recurrent seizures by age 5 months, status epilepticus, EEG evidence of migrating focal onset progressing to multifocal onset of seizures, progressive microcephaly, and profound psychomotor delay. She died at age 9 months. The findings expanded the severity of the phenotype associated with SCN1A mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21555645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397514459 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514459;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs397514459?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397514459" 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=rs397514459" 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=RCV000022765" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022765" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022765</a>
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<p>In an 8-year-old girl with Dravet syndrome (DRVT; <a href="/entry/607208">607208</a>) manifest clinically as 'malignant migrating partial seizures of infancy,' <a href="#5" class="mim-tip-reference" title="Carranza Rojo, D., Hamiwka, L., McMahon, J. M., Dibbens, L. M., Arsov, T., Suls, A., Stodberg, T., Kelley, K., Wirrell, E., Appleton, B., Mackay, M., Freeman, J. L., and 8 others. <strong>De novo SCN1A mutations in migrating partial seizures of infancy.</strong> Neurology 77: 380-383, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21753172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21753172</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318227046d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21753172">Carranza Rojo et al. (2011)</a> identified a de novo heterozygous c.2584C-G transversion in exon 14 of the SCN1A gene, resulting in an arg862-to-gly (R862G) substitution in the voltage sensor segment S4 of the second protein domain. The mutation was predicted to be deleterious; functional studies were not performed. The patient had onset of multifocal hemiclonic seizures at age 2 weeks with episodes of status epilepticus. She had acquired microcephaly, developmental regression, and severe intellectual disability. The findings expanded the severity of the phenotype associated with SCN1A mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21753172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0025 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 6B</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">rs886042528 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886042528;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=rs886042528" 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=rs886042528" 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=RCV001420525" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001420525" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001420525</a>
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<p>In a 6-year-old Japanese girl with developmental and epileptic encephalopathy-6B (DEE6B; <a href="/entry/619317">619317</a>), <a href="#37" class="mim-tip-reference" title="Ohashi, T., Akasaka, N., Kobayashi, Y., Magara, S., Kawashima, H., Matsumoto, N., Saitsu, H., Tohyama, J. <strong>Infantile epileptic encephalopathy with a hyperkinetic movement disorder and hand stereotypies associated with a novel SCN1A mutation.</strong> Epileptic Disord. 16: 208-212, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24776920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24776920</a>] [<a href="https://doi.org/10.1684/epd.2014.0649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24776920">Ohashi et al. (2014)</a> identified a de novo heterozygous c.1264G-T transversion in the SCN1A gene, resulting in a val422-to-leu (V422L) substitution in the transmembrane region S6 of the D1 domain. The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or in 408 in-house Japanese controls. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24776920" 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>.0026 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 6B</strong>
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SCN1A, THR226MET
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121917984 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917984;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=rs121917984" 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=rs121917984" 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=RCV000059454 OR RCV000188843 OR RCV000558296 OR RCV000763460 OR RCV001003956 OR RCV001420531 OR RCV002470755 OR RCV003764743" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000059454, RCV000188843, RCV000558296, RCV000763460, RCV001003956, RCV001420531, RCV002470755, RCV003764743" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000059454...</a>
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<p>In 8 unrelated children with developmental and epileptic encephalopathy-6B (DEE6B; <a href="/entry/619317">619317</a>), <a href="#42" class="mim-tip-reference" title="Sadleir, L. G., Mountier, E. I., Gill, D., Davis, S., Joshi, C., DeVile, C., Kurian, M. A., Mandelstam, S., Wirrell, E., Nickels, K. C., Murali, H. R., Carvill, G., Myers, C. T., Mefford, H. C., Scheffer, I. E. <strong>Not all SCN1A epileptic encephalopathies are Dravet syndrome: early profound thr226met phenotype.</strong> Neurology 89: 1035-1042, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28794249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28794249</a>] [<a href="https://doi.org/10.1212/WNL.0000000000004331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28794249">Sadleir et al. (2017)</a> identified a de novo heterozygous c.677C-T transition in exon 5 of the SCN1A gene, resulting in a thr226-to-met (T226M) substitution. The mutations were found by whole-exome or targeted sequencing. Functional studies of the variant were not performed, but the authors speculated a gain-of-function effect. The patients had onset of seizures between 6 and 12 weeks of age. Several patients had previously been reported, including patients 3 and 4 who had been reported by <a href="#9" class="mim-tip-reference" title="Dhamija, R., Erickson, M. K., St. Louis, E. K., Wirrell, E., Kotagal, S. <strong>Sleep abnormalities in children with Dravet syndrome.</strong> Pediat. Neurol. 50: 474-478, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24656210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24656210</a>] [<a href="https://doi.org/10.1016/j.pediatrneurol.2014.01.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24656210">Dhamija et al. (2014)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24656210+28794249" 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="#17" class="mim-tip-reference" title="Harkin, L. A., McMahon, J. M., Iona, X., Dibbens, L., Pelekanos, J. T., Zuberi, S. M., Sadleir, L. G., Andermann, E., Gill, D., Farrell, K., Connolly, M., Stanley, T., and 12 others. <strong>The spectrum of SCN1A-related infantile epileptic encephalopathies.</strong> Brain 130: 843-852, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17347258/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17347258</a>] [<a href="https://doi.org/10.1093/brain/awm002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17347258">Harkin et al. (2007)</a> had identified a de novo heterozygous T226M mutation in the SCN1A gene in a 5-year-old patient (patient 78) with onset of seizures at 2 months of age. The patient had severely impaired intellectual development and increased muscle tone. Another patient (patient 61) also carried the mutation; the latter patient was noted to have severe myoclonic epilepsy of infancy-borderland (SMEB), but clinical details were limited. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17347258" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0027 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 6B</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">rs1574006857 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1574006857;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=rs1574006857" 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=rs1574006857" 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=RCV000814237 OR RCV001420538" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000814237, RCV001420538" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000814237...</a>
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<p>In a 12-year-old boy (patient 9) with developmental and epileptic encephalopathy-6B (DEE6B; <a href="/entry/619317">619317</a>), <a href="#42" class="mim-tip-reference" title="Sadleir, L. G., Mountier, E. I., Gill, D., Davis, S., Joshi, C., DeVile, C., Kurian, M. A., Mandelstam, S., Wirrell, E., Nickels, K. C., Murali, H. R., Carvill, G., Myers, C. T., Mefford, H. C., Scheffer, I. E. <strong>Not all SCN1A epileptic encephalopathies are Dravet syndrome: early profound thr226met phenotype.</strong> Neurology 89: 1035-1042, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28794249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28794249</a>] [<a href="https://doi.org/10.1212/WNL.0000000000004331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28794249">Sadleir et al. (2017)</a> identified a de novo heterozygous c.4033C-T transition in the SCN1A gene, resulting in a pro1345-to-ser (P1345S) substitution. Functional studies of the variant were not performed. The patient had onset of epileptic spasms around 6 weeks of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28794249" 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>Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation.</strong>
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Neurology 57: 2265-2272, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11756608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11756608</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11756608" 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.57.12.2265" target="_blank">Full Text</a>]
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Baulac, S., Gourfinkel-An, I., Picard, F., Rosenberg-Bourgin, M., Prud'homme, J.-F., Baulac, M., Brice, A., LeGuern, E.
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<strong>A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21-q33.</strong>
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Am. J. Hum. Genet. 65: 1078-1085, 1999.
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[<a href="https://doi.org/10.1086/302593" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.WNL.0000198504.41315.B1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e318227046d" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.10217" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/320609" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2008.062323" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.pediatrneurol.2014.01.017" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0140-6736(05)66786-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/516650" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0813330106" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1684/epd.2014.0649" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3181c3fd6f" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000344401.02915.00" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17001291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17001291</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17001291" 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/10.1097/01.fpc.0000230114.41828.73" target="_blank">Full Text</a>]
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<a id="51" class="mim-anchor"></a>
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<a id="Thompson2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thompson, C. H., Porter, J. C., Kahling, K. M., Daniels, M. A., George, A. L., Jr.
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<strong>Nontruncating SCN1A mutations associated with severe myoclonic epilepsy of infancy impair cell surface expression.</strong>
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J. Biol. Chem. 287: 42001-42008, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23086956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23086956</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23086956" 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/10.1074/jbc.M112.421883" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="52" class="mim-anchor"></a>
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<a id="Vahedi2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vahedi, K., Depienne, C., Le Fort, D., Riant, F., Chaine, P., Trouillard, O., Gaudric, A., Morris, M. A., LeGuern, E., Tournier-Lasserve, E., Bousser, M.-G.
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<strong>Elicited repetitive daily blindness: a new phenotype associated with hemiplegic migraine and SCN1A mutations.</strong>
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Neurology 72: 1178-1183, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19332696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19332696</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19332696" 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/10.1212/01.wnl.0000345393.53132.8c" target="_blank">Full Text</a>]
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<li>
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<a id="53" class="mim-anchor"></a>
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<a id="Wallace2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wallace, R. H., Scheffer, I. E., Barnett, S., Richards, M., Dibbens, L., Desai, R. R., Lerman-Sagie, T., Lev, D., Mazarib, A., Brand, N., Ben-Zeev, B., Goikhman, I., Singh, R., Kremmidiotis, G., Gardner, A., Sutherland, G. R., George, A. L., Jr., Mulley, J. C., Berkovic, S. F.
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<strong>Neuronal sodium-channel alpha-1-subunit mutations in generalized epilepsy with febrile seizures plus.</strong>
|
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Am. J. Hum. Genet. 68: 859-865, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254444</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254444[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=11254444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/319516" target="_blank">Full Text</a>]
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<a id="54" class="mim-anchor"></a>
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<a id="Yu2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yu, F. H., Mantegazza, M., Westenbroek, R. E., Robbins, C. A., Kalume, F., Burton, K. A., Spain, W. J., McKnight, G. S., Scheuer, T., Catterall, W. A.
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<strong>Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy.</strong>
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Nature Neurosci. 9: 1142-1149, 2006. Note: Erratum: Nature Neurosci. 10: 134 only, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16921370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16921370</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16921370" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nn1754" target="_blank">Full Text</a>]
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<li>
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<a id="55" class="mim-anchor"></a>
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<a id="Zucca2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zucca, C., Redaelli, F., Epifanio, R., Zanotta, N., Romeo, A., Lodi, M., Veggiotti, P., Airoldi, G., Panzeri, C., Romaniello, R., De Polo, G., Bonanni, P., Cardinali, S., Baschirotto, C., Martorell, L., Borgatti, R., Bresolin, N., Bassi, M. T.
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<strong>Cryptogenic epileptic syndromes related to SCN1A: twelve novel mutations identified.</strong>
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Arch. Neurol. 65: 489-494, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18413471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18413471</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18413471" 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/10.1001/archneur.65.4.489" target="_blank">Full Text</a>]
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</ol>
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<br />
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</div>
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </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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Cassandra L. Kniffin - updated : 05/10/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 10/01/2020<br>Bao Lige - updated : 01/13/2020<br>Paul J. Converse - updated : 08/10/2016<br>Ada Hamosh - updated : 11/1/2012<br>Joanna S. Amberger - updated : 1/20/2012<br>Cassandra L. Kniffin - updated : 10/5/2011<br>Cassandra L. Kniffin - updated : 1/24/2011<br>Ada Hamosh - updated : 8/17/2010<br>Cassandra L. Kniffin - updated : 6/1/2010<br>Cassandra L. Kniffin - updated : 1/25/2010<br>Cassandra L. Kniffin - updated : 10/15/2009<br>Cassandra L. Kniffin - updated : 8/18/2009<br>Cassandra L. Kniffin - updated : 6/17/2009<br>Cassandra L. Kniffin - updated : 6/1/2009<br>Cassandra L. Kniffin - updated : 5/18/2009<br>Cassandra L. Kniffin - updated : 3/3/2009<br>Cassandra L. Kniffin - updated : 1/6/2009<br>Cassandra L. Kniffin - updated : 8/2/2007<br>Cassandra L. Kniffin - updated : 6/25/2007<br>Victor A. McKusick - updated : 5/1/2007<br>Cassandra L. Kniffin - updated : 12/21/2005<br>Cassandra L. Kniffin - updated : 11/14/2005<br>Cassandra L. Kniffin - updated : 11/3/2005<br>Victor A. McKusick - updated : 8/9/2005<br>Cassandra L. Kniffin - updated : 6/9/2005<br>Cassandra L. Kniffin - updated : 1/26/2005<br>Victor A. McKusick - updated : 7/11/2003<br>Cassandra L. Kniffin - updated : 11/12/2002<br>Victor A. McKusick - updated : 9/30/2002<br>Cassandra L. Kniffin - reorganized : 9/25/2002<br>Victor A. McKusick - updated : 8/28/2002<br>Cassandra L. Kniffin - updated : 5/24/2002<br>Victor A. McKusick - updated : 6/20/2001<br>Victor A. McKusick - updated : 5/3/2001<br>Ada Hamosh - updated : 3/29/2000
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</span>
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</div>
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</div>
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<div>
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<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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</span>
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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 : 6/20/1991
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 08/01/2023
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</span>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 05/18/2021<br>alopez : 05/17/2021<br>ckniffin : 05/10/2021<br>carol : 10/09/2020<br>ckniffin : 10/01/2020<br>carol : 09/01/2020<br>carol : 01/21/2020<br>mgross : 01/15/2020<br>mgross : 01/13/2020<br>carol : 12/15/2017<br>carol : 07/28/2017<br>carol : 07/18/2017<br>carol : 07/17/2017<br>mgross : 08/10/2016<br>mgross : 08/10/2016<br>joanna : 04/22/2014<br>carol : 8/15/2013<br>alopez : 12/4/2012<br>alopez : 11/2/2012<br>alopez : 11/2/2012<br>terry : 11/1/2012<br>carol : 1/20/2012<br>carol : 10/11/2011<br>ckniffin : 10/5/2011<br>carol : 4/18/2011<br>ckniffin : 4/12/2011<br>ckniffin : 2/9/2011<br>ckniffin : 2/9/2011<br>wwang : 2/9/2011<br>ckniffin : 1/24/2011<br>ckniffin : 12/20/2010<br>ckniffin : 12/20/2010<br>wwang : 12/7/2010<br>terry : 11/3/2010<br>alopez : 8/20/2010<br>terry : 8/17/2010<br>carol : 7/30/2010<br>carol : 6/11/2010<br>wwang : 6/4/2010<br>ckniffin : 6/1/2010<br>wwang : 2/1/2010<br>ckniffin : 1/25/2010<br>wwang : 11/12/2009<br>ckniffin : 10/15/2009<br>wwang : 10/12/2009<br>wwang : 9/10/2009<br>ckniffin : 9/3/2009<br>ckniffin : 8/18/2009<br>wwang : 7/17/2009<br>ckniffin : 6/17/2009<br>wwang : 6/9/2009<br>ckniffin : 6/1/2009<br>wwang : 6/1/2009<br>ckniffin : 5/18/2009<br>wwang : 4/15/2009<br>ckniffin : 3/3/2009<br>wwang : 1/13/2009<br>ckniffin : 1/6/2009<br>terry : 9/18/2007<br>wwang : 8/16/2007<br>ckniffin : 8/2/2007<br>wwang : 6/29/2007<br>ckniffin : 6/25/2007<br>alopez : 5/7/2007<br>terry : 5/1/2007<br>carol : 10/4/2006<br>carol : 10/4/2006<br>wwang : 2/2/2006<br>wwang : 2/1/2006<br>ckniffin : 12/21/2005<br>ckniffin : 11/21/2005<br>carol : 11/19/2005<br>ckniffin : 11/14/2005<br>wwang : 11/14/2005<br>ckniffin : 11/3/2005<br>alopez : 8/9/2005<br>wwang : 7/26/2005<br>wwang : 7/21/2005<br>ckniffin : 6/9/2005<br>tkritzer : 2/2/2005<br>ckniffin : 1/26/2005<br>cwells : 7/16/2003<br>terry : 7/11/2003<br>cwells : 11/26/2002<br>ckniffin : 11/12/2002<br>alopez : 9/30/2002<br>carol : 9/25/2002<br>ckniffin : 9/24/2002<br>carol : 9/23/2002<br>tkritzer : 9/6/2002<br>tkritzer : 9/5/2002<br>tkritzer : 8/30/2002<br>terry : 8/28/2002<br>carol : 5/24/2002<br>ckniffin : 5/24/2002<br>cwells : 7/2/2001<br>cwells : 6/25/2001<br>terry : 6/20/2001<br>mcapotos : 5/16/2001<br>mcapotos : 5/7/2001<br>terry : 5/3/2001<br>alopez : 4/17/2001<br>carol : 10/16/2000<br>alopez : 3/31/2000<br>alopez : 3/30/2000<br>terry : 3/29/2000<br>kayiaros : 7/8/1999<br>terry : 10/31/1994<br>carol : 6/7/1994<br>warfield : 4/14/1994<br>carol : 12/14/1993<br>supermim : 3/16/1992<br>carol : 2/23/1992
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</span>
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<div class="container visible-print-block">
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 182389
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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SODIUM VOLTAGE-GATED CHANNEL, ALPHA SUBUNIT 1; SCN1A
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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SODIUM CHANNEL, NEURONAL TYPE I, ALPHA SUBUNIT<br />
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SODIUM CHANNEL, BRAIN TYPE I, ALPHA SUBUNIT; NAC1<br />
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NAV1.1
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SCN1A</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 230437002;
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<strong>ICD10CM:</strong> G40.83, G40.834;
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</p>
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<div>
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<br />
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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: 2q24.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:165,984,641-166,149,161 </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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<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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<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="5">
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<span class="mim-font">
|
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2q24.3
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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 6B, non-Dravet
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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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619317
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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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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Dravet syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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607208
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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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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Febrile seizures, familial, 3A
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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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604403
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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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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Generalized epilepsy with febrile seizures plus, type 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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604403
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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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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Migraine, familial hemiplegic, 3
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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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609634
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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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</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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<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>TEXT</strong>
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</span>
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</h4>
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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 vertebrate sodium channel is a voltage-gated ion channel essential for the generation and propagation of action potentials, chiefly in nerve and muscle. Voltage-sensitive sodium channels are heteromeric complexes consisting of a large central pore-forming glycosylated alpha subunit and 2 smaller auxiliary beta subunits. Functional studies have indicated that the transmembrane alpha subunit of the brain sodium channels is sufficient for expression of functional sodium channels (Goldin et al., 1986; Isom, 2002). </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>Escayg et al. (2000) determined the coding sequence of the human SCN1A gene by aligning the rat cDNA sequence with genomic sequence. The deduced amino acid sequence of the 2,009-residue human SCN1A protein was determined. Human SCN1A is highly conserved, with 98% amino acid sequence identity to the corresponding rat sequence. </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 Structure</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>Escayg et al. (2000) determined that the SCN1A gene has 26 exons. Its intron-exon organization is identical to that of SCN8A (600702) at chromosome 12q13 and probably corresponds to that of the ancestral gene. </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>In the mouse, Malo et al. (1991) showed that Scn1a and Scn2a are tightly linked and separated by a distance of 0.7 cM. The latter gene (SCN2A; 182390) had been mapped to chromosome 2 in both man and mouse; by homology, SCN1A would be located on human chromosome 2. </p><p>By fluorescence in situ hybridization, Malo et al. (1994, 1994) mapped the SCN1A gene to chromosome 2q24. Escayg et al. (2000) confirmed the location of SCN1A within the candidate region for generalized epilepsy with febrile seizures plus, type 2 (GEFSP2; 604403) by typing the GB4 radiation hybrid panel with primers for intron 21, further localizing the SCN1A gene to the 4-cM interval between D2S156 and D2S399. </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 Function</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 axon initial segment (AIS) is the site at which neural signals arise, and should be the most efficient site to regulate neural activity. Kuba et al. (2010) reported that deprivation of auditory input in an avian brainstem auditory neuron leads to an increase in AIS length, thus augmenting the excitability of the neuron. The length of the AIS, defined by the distribution of voltage-gated sodium channels and the AIS anchoring protein, ankyrin G (106410), increased by 1.7 times in 7 days after auditory input deprivation. This was accompanied by an increase in the whole-cell sodium current, membrane excitability, and spontaneous firing. Kuba et al. (2010) concluded that their work demonstrated homeostatic regulations of the AIS, which may contribute to the maintenance of the auditory pathway after hearing loss. Furthermore, plasticity at the spike initiation site suggests a powerful pathway for refining neuronal computation in the face of strong sensory deprivation. </p><p>Osteen et al. (2016) identified and characterized tarantula toxins that selectively activated human and rodent NAV1.1. Using the spider toxin probes in mice, they showed that activated Nav1.1-expressing fibers elicited robust pain behavior without neurogenic inflammation and produced profound hypersensitivity to mechanical, but not thermal, stimuli. Mechanosensitive fibers expressing Nav1.1 were also present in gut and showed enhanced toxin sensitivity in a mouse model of irritable bowel syndrome. Osteen et al. (2016) concluded that NAV1.1 contributes to peripheral pain signaling, by both acute and repetitive mechanical stimulation, through myelinated afferent fibers expressing the receptor. </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">
|
|
<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">
|
|
<p>Mulley et al. (2005) stated that of all the known epilepsy genes, SCN1A was the most clinically relevant, with the largest number of epilepsy-related mutations characterized to that time. </p><p><strong><em>Generalized Epilepsy with Febrile Seizures Plus, Type 2</em></strong></p><p>
|
|
Baulac et al. (1999) and Moulard et al. (1999) reported 2 unrelated families with generalized epilepsy with febrile seizures plus who showed linkage to a locus on chromosome 2q21-q33, consistent with GEFS+ type 2 (GEFSP2; 604403). Using conformation-sensitive gel electrophoresis to scan the 26 exons of the SCN1A gene from 1 affected and 1 unaffected individual from each of these families, Escayg et al. (2000) identified 2 missense mutations. The mutant residues thr875 (see 182389.0002) and arg1648 (see 182389.0001) are located in the S4 transmembrane segments of the sodium channel alpha-subunit, which is composed of 4 homologous domains (D1-D4), each containing 6 transmembrane segments. The functional importance of the mutations was supported by the evolutionary conservation in other mammalian gene family members and in lower vertebrates and invertebrates. </p><p>Escayg et al. (2001) identified an additional SCN1A mutation (W1204R; 182389.0006) in a family with GEFS+2, but concluded that SCN1A is not a major contributor to idiopathic generalized epilepsy (EIG; 600669). </p><p>In affected members of 3 unrelated families with GEFS+2, Wallace et al. (2001) identified heterozygous missense mutations in the SCN1A gene: family A, the Australian family originally reported by Scheffer and Berkovic (1997), had a D188V mutation (182389.0003); family B, of Ashkenazi Jewish descent, had a V1353L mutation (182389.0004); and family C, of Druze origin, carried an I1656M mutation (182389.0005). Functional studies of the variants and studies of patient cells were not performed, but the authors noted that all occurred in functional domains and may result in neuronal hyperexcitability. </p><p>Orrico et al. (2009) identified 21 mutations, including 14 novel mutations, in the SCN1A gene in 22 (14.66%) of 150 Italian pediatric probands with epilepsy. SCN1A mutations were found in 21.2% of patients with GEFS+ and in 75% of patients with Dravet syndrome from the overall patient cohort. Only 1 potentially pathogenic mutation was identified in the SCN1B gene (600235), and no mutations were found in the GABRG2 gene (137164). </p><p><strong><em>Dravet Syndrome</em></strong></p><p>
|
|
Mutation in the SCN1A gene can cause a spectrum of early-onset epileptic encephalopathies, with the most common designation being Dravet syndrome (DRVT; 607208) (summary by Carranza Rojo et al., 2011). </p><p>Because both GEFS+ and Dravet syndrome, also known as severe myoclonic epilepsy of infancy (SMEI), involve fever-associated seizures, and because GEFS+ is associated with mutations in the SCN1A gene, Claes et al. (2001) screened 7 unrelated Belgian patients with SMEI for mutations in SCN1A. They identified de novo heterozygous mutations in each patient (see, e.g., 182389.0007-182389.0009). The mutations included 4 frameshifts, 1 nonsense, 1 splice site, and 1 missense. Functional studies of the variant and studies of patient cells were not performed. </p><p>In 14 patients, including a pair of monozygotic twins, with classic symptoms of SMEI, Sugawara et al. (2002) identified 10 heterozygous mutations in the SCN1A gene. There were 3 frameshift mutations that resulted in intragenic stop codons and truncated channels, and 7 nonsense mutations which also resulted in truncated channels. </p><p>In 29 patients with severe myoclonic epilepsy of infancy and 11 patients with other types of epilepsy, Ohmori et al. (2002) performed a mutation search of the SCN1A gene. They detected de novo heterozygous mutations in 24 of the 29 patients with SMEI, but in none of the patients with other types of epilepsy. The mutations included deletions, insertions, missense changes, and nonsense changes. The authors found no mutations in the SCN1B or GABRG2 (137164) genes. </p><p>Claes et al. (2003) investigated 9 patients with Dravet syndrome and observed 8 coding and 1 noncoding mutation in the SCN1A gene. In contrast to a previous study of 7 isolated patients (Claes et al., 2001), most mutations were found to be missense mutations clustering in the S4-S6 region of SCN1A. These findings demonstrated that de novo mutations in SCN1A are a major cause of isolated Dravet syndrome. </p><p>In 7 of 10 unrelated patients with intractable childhood epilepsy with generalized tonic-clonic seizures, a variant of Dravet syndrome without myoclonus, Fujiwara et al. (2003) identified heterozygous mutations in the SCN1A gene (see, e.g., 182389.0013; 182389.0014). All of the mutations were missense mutations. The findings extended the phenotypic spectrum associated with mutations in the SCN1A gene. </p><p>Using multiplex ligation-dependent probe amplification (MLPA), Mulley et al. (2006) identified exon deletions in the SCN1A gene (182389.0018 and 182389.0019) in 2 (15%) of 13 unrelated SMEI patients who did not have point or splice site mutations in the SCN1A gene. The findings provided a new molecular mechanism for the disorder. </p><p>Zucca et al. (2008) identified 13 mutations, including 12 novel mutations, in the SCN1A gene in 12 (20%) of 60 unrelated patients with cryptogenic epilepsy beginning in the first 2 years of life. Ten patients had SMEI, and 1 had GEFS+. The twelfth patient had severe mental retardation and generalized tonic-clonic seizures, which evolved to hemiclonic seizures suggestive of focal epilepsy; this phenotype was considered to be a variable expression of SMEI. No large deletions in the SCN1A gene were identified. </p><p>Depienne et al. (2009) identified pathogenic mutations or deletions, including 161 novel point mutations, in the SCN1A gene in 242 (73%) of 333 patients with Dravet syndrome. The most common mutations were missense (42%), and 14 patients had microrearrangements in or deletions of the gene. Thus, the disease mechanism appeared to be haploinsufficiency of the SCN1A gene. Mutations were scattered throughout the gene, and there were no apparent genotype/phenotype correlations. </p><p>Orrico et al. (2009) identified 21 mutations, including 14 novel mutations, in the SCN1A gene in 22 (14.66%) of 150 Italian pediatric probands with epilepsy. SCN1A mutations were found in 21.2% of patients with GEFS+ and in 75% of patients with Dravet syndrome from the overall patient cohort. Only 1 potentially pathogenic mutation was identified in the SCN1B gene (600235), and no mutations were found in the GABRG2 gene (137164). </p><p>Singh et al. (2009) presented preliminary evidence that mutations in the SCN9A gene (603415) may act as a genetic modifier of Dravet syndrome when found in conjunction with an SCN1A mutation. They identified mutations in the SCN9A gene in 9 (8%) of 109 patients with Dravet syndrome, including 6 with SCN1A mutation and 3 without SCN1A mutation. </p><p>Using Western blot analysis and ELISA, Thompson et al. (2012) showed that 7 different nontruncating SCN1A mutations associated with SMEI, including R1648C, impaired trafficking of SCN1A and reduced its cell surface expression. Treatment with the antiepileptic drugs phenytoin or lamotrigine increased the cell surface expression of R1648C and restored its voltage-gated sodium channel function. However, lamotrigine also increased persistent sodium current mediated by R1648C. Phenytoin increased surface expression of another mutant channel but did not restore its channel function, suggesting that some SCN1A mutations also cause intrinsic loss of function. </p><p><strong><em>Familial Hemiplegic Migraine 3</em></strong></p><p>
|
|
In affected members of 3 European families with familial hemiplegic migraine-3 (FHM3; 609634), Dichgans et al. (2005) identified a heterozygous mutation in the SCN1A gene (182389.0012). </p><p><strong><em>Familial Febrile Seizures 3A</em></strong></p><p>
|
|
In affected members of an Italian family with familial febrile convulsions-3A (FEB3A; see 604403), Mantegazza et al. (2005) identified heterozygosity for a mutation in the SCN1A gene (182389.0015). </p><p><strong><em>Developmental and Epileptic Encephalopathy 6B</em></strong></p><p>
|
|
In a 6-year-old Japanese girl with developmental and epileptic encephalopathy-6B (DEE6B; 619317), Ohashi et al. (2014) identified a de novo heterozygous missense mutation in the SCN1A gene (V422L; 182389.0025). The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or in 408 in-house Japanese controls. Functional studies of the variant were not performed. </p><p>In 8 unrelated patients with DEE6B, Sadleir et al. (2017) identified a de novo recurrent heterozygous missense mutation in the SCN1A gene (T226M; 182389.0026). Another patient (patient 9) carried a different de novo heterozygous missense mutation (P1345S; 182389.0027). Functional studies of the variants were not performed, but the authors speculated a gain-of-function effect. </p><p><strong><em>Studies of SCN1A Protein Variants</em></strong></p><p>
|
|
Lossin et al. (2002) characterized the functional effects of 3 mutations in SCN1A by heterologous expression with its accessory subunits, SCN1B and SCN2B (601327), in cultured mammalian cells. SCN1A mutations altered channel inactivation, resulting in persistent inward sodium current. This gain-of-function abnormality was expected to enhance excitability of neuronal membranes by causing prolonged membrane depolarization, a plausible underlying biophysical mechanism responsible for autosomal dominant generalized epilepsy with febrile seizures plus. </p><p>Tate et al. (2005) identified a G-to-A polymorphism in the SCN1A gene (rs3812718; 182389.0016) that affects alternative splicing of exon 5. The major A allele disrupts the consensus sequence of the fetal/neonatal exon 5N, reducing the expression of this exon relative to the adult exon 5A. Two antiepileptic drugs, carbamazepine and phenytoin, act by binding to the alpha-subunit of neuronal sodium channels encoded by SCN1A. Among 425 and 281 epileptic patients treated with carbamazepine and phenytoin, respectively, Tate et al. (2005) found a significant association with the rs3812718 polymorphism and maximum dose needed to control symptoms; those with the G allele (and the neonatal SCN1A isoform) needed less medication. Maximum doses of carbamazepine averaged 1,313, 1,225, and 1,083 mg for AA, AG, and GG individuals, respectively; maximum doses of phenytoin averaged 373, 340, and 326 mg, for AA, AG, and GG individuals, respectively, suggesting a trend of reduction in maximum dose required according to genotype. </p><p>Heinzen et al. (2007) found that individuals with the G allele of rs3812718 had significantly increased levels of SCN1A transcripts containing exon 5N, consistent with the neonatal isoform, compared to those with the A allele. In addition, the G allele exhibited a dominant effect. These results were confirmed in a minigene expression system. Further studies in the minigene expression system suggested a role for NOVA2 (601991) in the regulation of splicing, with higher NOVA2 expression increasing the proportion of the neonate isoform including exon 5N; this effect was seen particularly with the AA genotype. Heinzen et al. (2007) noted that individuals with the AA genotype require increased doses of antiepileptic drugs compared to those with the GG genotype, suggesting that patients with the AA genotype have a more severe form of epilepsy. Alternatively, the different splice forms may cause alterations in pharmacology, since the drugs act on the SCN1A gene. The findings emphasized an emerging role of genetic polymorphisms in modulation of drug effect, and illustrated the importance of considering the activity of compounds at alternative splice forms of drug targets. </p><p>Petrovski et al. (2009) was unable to replicate the association between rs3812718 and febrile seizures in a study of 558 Australian patients with seizures, including 76 (14%) with febrile seizures and 482 (86%) without febrile seizures. Only 10 (2%) had isolated febrile seizures. The association was also not replicated in a second cohort of 1,589 European patients with focal epilepsy, consisting of 232 with febrile seizures and 1,357 without febrile seizures. </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">
|
|
<strong>Genotype/Phenotype Correlations</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 an analysis of 14 GEFS+ and 60 SMEI SCN1A missense mutations previously reported, Kanai et al. (2004) found that mutations in SMEI occurred more frequently in the 'pore' regions of SCN1A than did those in GEFS+. The SMEI pore region mutations were more strongly associated with the presence of ataxia and slightly earlier onset compared to mutations in other regions of the gene. Although the genotype-phenotype correlation was statistically significant, SMEI mutations also occurred outside the pore region and GEFS+ mutations occurred inside the pore region. Three SCN1A mutations were identified in both groups. </p><p>Mulley et al. (2005) found that the more than 100 epilepsy-associated mutations reported in the SCN1A gene to that time were spread throughout the gene. Some clustering of mutations was observed in the C terminus and the loops between segments 5 and 6 of the first 3 domains of the protein. </p><p>Kanai et al. (2009) performed a metaanalysis of the physiochemical effects of amino acid substitutions resulting from missense mutations in the SCN1A gene and their phenotypes in order to assess genotype/phenotype correlations. From 33 articles, they studied 155 missense mutations, including 22 associated with GEFS+, 14 associated with an intermediate phenotype (e.g., T1709I; 182389.0013), and 119 associated with a severe phenotype, including SMEI. Changes that resulted in decreased hydrophobicity in the S1-S4 transmembrane region outside of the pore region were significantly associated with a more severe phenotype. These changes may affect the stability of the transmembrane domains, which lie within the hydrophobic lipid layer. In addition, mutations that resulted in large changes in the isoelectric point within the pore region were associated with a more severe phenotype. Changes in charge on the surface of the pore may affect the function of the pore of the ion channel. However, patch-clamp studies were unable to find significant associations between changes in physicochemical properties and functional characteristics of mutated channels. </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">
|
|
<strong>History</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">
|
|
<p>By polymerase chain reaction (PCR), Blanchard and Ingram (1991) isolated the SCN1A gene from a library of EcoRI fragments from flow-sorted chromosome 21. Primers were selected from a highly conserved region in the rat brain sodium channel I-alpha cDNA sequence. The assignment to chromosome 21 was subsequently found to be an error, presumably due to contamination of the chromosome 21 library by material from chromosome 2 (Malo, 1993).</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>Animal Model</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Yu et al. (2006) found that Scn1a -/- mice developed severe ataxia and seizures and died on postnatal day 15. Scn1a +/- mice had spontaneous seizures and sporadic deaths beginning after postnatal day 21, with a notable dependence on genetic background. Loss of Scn1a did not change voltage-dependent activation or inactivation of sodium channels in hippocampal neurons. However, the sodium current density was substantially reduced in inhibitory interneurons of Scn1a -/- and +/- mice. The findings suggested that reduced sodium currents in GABAergic inhibitory interneurons resulting from heterozygous SCN1A mutations may cause the hyperexcitability that leads to epilepsy in patients with SMEI. </p><p>Ogiwara et al. (2007) generated a knockin mouse line with a loss-of-function mutation in the Scn1a gene. Both homozygous and heterozygous mutant mice developed seizures within the first postnatal month. Homozygous mice also showed gait instability, and both groups showed early death. Immunohistochemical studies on wildtype mice showed relatively intense Scn1a expression in caudal brain parts, including the thalamus, superior colliculus, inferior colliculus, pons, medulla, deep cerebellar nuclei, and spinal cord, with lower expression in the hippocampus, cerebral cortex, and cerebellum. In the developing neocortex, Scn1a expression was clustered predominantly in axon initial segments of parvalbumin-positive interneurons and in nodes of Ranvier in the cerebellar white matter. Pyramidal neurons in the hippocampus showed low levels of Scn1a. Scn1a expression was absent in homozygous knockin mutant mice. In heterozygous mice, trains of evoked action potentials in fast-spiking inhibitory cells showed pronounced spike amplitude decrements late in the burst, suggesting that Scn1a is necessary to maintain but not initiate fast spiking. Ogiwara et al. (2007) concluded that haploinsufficiency of the Scn1a gene underlies seizures. </p><p>Martin et al. (2007) showed that the seizure severity of heterozygous Scn1a +/- mice (see Yu et al., 2006), which is a mouse model for SMEI, was ameliorated by a heterozygous point mutation (med-jo) in the Scn8a gene (600702). Double-heterozygous Scn1a +/- and Scn8a +/(med-jo) mice had seizure thresholds that were comparable to wildtype littermates, and the Scn8a(med-jo) allele was also able to rescue the premature lethality of Scn1a +/- mice and extended the life span of Scn1a -/- mice. The authors hypothesized that the opposing effects of Scn1a and Scn8a dysfunction on seizure thresholds result from differences in the cell types that are influenced by the respective sodium channel subtypes. Scn1a mutants result in reduced sodium currents in inhibitory GABAergic interneurons of the hippocampus and cortex, whereas Scn8a mutants affect excitatory pyramidal cells of the hippocampus and cortex, suggesting that reduced excitability of these cells may underlie the elevated seizure resistance of Scn8a-mutant mice. Martin et al. (2007) suggested that their results demonstrated that genetic interactions can alter seizure severity, and supported the hypothesis that genetic modifiers, including the SCN8A gene, contribute to the clinical variability observed in SMEI and GEFS+. </p><p>Oakley et al. (2009) generated a mouse model of SMEI by targeted heterozygous deletion of the Scn1a gene. Mutant mice developed seizures induced by elevated core body temperature, whereas wildtype mice were unaffected. In 3 age groups studied, none of postnatal day (P) 17 to 18 mutant mice had temperature-induced seizures, but nearly all P20 to P22 and P30 to P46 mutant mice developed myoclonic seizures followed by generalized seizures caused by elevated core body temperature. There was an age-related susceptibility to seizures at lower temperatures as well as a general increase in severity of seizures with increasing age. Spontaneous seizures were only observed in mice older than P32, suggesting that mutant mice become susceptible to temperature-induced seizures before spontaneous seizures. Interictal EEG spike activity was seen at normal body temperature in most P30 to P46 mutant mice, but not in P20 to P22 or P17 to P18 mutant mice, indicating that interictal epileptic activity correlates with seizure susceptibility. Most P20 to P22 mutant mice had interictal spike activity with elevated body temperature. Oakley et al. (2009) concluded that their results defined a critical developmental transition for susceptibility to seizures in SMEI, demonstrated that body temperature elevation alone is sufficient to induce seizures in mutation carriers, and revealed a close correspondence between human and mouse SMEI in the temperature and age dependence of seizure frequency and severity. </p><p>Han et al. (2012) reported that mice with Scn1a haploinsufficiency exhibit hyperactivity, stereotyped behaviors, social interaction deficits, and impaired context-dependent spatial memory. Olfactory sensitivity is retained, but novel food odors and social odors are aversive to Scn1a +/- mice. GABAergic neurotransmission is specifically impaired by this mutation, and selective deletion of Na(v)1.1 channels in forebrain interneurons is sufficient to cause these behavioral and cognitive impairments. Remarkably, treatment with low-dose clonazepam, a positive allosteric modulator of GABA(A) receptors, completely rescued the abnormal social behaviors and deficits in fear memory in the mouse model of Dravet syndrome (607208), demonstrating that they are caused by impaired GABAergic neurotransmission and not by neuronal damage from recurrent seizures. Han et al. (2012) concluded that their results demonstrated a critical role for Na(v)1.1 channels in neuropsychiatric functions and provided a potential therapeutic strategy for cognitive deficit and autism spectrum behaviors in Dravet syndrome. </p><p>Stein et al. (2019) found that hippocampus-specific deletion of Scn1a in mice resulted in selective reduction in excitability of inhibitory neurons. It also induced thermally evoked seizures, as well as spatial learning and memory defects, as seen in mice with global deletion of Scn1a. However, unlike global deletion of Scn1a, hippocampal deletion of Scn1a did not cause hyperactivity or defects in cognitive abilities, social interaction, and context-dependent fear conditioning. </p>
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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>27 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN1A, ARG1648HIS
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<br />
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SNP: rs121918622,
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gnomAD: rs121918622,
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ClinVar: RCV000013742, RCV000059521, RCV000484119, RCV001040793, RCV001192959
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 3-generation pedigree segregating autosomal dominant generalized epilepsy with febrile seizures plus, type 2 (GEFSP2; 604403) previously reported by Baulac et al. (1999), Escayg et al. (2000) identified a G-to-A transition at nucleotide 4943 in exon 26 of the SCN1A gene that resulted in an amino acid substitution, arg1648 to his. This mutation causes loss of the MaeII site and cosegregated with GEFS+2 in this family. The mutation was identified in 1 asymptomatic individual and was interpreted as an example of incomplete penetrance. One seemingly affected individual did not carry the mutation, suggesting it as a phenocopy; this was previously suggested by haplotype reconstruction. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN1A, THR875MET
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<br />
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SNP: rs121918623,
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ClinVar: RCV000013743, RCV000059471, RCV000686817, RCV001253103, RCV001311218, RCV002316193, RCV004554602, RCV004724740
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family previously reported by Moulard et al. (1999) with GEFS+2 (GEFSP2; 604403), Escayg et al. (2000) identified a C-to-T transition at nucleotide 2624 of the SCN1A gene, resulting in an amino acid substitution thr875 to met. This mutation results from the loss of an Acl1 site. Eleven affected individuals and an obligate carrier were heterozygous for the mutation, whereas 4 unaffected relatives carried 2 normal alleles. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN1A, ASP188VAL
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<br />
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SNP: rs121917953,
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ClinVar: RCV000013744, RCV000059448, RCV000636336
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a large multigenerational Australian family (family A) with GEFS+2 (GEFSP2; 604403), Wallace et al. (2001) identified a heterozygous c.563A-T transversion in exon 4 of the SCN1A gene, resulting in an asp188-to-val (D188V) substitution at a conserved residue. The family had previously been reported by Scheffer and Berkovic (1997). Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN1A, VAL1353LEU
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<br />
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SNP: rs121917954,
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ClinVar: RCV000013745, RCV000059409, RCV003992150
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of an Ashkenazi Jewish family (family B) with GEFS+2 (GEFSP2; 604403), Wallace et al. (2001) used single-strand conformation analysis (SSCA) to identify a heterozygous c.4057G-C transversion in exon 21 of the SCN1A gene, resulting in a val1353-to-leu (V1353L) substitution at a highly conserved residue in the S5 segment of domain III. Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN1A, ILE1656MET
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<br />
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SNP: rs121917955,
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ClinVar: RCV000013746, RCV000059433, RCV001385324, RCV003992151
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a Druze family (family C) with GEFS+2 (GEFSP2; 604403), Wallace et al. (2001) identified a heterozygous c.4968C-G transversion in the SCN1A gene, resulting in an ile1656-to-met (I1656M) substitution in the S4 segment of domain IV. Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0006 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN1A, TRP1204ARG
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<br />
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SNP: rs121917930,
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ClinVar: RCV000013747, RCV000059402, RCV001091670
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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>Escayg et al. (2001) identified a T-to-C transition in exon 18 of the SCN1A gene, resulting in a trp1204-to-arg (W1204R) missense mutation, as the cause of GEFS+2 (GEFSP2; 604403). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0007 DRAVET SYNDROME</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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SCN1A, 2-BP DEL, 657AG
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<br />
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SNP: rs1574272192,
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ClinVar: RCV000032603
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a 4-year-old boy (EP153) with Dravet syndrome (DRVT; 607208), Claes et al. (2001) identified a de novo heterozygous 2-bp deletion (c.657_658delAG) in exon 5 of the SCN1A gene, predicted to result in a frameshift and premature termination (Ser219fsTer275). Functional studies of the variant and studies of patient cells were not performed. The patient presented with seizures at 3 months of age; he died at 4 years of age. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0008 DRAVET SYNDROME</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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SCN1A, ARG222TER
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<br />
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SNP: rs121918624,
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ClinVar: RCV000032604, RCV000188841, RCV000763461, RCV001037392, RCV001257707, RCV002316194, RCV003388823
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a 6-year-old boy (EP78) with Dravet syndrome (DRVT; 607208), Claes et al. (2001) identified a de novo heterozygous c.664C-T transition in exon 5 of the SCN1A gene, resulting in an arg222-to-ter (R222X) substitution. Functional studies of the variant and studies of patient cells were not performed. The patient developed seizures at 6 months of age. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0009 DRAVET SYNDROME</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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SCN1A, LEU986PHE
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<br />
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SNP: rs121918625,
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ClinVar: RCV000032605, RCV000794577
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a 2-year-old girl (EP147) with Dravet syndrome (DRVT; 607208), Claes et al. (2001) identified a de novo heterozygous c.2956C-T transition in exon 16 of the SCN1A gene, resulting in a leu986-to-phe (L986F) substitution in the S6 region of domain II. Functional studies of the variant and studies of patient cells were not performed. She had onset of seizures at 4 months of age. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0010 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN1A, LYS1270THR
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<br />
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SNP: rs121918626,
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ClinVar: RCV000013751, RCV000059501, RCV002513023
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a large family in which 27 members (18 still living) had febrile seizures accompanied in some by partial as well as generalized seizures (GEFSP2; 604403), Abou-Khalil et al. (2001) identified an A-to-C transversion at nucleotide 3809 of the SCN1A gene, resulting in a lys1270-to-thr (K1270T) substitution, in all affected members. The mutation was also present in 1 asymptomatic member, which was explained by the authors as incomplete penetrance. Pedigree analysis revealed autosomal dominant transmission. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0011 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SCN1A, VAL1428ALA
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<br />
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SNP: rs121918627,
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ClinVar: RCV000013752, RCV000059508
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a Japanese patient with GEFS+2 (GEFSP2; 604403) associated with the development of partial epilepsy, Sugawara et al. (2001) identified a 4283T-C missense mutation in the SCN1A gene, resulting in a val1428-to-ala substitution. The mutation occurred in the pore-forming region of the sodium channel, which the authors hypothesized may affect ion selectivity. </p>
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</span>
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</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0012 MIGRAINE, FAMILIAL HEMIPLEGIC, 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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SCN1A, GLN1489LYS
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|
<br />
|
|
|
|
SNP: rs121918628,
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|
|
|
|
|
|
|
ClinVar: RCV000013753, RCV003992152
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|
|
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|
|
</span>
|
|
</div>
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|
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<div>
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<span class="mim-text-font">
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|
<p>In affected members of 3 European families with familial hemiplegic migraine-3 (609634), Dichgans et al. (2005) identified a heterozygous 4465C-A transversion in exon 23 of the SCN1A gene, resulting in a gln1489-to-lys (Q1489K) substitution in the cytoplasmic linker between domains III and IV, which is critical for fast inactivation. The mutation occurs in a highly conserved residue of the protein and was not identified in 1400 control chromosomes. Functional expression studies showed that the Q1489K substitution resulted in a 2- to 4-fold faster recovery from fast inactivation. The mutation was predicted to allow higher neuronal firing rates and enhanced excitability. Dichgans et al. (2005) suggested that the mutation may facilitate initiation and propagation of cortical spreading depression, which is thought to be related to migraine aura. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>.0013 DRAVET SYNDROME</strong>
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|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2, INCLUDED
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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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SCN1A, THR1709ILE
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<br />
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SNP: rs121918629,
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ClinVar: RCV000013754, RCV000013755, RCV001296128
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|
|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a patient with Dravet syndrome (DRVT; 607208), Fujiwara et al. (2003) identified a heterozygous c.5126C-T transition in the SCN1A gene, resulting in a thr1709-to-ile (T1709I) substitution in domain IV of the protein. The patient's mother, who also carried the mutation, had a history of febrile seizures consistent with GEFS+ (GEFSP2; 604403). The T1709I substitution was not identified in 109 control chromosomes. </p>
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|
</span>
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|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0014 DRAVET SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2, INCLUDED
|
|
</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
SCN1A, VAL1611PHE
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<br />
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|
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SNP: rs121918630,
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|
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gnomAD: rs121918630,
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ClinVar: RCV000013756, RCV000013757
|
|
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|
|
</span>
|
|
</div>
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|
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|
<div>
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|
<span class="mim-text-font">
|
|
<p>In a patient with a Dravet syndrome (DRVT; 607208), Fujiwara et al. (2003) identified a heterozygous c.4831G-T transversion in the SCN1A gene, resulting in a val1611-to-phe (V1611F) substitution in domain IV of the protein. The patient's mother, who also had the mutation, had a history of febrile seizures consistent with GEFS+ (GEFSP2; 604403). The V1611F substitution was not identified in 93 control chromosomes. </p>
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|
</span>
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|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 FEBRILE SEIZURES, FAMILIAL, 3A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
SCN1A, MET145THR
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|
|
<br />
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|
|
SNP: rs121918631,
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|
|
ClinVar: RCV000013758, RCV000255880, RCV000993711, RCV003595856, RCV003992153
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 12 affected members of an Italian family with simple febrile seizures-3 (FEB3A; see 604403), Mantegazza et al. (2005) identified a heterozygous 434T-C transition in exon 3 of the SCN1A gene, resulting in a met145-to-thr (M145T) substitution of a highly conserved residue in the first transmembrane segment (S1) of domain I. The mutation was not identified in unaffected family members or in 50 control individuals. Functional expression studies showed that the M145T mutation resulted in a 60% reduction of current density and a 10-mV positive shift of the activation curve. Mantegazza et al. (2005) considered the findings consistent with a loss-of-function mutation. Three affected individuals later developed mesial temporal lobe epilepsy, 2 of whom had associated mesial temporal sclerosis on MRI. </p>
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|
</span>
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</div>
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<div>
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<br />
|
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 FEBRILE SEIZURES, FAMILIAL, 3A, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN1A, IVS5N+5G-A ({dbSNP rs3812718})
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs3812718,
|
|
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|
|
|
gnomAD: rs3812718,
|
|
|
|
|
|
ClinVar: RCV000013759, RCV000211149, RCV001510181
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 2-stage case-control study including a total of 234 patients with febrile seizures (FEB3A; see 604403), Schlachter et al. (2009) found a significant association between the major A allele of rs3812718 and febrile seizures (first stage p value of 0.000017; replication p value of 0.00069). The data suggested that homozygosity for the A allele confers a 3-fold increased relative risk of febrile seizures and may account for a population attributable risk factor of up to 50%. The data were consistent with the hypothesis that low-risk variants with a high population frequency contribute to the risk of common and genetically complex diseases such as epilepsy. </p><p>The SCN1A IVS5N+5G-A polymorphism, formerly SCN1A IVS5-91G-A (rs3812718), was shown by Tate et al. (2005) to affect the alternative splicing of exon 5. The major allele, A, disrupts the consensus sequence of fetal exon 5N, resulting in decreased expression of the fetal SCN1A isoform compared to the adult isoform. Among a total of 706 patients with epilepsy, Tate et al. (2005) found maximum required antiepileptic drug dose to be lowest in patients with a GG genotype, intermediate in those with the GA genotype, and highest in those with the AA genotype. Tate et al. (2005) emphasized that their findings required replication. In a separate study by Tate et al. (2006) that involved patients of Chinese ancestry, an association was found between SCN1A IVS5N+5G-A and phenytoin serum concentrations at maintenance dose; presence of the A allele was associated with higher doses. </p><p>Heinzen et al. (2007) found that in human brain tissue, the SCN1A IVS5N+5G-A polymorphism has a substantial effect on the percentage of transcripts containing exon 5N (neonatal form) of SCN1A. Individuals with the AA genotype had a mean of 0.7% of SCN1A transcripts in the neonatal form, whereas subjects with the GG genotype had 41% of transcripts containing exon 5N. The G allele elicited a dominant effect, with those with the AG genotype having 28% of transcripts in the neonatal form. Heinzen et al. (2007) noted that individuals with the AA genotype require increased doses of antiepileptic drugs compared to those with the GG genotype, suggesting that patients with the AA genotype have a more severe form of epilepsy. Alternatively, the different splice forms may cause alterations in pharmacology, since the drugs act on the SCN1A gene. The authors noted that future work was required to elucidate the functional differences between the transcripts containing exons 5A and 5N. The findings emphasized an emerging role of genetic polymorphisms in modulation of drug effect, and illustrated the importance of considering the activity of compounds at alternative splice forms of drug targets. </p><p>Petrovski et al. (2009) was unable to replicate the association between rs3812718 and febrile seizures in a study of 558 Australian patients with seizures, including 76 (14%) with febrile seizures and 482 (86%) without febrile seizures. Only 10 (2%) had isolated febrile seizures. The association was also not replicated in a second cohort of 1,589 European patients with focal epilepsy, consisting of 232 with febrile seizures and 1,357 without febrile seizures. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN1A, 1-BP DEL, 2528G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2105816922,
|
|
|
|
|
|
|
|
ClinVar: RCV000013761
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Buoni et al. (2006) identified a de novo heterozygous 1-bp deletion (c.2528delG) in exon 14 of the SCN1A gene in a 13-year-old boy with generalized epilepsy with febrile seizures plus, type 2 (GEFSP2; 604403). The mutation was predicted to result in a frameshift and premature termination of the protein at codon 853. The patient had prolonged febrile seizures at ages 6, 10, and 13 months, afebrile complex partial seizures with secondary generalization beginning at age 18 months, and 2 episodes of status epilepticus at age 2 years. He also had abnormal EEG findings and myoclonic jerks. Antiepileptic medication was unsuccessful. At age 4 years, the seizure frequency decreased in response to medication, and by age 9, he had complex partial seizures with secondary generalization. By age 13, he was treated with valproate and had a febrile seizure. He did not have intellectual disability. Buoni et al. (2006) emphasized the relatively benign outcome in this patient despite a truncating mutation in the SCN1A gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 DRAVET SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN1A, EX21-26DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000032607
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Dravet syndrome (DRVT; 607208) manifest as severe myoclonic epilepsy of infancy (SMEI), Mulley et al. (2006) used multiplex ligation-dependent probe amplification (MLPA) to identify a de novo heterozygous deletion of exons 21 through 26 of the SCN1A gene. The phenotype was similar to SMEI patients with coding or splicing SCN1A mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 DRAVET SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN1A, 6.5-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000032608
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Dravet syndrome (DRVT; 607208) manifest as severe myoclonic epilepsy of infancy (SMEI), Mulley et al. (2006) used multiplex ligation-dependent probe amplification (MLPA) to identify a de novo heterozygous deletion of exon 21 of the SCN1A gene. Sequence analysis showed that the deletion was 6,499 bp in size and encompassed part of intron 20, all of exon 21, and part of intron 21. The phenotype was similar to SMEI patients with coding or splicing SCN1A mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 DRAVET SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN1A, 1-BP DEL, 3608A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1574061044,
|
|
|
|
|
|
|
|
ClinVar: RCV000032609
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female patient with Dravet syndrome (DRVT; 607208), McArdle et al. (2008) identified a heterozygous 1-bp deletion (c.3608delA) in the SCN1A gene, predicted to result in a frameshift and premature termination in the intracellular cytoplasmic linker region between domains D2 and D3. She died at age 5 years. Postmortem Western blot analysis of cerebellar tissue did not detect the truncated protein but only the full-length protein. However, RT-PCR analysis found expression of both alleles in cerebellar tissue from the patient, with slightly greater expression of the wildtype transcript. The findings indicated that nonsense-mediated mRNA decay could not explain the lack of mutant protein expression. McArdle et al. (2008) speculated that the mutant truncated protein may have been misfolded in the endoplasmic reticulum and then been targeted for ER-associated protein degradation, suggesting haploinsufficiency as the disease mechanism. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 MIGRAINE, FAMILIAL HEMIPLEGIC, 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN1A, PHE1499LEU
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs121918632,
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|
|
|
|
|
ClinVar: RCV000013765, RCV001090363, RCV001857344, RCV003992154
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a 3-generation French family with familial hemiplegic migraine (FHM3; 609634), Vahedi et al. (2009) identified a heterozygous 4495T-C transition in exon 24 of the SCN1A gene, resulting in a phe1499-to-leu (F1499L) substitution in a highly conserved residue in an intracellular loop. The proband was an 18-year-old woman who also had episodes of elicited repetitive daily blindness (ERDB) that was temporally unrelated to the FHM episodes; her affected mother, sister, and maternal grandfather did not have episodic blindness. Vahedi et al. (2009) noted that ERDB has features of spreading depression in the retina, with propagation of the darkness from the periphery to the center and a refractory period. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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|
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 MIGRAINE, FAMILIAL HEMIPLEGIC, 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN1A, GLN1489HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918633,
|
|
|
|
|
|
|
|
ClinVar: RCV000013766
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 affected members of a Swiss family with familial hemiplegic migraine (FHM3; 609634), previously reported by Le Fort et al. (2004), Vahedi et al. (2009) identified a heterozygous 4467G-C transversion in exon 23 of the SCN1A gene, resulting in a gln1489-to-his (Q1489H) substitution in a highly conserved residue in an intracellular loop. All 4 affected family members also had episodes of elicited repetitive daily blindness (ERDB) that was temporally unrelated to the FHM episodes. Vahedi et al. (2009) noted that ERDB has features of spreading depression, with propagation of the darkness from the periphery to the center and a refractory period. A different mutation in this same codon has also been associated with FHM3 (Q1489K; 182389.0012). </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 DRAVET SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN1A, ALA1669GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397514458,
|
|
|
|
|
|
|
|
ClinVar: RCV000022764, RCV001379443
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
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<p>In a female infant with Dravet syndrome (DRVT; 607208) manifest clinically as 'malignant migrating partial seizures of infancy' (MPSI, MMPSI), Freilich et al. (2011) identified a heterozygous c.5006C-A transversion in the SCN1A gene, resulting in an ala1669-to-glu (A1669E) substitution in a highly conserved residue in a cytoplasmic linker region between transmembrane segments 4 and 5 of domain 4. The mutation was predicted to be deleterious; functional studies were not performed. RT-PCR studies of the patient's brain matter showed that the mutant transcript was expressed similar to wildtype (ratio of 40:60). The patient was born by in vitro fertilization from a donor ovum and paternal sperm; the father did not carry the mutation, and DNA was not available from the ovum donor. The patient had a severe phenotype, with onset of seizures at age 10 weeks, progression to refractory recurrent seizures by age 5 months, status epilepticus, EEG evidence of migrating focal onset progressing to multifocal onset of seizures, progressive microcephaly, and profound psychomotor delay. She died at age 9 months. The findings expanded the severity of the phenotype associated with SCN1A mutations. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>.0024 DRAVET SYNDROME</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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SCN1A, ARG862GLY
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<br />
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SNP: rs397514459,
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gnomAD: rs397514459,
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ClinVar: RCV000022765
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</span>
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<span class="mim-text-font">
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<p>In an 8-year-old girl with Dravet syndrome (DRVT; 607208) manifest clinically as 'malignant migrating partial seizures of infancy,' Carranza Rojo et al. (2011) identified a de novo heterozygous c.2584C-G transversion in exon 14 of the SCN1A gene, resulting in an arg862-to-gly (R862G) substitution in the voltage sensor segment S4 of the second protein domain. The mutation was predicted to be deleterious; functional studies were not performed. The patient had onset of multifocal hemiclonic seizures at age 2 weeks with episodes of status epilepticus. She had acquired microcephaly, developmental regression, and severe intellectual disability. The findings expanded the severity of the phenotype associated with SCN1A mutations. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0025 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 6B</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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SCN1A, VAL422LEU
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<br />
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SNP: rs886042528,
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ClinVar: RCV001420525
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<span class="mim-text-font">
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<p>In a 6-year-old Japanese girl with developmental and epileptic encephalopathy-6B (DEE6B; 619317), Ohashi et al. (2014) identified a de novo heterozygous c.1264G-T transversion in the SCN1A gene, resulting in a val422-to-leu (V422L) substitution in the transmembrane region S6 of the D1 domain. The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or in 408 in-house Japanese controls. Functional studies of the variant were not performed. </p>
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</span>
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</div>
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<div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0026 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 6B</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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SCN1A, THR226MET
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<br />
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SNP: rs121917984,
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ClinVar: RCV000059454, RCV000188843, RCV000558296, RCV000763460, RCV001003956, RCV001420531, RCV002470755, RCV003764743
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</span>
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<span class="mim-text-font">
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<p>In 8 unrelated children with developmental and epileptic encephalopathy-6B (DEE6B; 619317), Sadleir et al. (2017) identified a de novo heterozygous c.677C-T transition in exon 5 of the SCN1A gene, resulting in a thr226-to-met (T226M) substitution. The mutations were found by whole-exome or targeted sequencing. Functional studies of the variant were not performed, but the authors speculated a gain-of-function effect. The patients had onset of seizures between 6 and 12 weeks of age. Several patients had previously been reported, including patients 3 and 4 who had been reported by Dhamija et al. (2014). </p><p>Harkin et al. (2007) had identified a de novo heterozygous T226M mutation in the SCN1A gene in a 5-year-old patient (patient 78) with onset of seizures at 2 months of age. The patient had severely impaired intellectual development and increased muscle tone. Another patient (patient 61) also carried the mutation; the latter patient was noted to have severe myoclonic epilepsy of infancy-borderland (SMEB), but clinical details were limited. Functional studies of the variant were not performed. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0027 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 6B</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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SCN1A, PRO1345SER
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<br />
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SNP: rs1574006857,
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ClinVar: RCV000814237, RCV001420538
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 12-year-old boy (patient 9) with developmental and epileptic encephalopathy-6B (DEE6B; 619317), Sadleir et al. (2017) identified a de novo heterozygous c.4033C-T transition in the SCN1A gene, resulting in a pro1345-to-ser (P1345S) substitution. Functional studies of the variant were not performed. The patient had onset of epileptic spasms around 6 weeks of age. </p>
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</span>
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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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Abou-Khalil, B., Ge, Q., Desai, R., Ryther, R., Bazyk, A., Bailey, R., Haines, J. L., Sutcliffe, J. S., George, A. L., Jr.
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Freilich, E. R., Jones, J. M., Gaillard, W. D., Conry, J. A., Tsuchida, T. N., Reyes, C., Dib-Hajj, S., Waxman, S. G., Meisler, M. H., Pearl, P. L.
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Fujiwara, T., Sugawara, T., Mazaki-Miyazaki, E., Takahashi, Y., Fukushima, K., Watanabe, M., Hara, K., Morikawa, T., Yagi, K., Yamakawa, K., Inoue, Y.
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Goldin, A. L., Snutch, T., Lubbert, H., Dowsett, A., Marshall, J., Auld, V., Downey, W., Fritz, L. C., Lester, H. A., Dunn, R., Catterall, W. A., Davidson, N.
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<strong>Messenger RNA coding for only the alpha subunit of the rat brain Na channel is sufficient for expression of functional channels in Xenopus oocytes.</strong>
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Han, S., Tai, C., Westenbroek, R. E., Yu, F. H., Cheah, C. S., Potter, G. B., Rubenstein, J. L., Scheuer, T., de la Iglesia, H. O., Catterall, W. A.
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Harkin, L. A., McMahon, J. M., Iona, X., Dibbens, L., Pelekanos, J. T., Zuberi, S. M., Sadleir, L. G., Andermann, E., Gill, D., Farrell, K., Connolly, M., Stanley, T., and 12 others.
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<p class="mim-text-font">
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Heinzen, E. L., Yoon, W., Tate, S. K., Sen, A., Wood, N. W., Sisodiya, S. M., Goldstein, D. B.
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<strong>Nova2 interacts with a Cis-acting polymorphism to influence the proportions of drug-responsive splice variants of SCN1A.</strong>
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[PubMed: 17436242]
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<p class="mim-text-font">
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Isom, L. L.
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<strong>The role of sodium channels in cell adhesion.</strong>
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Front. Biosci. 7: 12-23, 2002.
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[PubMed: 11779698]
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</p>
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<li>
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<p class="mim-text-font">
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[Full Text: https://doi.org/10.1074/jbc.M112.421883]
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Vahedi, K., Depienne, C., Le Fort, D., Riant, F., Chaine, P., Trouillard, O., Gaudric, A., Morris, M. A., LeGuern, E., Tournier-Lasserve, E., Bousser, M.-G.
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<strong>Elicited repetitive daily blindness: a new phenotype associated with hemiplegic migraine and SCN1A mutations.</strong>
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Wallace, R. H., Scheffer, I. E., Barnett, S., Richards, M., Dibbens, L., Desai, R. R., Lerman-Sagie, T., Lev, D., Mazarib, A., Brand, N., Ben-Zeev, B., Goikhman, I., Singh, R., Kremmidiotis, G., Gardner, A., Sutherland, G. R., George, A. L., Jr., Mulley, J. C., Berkovic, S. F.
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<strong>Neuronal sodium-channel alpha-1-subunit mutations in generalized epilepsy with febrile seizures plus.</strong>
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Yu, F. H., Mantegazza, M., Westenbroek, R. E., Robbins, C. A., Kalume, F., Burton, K. A., Spain, W. J., McKnight, G. S., Scheuer, T., Catterall, W. A.
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<strong>Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy.</strong>
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Nature Neurosci. 9: 1142-1149, 2006. Note: Erratum: Nature Neurosci. 10: 134 only, 2007.
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[Full Text: https://doi.org/10.1038/nn1754]
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Zucca, C., Redaelli, F., Epifanio, R., Zanotta, N., Romeo, A., Lodi, M., Veggiotti, P., Airoldi, G., Panzeri, C., Romaniello, R., De Polo, G., Bonanni, P., Cardinali, S., Baschirotto, C., Martorell, L., Borgatti, R., Bresolin, N., Bassi, M. T.
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<strong>Cryptogenic epileptic syndromes related to SCN1A: twelve novel mutations identified.</strong>
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[Full Text: https://doi.org/10.1001/archneur.65.4.489]
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Cassandra L. Kniffin - updated : 05/10/2021<br>Cassandra L. Kniffin - updated : 10/01/2020<br>Bao Lige - updated : 01/13/2020<br>Paul J. Converse - updated : 08/10/2016<br>Ada Hamosh - updated : 11/1/2012<br>Joanna S. Amberger - updated : 1/20/2012<br>Cassandra L. Kniffin - updated : 10/5/2011<br>Cassandra L. Kniffin - updated : 1/24/2011<br>Ada Hamosh - updated : 8/17/2010<br>Cassandra L. Kniffin - updated : 6/1/2010<br>Cassandra L. Kniffin - updated : 1/25/2010<br>Cassandra L. Kniffin - updated : 10/15/2009<br>Cassandra L. Kniffin - updated : 8/18/2009<br>Cassandra L. Kniffin - updated : 6/17/2009<br>Cassandra L. Kniffin - updated : 6/1/2009<br>Cassandra L. Kniffin - updated : 5/18/2009<br>Cassandra L. Kniffin - updated : 3/3/2009<br>Cassandra L. Kniffin - updated : 1/6/2009<br>Cassandra L. Kniffin - updated : 8/2/2007<br>Cassandra L. Kniffin - updated : 6/25/2007<br>Victor A. McKusick - updated : 5/1/2007<br>Cassandra L. Kniffin - updated : 12/21/2005<br>Cassandra L. Kniffin - updated : 11/14/2005<br>Cassandra L. Kniffin - updated : 11/3/2005<br>Victor A. McKusick - updated : 8/9/2005<br>Cassandra L. Kniffin - updated : 6/9/2005<br>Cassandra L. Kniffin - updated : 1/26/2005<br>Victor A. McKusick - updated : 7/11/2003<br>Cassandra L. Kniffin - updated : 11/12/2002<br>Victor A. McKusick - updated : 9/30/2002<br>Cassandra L. Kniffin - reorganized : 9/25/2002<br>Victor A. McKusick - updated : 8/28/2002<br>Cassandra L. Kniffin - updated : 5/24/2002<br>Victor A. McKusick - updated : 6/20/2001<br>Victor A. McKusick - updated : 5/3/2001<br>Ada Hamosh - updated : 3/29/2000
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Victor A. McKusick : 6/20/1991
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