4943 lines
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Entry
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- *300203 - CYCLIN-DEPENDENT KINASE-LIKE 5; CDKL5
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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">*300203</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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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/300203">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li 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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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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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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<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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<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=ENSG00000008086;t=ENST00000623535" 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=6792" 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=300203" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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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=ENSG00000008086;t=ENST00000623535" 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_001037343,NM_001323289,NM_003159" 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_001323289" 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=300203" 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=02190&isoform_id=02190_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/CDKL5" 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/929631,3559925,4507281,30983553,83367069,119619346,119619347,307148972,1020159025,1915398762" 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/O76039" 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=6792" 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=ENSG00000008086;t=ENST00000623535" 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=CDKL5" 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=CDKL5" 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+6792" 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/CDKL5" 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:6792" 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/6792" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chrX&hgg_gene=ENST00000623535.2&hgg_start=18425608&hgg_end=18653629&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 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:11411" 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:11411" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/cdkl5" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300203[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/b5d37ade-20c8-49be-a6e7-a440e5d21950/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=300203[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/CDKL5/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/ENSG00000008086" 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=CDKL5" 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=CDKL5" 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=CDKL5" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/CDKL5" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CDKL5&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/PA36218" 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:11411" 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://www.mousephenotype.org/data/genes/MGI:1278336" 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/CDKL5#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:1278336" 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/6792/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=6792" 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-081022-110" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=CDKL5&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 773230003<br />
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<strong>ICD10CM:</strong> G40.42<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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300203
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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CYCLIN-DEPENDENT KINASE-LIKE 5; CDKL5
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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SERINE/THREONINE PROTEIN KINASE 9; STK9
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CDKL5" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CDKL5</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/X/99?start=-3&limit=10&highlight=99">Xp22.13</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:18425608-18653629&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">X:18,425,608-18,653,629</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/X/99?start=-3&limit=10&highlight=99">
|
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Xp22.13
|
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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 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/300672"> 300672 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="X-linked dominant">XLD</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</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>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/300203" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/300203" 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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<p>During transcriptional mapping in the Xp22 region, <a href="#15" class="mim-tip-reference" title="Montini, E., Andolfi, G., Caruso, A., Buchner, G., Walpole, S. M., Mariani, M., Consalez, G., Trump, D., Ballabio, A., Franco, B. <strong>Identification and characterization of a novel serine-threonine kinase gene from the Xp22 region.</strong> Genomics 51: 427-433, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9721213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9721213</a>] [<a href="https://doi.org/10.1006/geno.1998.5391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9721213">Montini et al. (1998)</a> found an exon encoding a product with homology to serine-threonine protein kinases. They cloned the corresponding cDNA, designated STK9, from several adult human tissue cDNA libraries. The STK9 cDNA predicts a protein product of 1,022 or 1,030 amino acids, depending on which initiating methionine is used. Northern blot analysis of human and mouse tissues detected a transcript larger than 9.5 kb expressed in a variety of tissues, and an abundant 3.5-kb transcript expressed only in testis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9721213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Kalscheuer, V. M., Tao, J., Donnelly, A., Hollway, G., Schwinger, E., Kubart, S., Menzel, C., Hoeltzenbein, M., Tommerup, N., Eyre, H., Harbord, M., Haan, E., Sutherland, G. R., Ropers, H.-H., Gecz, J. <strong>Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation.</strong> Am. J. Hum. Genet. 72: 1401-1411, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12736870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12736870</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12736870[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/10.1086/375538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12736870">Kalscheuer et al. (2003)</a> reported that the STK9 RNA isoform containing exons 1a and 1b (isoform II) is transcribed at very low levels in human fetal brain and testis but not in lymphoblastoid cell lines, whereas the STK9 RNA isoform containing exon 1 (isoform I) is expressed in a wide range of cells, including human fibroblasts and lymphoblastoid cell lines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12736870" 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 RT-PCR of human fibroblast total RNA, <a href="#7" class="mim-tip-reference" title="Fichou, Y., Nectoux, J., Bahi-Buisson, N., Chelly, J., Bienvenu, T. <strong>An isoform of the severe encephalopathy-related CDKL5 gene, including a novel exon with extremely high sequence conservation, is specifically expressed in brain.</strong> J. Hum. Genet. 56: 52-57, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21124335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21124335</a>] [<a href="https://doi.org/10.1038/jhg.2010.143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21124335">Fichou et al. (2011)</a> isolated a CDKL5 splice variant that includes an alternative exon, exon 16b. The 41 residues introduced by exon 16b are inserted in-frame in the C-terminal half of the 1,030-amino acid CDKL5 protein, resulting in a deduced 1,071-amino acid protein. Phylogenetic analysis revealed over 95% sequence similarity in the inserted region in 17 of 24 vertebrate species. RT-PCR analysis of mouse tissues detected high expression of the Cdkl5 variant lacking exon 16b in skeletal muscle, cerebellum, cortex, hippocampus, and olfactory bulb, with low expression in kidney, lung, and heart, and no expression in liver. Expression of the Cdkl5 variant that includes exon 16b was detected almost exclusively in cerebellum, cortex, hippocampus, and olfactory bulb, with low expression in liver, and little to no expression in other tissues examined, including skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21124335" 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 RT-PCR analysis on mouse brain RNA, <a href="#19" class="mim-tip-reference" title="Rademacher, N., Hambrock, M., Fischer, U., Moser, B., Ceulemans, B., Lieb, W., Boor, R., Stefanova, I., Gillessen-Kaesbach, G., Runge, C., Korenke, G. C., Spranger, S., Laccone, F., Tzschach, A., Kalscheuer, V. M. <strong>Identification of a novel CDKL5 exon and pathogenic mutations in patients with severe mental retardation, early-onset seizures and Rett-like features. (Letter)</strong> Neurogenetics 12: 165-167, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21318334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21318334</a>] [<a href="https://doi.org/10.1007/s10048-011-0277-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21318334">Rademacher et al. (2011)</a> also identified an additional exon in the Cdkl5 gene between exons 16 and 17, which they termed exon 16a. The exon encoded 41 residues and was identical to that identified by <a href="#7" class="mim-tip-reference" title="Fichou, Y., Nectoux, J., Bahi-Buisson, N., Chelly, J., Bienvenu, T. <strong>An isoform of the severe encephalopathy-related CDKL5 gene, including a novel exon with extremely high sequence conservation, is specifically expressed in brain.</strong> J. Hum. Genet. 56: 52-57, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21124335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21124335</a>] [<a href="https://doi.org/10.1038/jhg.2010.143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21124335">Fichou et al. (2011)</a>. Expression of the CDKL5 variant with exon 16a was found in human adult and fetal brain, but was barely detectable in lymphoblasts, suggesting tissue-restricted alternative splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21124335+21318334" 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="Williamson, S. L., Giudici, L., Kilstrup-Nielsen, C., Gold, W., Pelka, G. J., Tam, P. P. L., Grimm, A., Prodi, D., Landsberger, N., Christodoulou, J. <strong>A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain.</strong> Hum. Genet. 131: 187-200, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21748340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21748340</a>] [<a href="https://doi.org/10.1007/s00439-011-1058-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21748340">Williamson et al. (2012)</a> identified a splice variant of CDKL5 that includes and terminates in intron 18. The deduced 960-amino acid protein, which the authors designated CKDL5(107) based on its calculated molecular mass, contains the N-terminal kinase domain, but differs in its C terminus, compared with the previously identified full-length protein, CDKL5(115). RT-PCR detected both transcripts in all human tissues and cell lines examined, with highest expression of CDKL5(115) in testis, and highest expression of CDKL5(107) in brain. Fluorescence-tagged CDKL5(115) and CDKL5(107) localized to both the nucleus and cytoplasm in transfected HeLa cells. By database analysis, <a href="#30" class="mim-tip-reference" title="Williamson, S. L., Giudici, L., Kilstrup-Nielsen, C., Gold, W., Pelka, G. J., Tam, P. P. L., Grimm, A., Prodi, D., Landsberger, N., Christodoulou, J. <strong>A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain.</strong> Hum. Genet. 131: 187-200, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21748340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21748340</a>] [<a href="https://doi.org/10.1007/s00439-011-1058-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21748340">Williamson et al. (2012)</a> detected orthologs of CDKL5(107) in several vertebrate species, and they identified species-specific variants, including Cdkl5(105) in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21748340" 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 genomic analysis, <a href="#15" class="mim-tip-reference" title="Montini, E., Andolfi, G., Caruso, A., Buchner, G., Walpole, S. M., Mariani, M., Consalez, G., Trump, D., Ballabio, A., Franco, B. <strong>Identification and characterization of a novel serine-threonine kinase gene from the Xp22 region.</strong> Genomics 51: 427-433, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9721213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9721213</a>] [<a href="https://doi.org/10.1006/geno.1998.5391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9721213">Montini et al. (1998)</a> found that STK9 is composed of 20 coding exons. The gene spans the region of marker DXS8000, near the XLRS1 gene (<a href="/entry/300839">300839</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9721213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Kalscheuer, V. M., Tao, J., Donnelly, A., Hollway, G., Schwinger, E., Kubart, S., Menzel, C., Hoeltzenbein, M., Tommerup, N., Eyre, H., Harbord, M., Haan, E., Sutherland, G. R., Ropers, H.-H., Gecz, J. <strong>Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation.</strong> Am. J. Hum. Genet. 72: 1401-1411, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12736870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12736870</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12736870[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/10.1086/375538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12736870">Kalscheuer et al. (2003)</a> determined that the STK9 gene contains at least 23 exons; the first 3 exons (1, 1a, and 1b) are untranslated and probably represent 2 transcription start sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12736870" 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="#7" class="mim-tip-reference" title="Fichou, Y., Nectoux, J., Bahi-Buisson, N., Chelly, J., Bienvenu, T. <strong>An isoform of the severe encephalopathy-related CDKL5 gene, including a novel exon with extremely high sequence conservation, is specifically expressed in brain.</strong> J. Hum. Genet. 56: 52-57, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21124335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21124335</a>] [<a href="https://doi.org/10.1038/jhg.2010.143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21124335">Fichou et al. (2011)</a> identified an additional coding exon in the CDKL5 gene that they called 16b due to its location between exons 16 and 17. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21124335" 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>During transcriptional mapping in the Xp22 region, <a href="#15" class="mim-tip-reference" title="Montini, E., Andolfi, G., Caruso, A., Buchner, G., Walpole, S. M., Mariani, M., Consalez, G., Trump, D., Ballabio, A., Franco, B. <strong>Identification and characterization of a novel serine-threonine kinase gene from the Xp22 region.</strong> Genomics 51: 427-433, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9721213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9721213</a>] [<a href="https://doi.org/10.1006/geno.1998.5391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9721213">Montini et al. (1998)</a> identified the STK9 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9721213" 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="Erez, A., Patel, A. J., Wang, X., Xia, Z., Bhatt, S. S., Craigen, W., Cheung, S. W., Lewis, R. A., Fang, P., Davenport, S. L. H., Stankiewicz, P., Lalani, S. R. <strong>Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder.</strong> Neurogenetics 10: 363-369, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19471977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19471977</a>] [<a href="https://doi.org/10.1007/s10048-009-0195-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19471977">Erez et al. (2009)</a> stated that the CDKL5 gene maps to chromosome Xp22.13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19471977" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Mari, F., Azimonti, S., Bertani, I., Bolognese, F., Colombo, E., Caselli, R., Scala, E., Longo, I., Grosso, S., Pescucci, C., Ariani, F., Hayek, G., Balestri, P., Bergo, A., Badaracco, G., Zappella, M., Broccoli, V., Renieri, A., Kilstrup-Nielsen, C., Landsberger, N. <strong>CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome.</strong> Hum. Molec. Genet. 14: 1935-1946, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15917271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15917271</a>] [<a href="https://doi.org/10.1093/hmg/ddi198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15917271">Mari et al. (2005)</a> demonstrated that expression of CDKL5 in mouse brain overlapped with that of MeCP2 (<a href="/entry/300005">300005</a>) during neural maturation and synaptogenesis. GST pull-down assays, coimmunoprecipitation, and immunoblotting showed that MeCP2 and CDKL5 interacted in vivo and in vitro. CDKL5 possesses kinase activity and is able to autophosphorylate as well as to mediate MeCP2 phosphorylation, suggesting that CDKL5 and MeCP2 may belong to the same molecular pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15917271" 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="Lin, C., Franco, B., Rosner, M. R. <strong>CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders.</strong> Hum. Molec. Genet. 14: 3775-3786, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16330482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16330482</a>] [<a href="https://doi.org/10.1093/hmg/ddi391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16330482">Lin et al. (2005)</a> expressed and characterized CDKL5. CDKL5 is a 118-kD protein that is widely distributed in all tissues, with highest levels in brain, thymus, and testis. Whole-mount embryo staining revealed CDKL5 to be ubiquitous. Within cells, CDKL5 was localized primarily in the nucleus. Removal of the C-terminal domain increased CDKL5 expression, enhanced autophosphorylation activity, and caused perinuclear localization, indicating that the C terminus may regulate CDKL5 function. Although MECP2 bound to CDKL5, the results obtained by <a href="#11" class="mim-tip-reference" title="Lin, C., Franco, B., Rosner, M. R. <strong>CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders.</strong> Hum. Molec. Genet. 14: 3775-3786, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16330482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16330482</a>] [<a href="https://doi.org/10.1093/hmg/ddi391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16330482">Lin et al. (2005)</a> suggested that the phosphorylation of MECP2 by CDKL5 reported by <a href="#13" class="mim-tip-reference" title="Mari, F., Azimonti, S., Bertani, I., Bolognese, F., Colombo, E., Caselli, R., Scala, E., Longo, I., Grosso, S., Pescucci, C., Ariani, F., Hayek, G., Balestri, P., Bergo, A., Badaracco, G., Zappella, M., Broccoli, V., Renieri, A., Kilstrup-Nielsen, C., Landsberger, N. <strong>CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome.</strong> Hum. Molec. Genet. 14: 1935-1946, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15917271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15917271</a>] [<a href="https://doi.org/10.1093/hmg/ddi198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15917271">Mari et al. (2005)</a> resulted from nonspecific kinases in the immunoprecipitate. The observation that MECP2 is not a direct substrate does not rule out CDKL5 regulation of MECP2 function. <a href="#11" class="mim-tip-reference" title="Lin, C., Franco, B., Rosner, M. R. <strong>CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders.</strong> Hum. Molec. Genet. 14: 3775-3786, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16330482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16330482</a>] [<a href="https://doi.org/10.1093/hmg/ddi391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16330482">Lin et al. (2005)</a> suggested that MECP2 may recruit CDKL5 to a DNA binding complex that contains a functional substrate of the kinase. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16330482+15917271" 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="#20" class="mim-tip-reference" title="Ricciardi, S., Kilstrup-Nielsen, C., Bienvenu, T,, Jacquette, A., Landsberger, N., Broccoli, V. <strong>CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery.</strong> Hum. Molec. Genet. 18: 4590-4602, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19740913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19740913</a>] [<a href="https://doi.org/10.1093/hmg/ddp426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19740913">Ricciardi et al. (2009)</a> reported that CDKL5 localized to specific nuclear foci referred to as nuclear speckles in NIH3T3 and HeLa cells and primary mouse hippocampal neurons. CDKL5 overexpression led to nuclear speckle disassembly, and this event was strictly dependent on its kinase activity. Conversely, its downregulation affected nuclear speckle morphology leading to abnormally large and uneven speckles. Similar results were obtained for primary adult fibroblasts isolated from CDKL5-mutated patients. <a href="#20" class="mim-tip-reference" title="Ricciardi, S., Kilstrup-Nielsen, C., Bienvenu, T,, Jacquette, A., Landsberger, N., Broccoli, V. <strong>CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery.</strong> Hum. Molec. Genet. 18: 4590-4602, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19740913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19740913</a>] [<a href="https://doi.org/10.1093/hmg/ddp426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19740913">Ricciardi et al. (2009)</a> hypothesized that CDKL5 may control nuclear speckle morphology by regulating the phosphorylation state of splicing regulatory proteins, and may be involved indirectly in pre-mRNA processing, by controlling splicing factor dynamics. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19740913" 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 an in vitro kinase assay with epitope-tagged proteins expressed in HEK293 cells, <a href="#30" class="mim-tip-reference" title="Williamson, S. L., Giudici, L., Kilstrup-Nielsen, C., Gold, W., Pelka, G. J., Tam, P. P. L., Grimm, A., Prodi, D., Landsberger, N., Christodoulou, J. <strong>A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain.</strong> Hum. Genet. 131: 187-200, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21748340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21748340</a>] [<a href="https://doi.org/10.1007/s00439-011-1058-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21748340">Williamson et al. (2012)</a> found that both CDKL5(115) and CDKL5(107) phosphorylated MECP2 and underwent autophosphorylation. The kinase activity of CDKL5(115) was about twice that of CDKL(107). Inhibitor studies revealed that both isoforms shuttled between the nucleus and cytoplasm and exited the nucleus via the export protein CRM1 (XPO1; <a href="/entry/602559">602559</a>). CDKL5(107) was significantly more stable than CDKL5(115). Proteasome inhibition increased the stability of CDKL5(115), but not CDKL5(107). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21748340" 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="#27" class="mim-tip-reference" title="Van Esch, H., Jansen, A., Bauters, M., Froyen, G., Fryns, J.-P. <strong>Encephalopathy and bilateral cataract in a boy with an interstitial deletion of Xp22 comprising the CDKL5 and NHS genes.</strong> Am. J. Med. Genet. 143A: 364-369, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17256798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17256798</a>] [<a href="https://doi.org/10.1002/ajmg.a.31572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17256798">Van Esch et al. (2007)</a> reported a 10-month-old male infant with severe encephalopathy, congenital cataracts, and tetralogy of Fallot who had a hemizygous de novo 2.8-Mb microdeletion at chromosome Xp22.2-Xp22.13, including the CDKL5 and NHS (<a href="/entry/300457">300457</a>) genes. He had microphthalmia, refractory myoclonic seizures, and hypotonia. The clinical features were consistent with both DEE2 and the Nance-Horan syndrome (<a href="/entry/302350">302350</a>), which is caused by mutation in the NHS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17256798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Kalscheuer, V. M., Tao, J., Donnelly, A., Hollway, G., Schwinger, E., Kubart, S., Menzel, C., Hoeltzenbein, M., Tommerup, N., Eyre, H., Harbord, M., Haan, E., Sutherland, G. R., Ropers, H.-H., Gecz, J. <strong>Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation.</strong> Am. J. Hum. Genet. 72: 1401-1411, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12736870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12736870</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12736870[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/10.1086/375538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12736870">Kalscheuer et al. (2003)</a> reported 2 unrelated severely affected girls with developmental and epileptic encephalopathy (DEE2; <a href="/entry/300672">300672</a>), diagnosed with infantile spasm syndrome, which was associated with de novo balanced X-autosome translocations, t(X;7)(p22.3;p15) or t(X;6)(p22.3;q14), respectively, that disrupted the STK9 gene. <a href="#9" class="mim-tip-reference" title="Kalscheuer, V. M., Tao, J., Donnelly, A., Hollway, G., Schwinger, E., Kubart, S., Menzel, C., Hoeltzenbein, M., Tommerup, N., Eyre, H., Harbord, M., Haan, E., Sutherland, G. R., Ropers, H.-H., Gecz, J. <strong>Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation.</strong> Am. J. Hum. Genet. 72: 1401-1411, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12736870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12736870</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12736870[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/10.1086/375538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12736870">Kalscheuer et al. (2003)</a> showed that STK9 is subject to X inactivation in normal female somatic cells and that the protein was functionally absent in the 2 patients because of preferential inactivation of the normal X chromosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12736870" 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 individuals from families with DEE2, <a href="#29" class="mim-tip-reference" title="Weaving, L. S., Christodoulou, J., Williamson, S. L., Friend, K. L., McKenzie, O. L. D., Archer, H., Evans, J., Clarke, A., Pelka, G. J., Tam, P. P. L., Watson, C., Lahooti, H., Ellaway, C. J., Bennetts, B., Leonard, H., Gecz, J. <strong>Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.</strong> Am. J. Hum. Genet. 75: 1079-1093, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15492925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15492925</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15492925[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/10.1086/426462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15492925">Weaving et al. (2004)</a> and <a href="#25" class="mim-tip-reference" title="Tao, J., Van Esch, H., Hagedorn-Greiwe, M., Hoffmann, K., Moser, B., Raynaud, M., Sperner, J., Fryns, J.-P., Schwinger, E., Gecz, J., Ropers, H.-H., Kalscheuer, V. M. <strong>Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation.</strong> Am. J. Hum. Genet. 75: 1149-1154, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15499549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15499549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15499549[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/10.1086/426460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15499549">Tao et al. (2004)</a> identified mutations in the CDKL5 gene (<a href="#0001">300203.0001</a>-<a href="#0004">300203.0004</a>). The disorder had some phenotypic features of atypical Rett syndrome (see <a href="/entry/312750">312750</a>). All the patients in the report of <a href="#25" class="mim-tip-reference" title="Tao, J., Van Esch, H., Hagedorn-Greiwe, M., Hoffmann, K., Moser, B., Raynaud, M., Sperner, J., Fryns, J.-P., Schwinger, E., Gecz, J., Ropers, H.-H., Kalscheuer, V. M. <strong>Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation.</strong> Am. J. Hum. Genet. 75: 1149-1154, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15499549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15499549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15499549[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/10.1086/426460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15499549">Tao et al. (2004)</a> were girls. The family of <a href="#29" class="mim-tip-reference" title="Weaving, L. S., Christodoulou, J., Williamson, S. L., Friend, K. L., McKenzie, O. L. D., Archer, H., Evans, J., Clarke, A., Pelka, G. J., Tam, P. P. L., Watson, C., Lahooti, H., Ellaway, C. J., Bennetts, B., Leonard, H., Gecz, J. <strong>Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.</strong> Am. J. Hum. Genet. 75: 1079-1093, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15492925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15492925</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15492925[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/10.1086/426462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15492925">Weaving et al. (2004)</a> contained 2 twin girls and a brother, who was profoundly affected. The brother had infantile seizures, a mixed seizure disorder, severe global developmental delay with no visual or social responses, spastic quadriparesis, cortical blindness, episodes of hyperventilation, and marked kyphoscoliosis. He died of respiratory failure at the age of 16 years. In the mouse brain, <a href="#29" class="mim-tip-reference" title="Weaving, L. S., Christodoulou, J., Williamson, S. L., Friend, K. L., McKenzie, O. L. D., Archer, H., Evans, J., Clarke, A., Pelka, G. J., Tam, P. P. L., Watson, C., Lahooti, H., Ellaway, C. J., Bennetts, B., Leonard, H., Gecz, J. <strong>Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.</strong> Am. J. Hum. Genet. 75: 1079-1093, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15492925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15492925</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15492925[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/10.1086/426462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15492925">Weaving et al. (2004)</a> showed that Cdkl5 expression overlapped with that of Mecp2 (<a href="/entry/300005">300005</a>), which is mutated in classic Rett syndrome, and that its expression was unaffected by the loss of Mecp2. In view of the overlapping phenotypic spectrum of CDKL5 and MECP2 mutations, <a href="#25" class="mim-tip-reference" title="Tao, J., Van Esch, H., Hagedorn-Greiwe, M., Hoffmann, K., Moser, B., Raynaud, M., Sperner, J., Fryns, J.-P., Schwinger, E., Gecz, J., Ropers, H.-H., Kalscheuer, V. M. <strong>Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation.</strong> Am. J. Hum. Genet. 75: 1149-1154, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15499549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15499549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15499549[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/10.1086/426460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15499549">Tao et al. (2004)</a> suggested that these 2 genes may play a role in a common pathogenic process. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15492925+15499549" 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="Lin, C., Franco, B., Rosner, M. R. <strong>CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders.</strong> Hum. Molec. Genet. 14: 3775-3786, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16330482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16330482</a>] [<a href="https://doi.org/10.1093/hmg/ddi391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16330482">Lin et al. (2005)</a> expressed and characterized CDKL5 mutant forms. All CDKL5 mutations associated with a disease phenotype tested caused loss of kinase activity as assessed by autophosphorylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16330482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bienvenu, T., Chelly, J. <strong>Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized.</strong> Nature Rev. Genet. 7: 415-426, 2006. Note: Erratum: Nature Rev. Genet. 7: 583 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16708070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16708070</a>] [<a href="https://doi.org/10.1038/nrg1878" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16708070">Bienvenu and Chelly (2006)</a> reported 2 additional mutations in CDKL5 associated with an atypical Rett syndrome phenotype. They stated that at least 12 point mutations and 2 translocations involving this gene had been reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16708070" 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>Among 16 Chinese patients diagnosed with Rett syndrome who had no mutation in MECP2, <a href="#10" class="mim-tip-reference" title="Li, M., Pan, H., Bao, X.-H., Zhang, Y.-Z., Wu, X.-R. <strong>MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome.</strong> J. Hum. Genet. 52: 38-47, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17089071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17089071</a>] [<a href="https://doi.org/10.1007/s10038-006-0079-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17089071">Li et al. (2007)</a> detected 1 synonymous mutation in exon 5 of the CDKL5 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17089071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Archer, H. L., Evans, J., Edwards, S., Colley, J., Newbury-Ecob, R., O'Callaghan, F., Huyton, M., O'Regan, M., Tolmie, J., Sampson, J., Clarke, A., Osborne, J. <strong>CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients.</strong> J. Med. Genet. 43: 729-734, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16611748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16611748</a>] [<a href="https://doi.org/10.1136/jmg.2006.041467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16611748">Archer et al. (2006)</a> searched for CDKL5 mutations in a group of 73 patients referred for CDKL5 analysis, of whom 49 had epileptic seizure onset in the first 6 months of life, and in a group of 26 patients with infantile spasms previously recruited to a clinical trial of that disorder. Seven likely pathogenic mutations were found among female patients from group 1 with epileptic seizure onset in the first 6 months of life, accounting for 7 of the 42 in this group (17%). No mutations other than the already published mutations were found in female patients from group 2, or in any male patient from either study group. All patients with mutations had early signs of developmental delay and most had made little developmental progress. Further clinical information, available for 6 patients, indicated that autistic features and tactile hypersensitivity were common, but only 1 had suggestive Rett-like features. All had a severe epileptic seizure disorder; all but 1 had myoclonic jerks. <a href="#1" class="mim-tip-reference" title="Archer, H. L., Evans, J., Edwards, S., Colley, J., Newbury-Ecob, R., O'Callaghan, F., Huyton, M., O'Regan, M., Tolmie, J., Sampson, J., Clarke, A., Osborne, J. <strong>CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients.</strong> J. Med. Genet. 43: 729-734, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16611748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16611748</a>] [<a href="https://doi.org/10.1136/jmg.2006.041467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16611748">Archer et al. (2006)</a> suggested that the spectrum of the epileptic seizure disorder and associated EEG changes in patients with CDKL5 mutations is broader than previously reported, and that CDKL5 mutations are a significant cause of infantile spasms and early epileptic seizures in female patients, and of a later intractable seizure disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16611748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated Italian boys with severe encephalopathy and early-onset intractable seizures, <a href="#5" class="mim-tip-reference" title="Elia, M., Falco, M., Ferri, R., Spalletta, A., Bottitta, M., Calabrese, G., Carotenuto, M., Musumeci, S. A., Lo Giudice, M., Fichera, M. <strong>CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy.</strong> Neurology 71: 997-999, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18809835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18809835</a>] [<a href="https://doi.org/10.1212/01.wnl.0000326592.37105.88" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18809835">Elia et al. (2008)</a> identified 3 different mutations in the CDKL5 gene (see, e.g., <a href="#0011">300203.0011</a> and <a href="#0012">300203.0012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18809835" 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="Erez, A., Patel, A. J., Wang, X., Xia, Z., Bhatt, S. S., Craigen, W., Cheung, S. W., Lewis, R. A., Fang, P., Davenport, S. L. H., Stankiewicz, P., Lalani, S. R. <strong>Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder.</strong> Neurogenetics 10: 363-369, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19471977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19471977</a>] [<a href="https://doi.org/10.1007/s10048-009-0195-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19471977">Erez et al. (2009)</a> identified variable-sized microdeletions involving exons 1 to 4 of the CDKL5 gene in 3 girls with early-onset seizures. Two of the deletions were flanked by Alu repetitive elements and may have resulted from either nonallelic homologous recombination or a mechanism involving microhomology-mediated fork stalling and template switching/microhomology-mediated break-induced replication. The findings indicated the importance of exon-targeted array CGH analysis for proper analysis of the CDKL5 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19471977" 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="Nemos, C., Lambert, L., Giuliano, F., Doray, B., Roubertie, A., Goldenberg, A., Delobel, B., Layet, V., N'guyen, M. A., Saunier, A., Verneau, F., Jonveaux, P., Philippe, C. <strong>Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature.</strong> Clin. Genet. 76: 357-371, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19793311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19793311</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01194.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19793311">Nemos et al. (2009)</a> screened the CDKL5 gene in a cohort of 177 patients with early-onset seizures, including 30 boys and 10 girls with Aicardi syndrome (AIC; <a href="/entry/304050">304050</a>). Eleven girls had 9 different de novo mutations in the CDKL5 gene, including 1 large deletion found by multiplex ligation-dependent probe amplification (MLPA). Studies of genomic DNA extracted from patient peripheral blood lymphocytes showed that all mutations were associated with random X inactivation at the HUMARA locus. <a href="#17" class="mim-tip-reference" title="Nemos, C., Lambert, L., Giuliano, F., Doray, B., Roubertie, A., Goldenberg, A., Delobel, B., Layet, V., N'guyen, M. A., Saunier, A., Verneau, F., Jonveaux, P., Philippe, C. <strong>Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature.</strong> Clin. Genet. 76: 357-371, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19793311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19793311</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01194.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19793311">Nemos et al. (2009)</a> generated cell lines that exclusively expressed mutant missense mutations (see, e.g., A40V; <a href="#0009">300203.0009</a>) and found that the mutant missense proteins properly localized to the nucleus. None of the girls with Aicardi syndrome had a CDKL5 mutation. <a href="#17" class="mim-tip-reference" title="Nemos, C., Lambert, L., Giuliano, F., Doray, B., Roubertie, A., Goldenberg, A., Delobel, B., Layet, V., N'guyen, M. A., Saunier, A., Verneau, F., Jonveaux, P., Philippe, C. <strong>Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature.</strong> Clin. Genet. 76: 357-371, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19793311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19793311</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01194.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19793311">Nemos et al. (2009)</a> noted that this study brought the number of published CDKL5 mutations to 59, and indicated that CDKL5 mutations account for up to 28% of females with early-onset seizures and intractable epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19793311" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Rademacher, N., Hambrock, M., Fischer, U., Moser, B., Ceulemans, B., Lieb, W., Boor, R., Stefanova, I., Gillessen-Kaesbach, G., Runge, C., Korenke, G. C., Spranger, S., Laccone, F., Tzschach, A., Kalscheuer, V. M. <strong>Identification of a novel CDKL5 exon and pathogenic mutations in patients with severe mental retardation, early-onset seizures and Rett-like features. (Letter)</strong> Neurogenetics 12: 165-167, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21318334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21318334</a>] [<a href="https://doi.org/10.1007/s10048-011-0277-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21318334">Rademacher et al. (2011)</a> identified 5 pathogenic mutations in the CDKL5 gene in 5 of 345 female patients with a clinical diagnosis of Rett syndrome, severe infantile seizures, or atypical Rett syndrome. No mutations were identified in the newly identified exon (exon 16a) that is highly expressed in the brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21318334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bartnik, M., Derwinska, K., Gos, M., Obersztyn, E., Kolodziejska, K. E., Erez, A., Szpecht-Potocka, A., Fang, P., Terczynska, I., Mierzewska, H., Lohr, N. J., Bellus, G. A., Reimschiesel, T., Bocian, E., Mazurczak, T., Cheung, S. W., Stankiewicz, P. <strong>Early-onset seizures due to mosaic exonic deletions of CDKL5 in a male and two females.</strong> Genet. Med. 13: 447-452, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21293276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21293276</a>] [<a href="https://doi.org/10.1097/GIM.0b013e31820605f5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21293276">Bartnik et al. (2011)</a> used CGH with a custom-designed clinical oligonucleotide array targeting exons of selected disease and candidate genes, including CDKL5, and identified mosaic exonic deletions of this gene in 1 male and 2 females with developmental delay and medically intractable seizures. These 3 mosaic changes represented 60% of all deletions detected in 12,000 patients analyzed by array CGH and involving the exonic portion of CDKL5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21293276" 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>Associations Pending Confirmation</em></strong></p><p>
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In a 13-year-old boy with severely impaired intellectual development and late-onset generalized epilepsy, <a href="#8" class="mim-tip-reference" title="Fraser, H., Goldman, A., Wright, R., Deciphering Developmental Disorders Study, Banka, S. <strong>A maternally inherited frameshift CDKL5 variant in a male with global developmental delay and late-onset generalized epilepsy.</strong> Am. J. Med. Genet. 179A: 507-511, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30624022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30624022</a>] [<a href="https://doi.org/10.1002/ajmg.a.40661" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30624022">Fraser et al. (2019)</a> identified a 1-bp insertion (c.2809_2810insA, ENST00000379996.7) in exon 20 the CDKL5 gene, resulting in a cys937-to-ter (C937X) substitution. The mutation was identified by trio whole-exome sequencing; no other likely pathogenic variants were identified. The variant was inherited from the boy's mother, who was asymptomatic with no intellectual or neurologic problems, and X-inactivation studies showed random X-inactivation in peripheral DNA. An asymptomatic maternal aunt also carried the variant. Two asymptomatic boys who were at risk of inheriting the variant were tested and did not carry the variant; thus, segregation analysis was consistent with X-linked recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30624022" 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="#22" class="mim-tip-reference" title="Russo, S., Marchi, M., Cogliati, F., Bontai, M. T., Pintaudi, M., Veneselli, E., Saletti, V., Balestrini, M., Ben-Zeev, B., Larizza, L. <strong>Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes.</strong> Neurogenetics 10: 241-250, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19241098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19241098</a>] [<a href="https://doi.org/10.1007/s10048-009-0177-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19241098">Russo et al. (2009)</a> identified 7 different mutations in the CDKL5 gene in 6 of 93 patients with classic or atypical Rett syndrome and in 1 of 17 patients with Angelman/Angelman-like patients (see <a href="/entry/105830">105830</a>). Two of the patients were reported by <a href="#18" class="mim-tip-reference" title="Pintaudi, M., Baglietto, M. G., Gaggero, R., Parodi, E., Pessagno, A., Marchi, M., Russo, S., Veneselli, E. <strong>Clinical and electroencephalographic features in patients with CDKL5 mutations: two new Italian cases and review of the literature.</strong> Epilepsy Behav. 12: 326-331, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18063413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18063413</a>] [<a href="https://doi.org/10.1016/j.yebeh.2007.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18063413">Pintaudi et al. (2008)</a> and 1 by <a href="#23" class="mim-tip-reference" title="Saletti, V., Canafoglia, L., Cambiaso, P., Russo, S., Marchi, M., Riva, D. <strong>A CDKL5 mutated child with precocious puberty.</strong> Am. J. Med. Genet. 149A: 1046-1051, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396824</a>] [<a href="https://doi.org/10.1002/ajmg.a.32806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396824">Saletti et al. (2009)</a>. All were girls, and all except 1 showed progressive microcephaly during the first 2 years of life. All girls had severe intellectual disability, limited hand skills, hypotonia, lack of eye contact, and the absence of speech and walking, except for 1. Only 2 patients showed a clear regressive stage. Seizures appeared by the second week of life: 3 patients had drug-resistant seizures, 3 had some response, and 1 had spontaneous resolution of seizures at 6 months. The patient with features consistent with an Angelman-like syndrome, resulting from a 2-bp insertion (903insGA; <a href="#0013">300203.0013</a>) had absence of speech, severe developmental delay, ataxic gait, hypermotoric behavior, and easily excitable personality with uplifted hand-flapping. She was also autistic but had relatively better motor skills than the other girls. Overall, the CDKL5 mutations included 2 missense, 2 splicing, 1 in-frame deletion, 1 nonsense mutation, and 1 insertion. Four of the mutations affected the predicted N-terminal catalytic domain. Nonsense mutation carriers tended to have a milder phenotype than those with missense or splicing mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19396824+19241098+18063413" 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="#28" class="mim-tip-reference" title="Wang, I-T. J., Allen, M., Goffin, D., Zhu, X., Fairless, A. H., Brodkin, E. S., Siegel, S. J., Marsh, E. D., Blendy, J. A., Zhou, Z. <strong>Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice.</strong> Proc. Nat. Acad. Sci. 109: 21516-21521, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23236174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23236174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23236174[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.1216988110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23236174">Wang et al. (2012)</a> found that male Cdkl5 -/y mice and female Cdkl5 +/- mice were viable and fertile, with normal appearance, growth, and overall brain morphology. Cdkl5 -/y males were hyperactive, showed motor, learning, memory, and social impairments, and had reduced anxiety relative to wildtype mice. Compared with wildtype, Cdkl5 -/y brains showed decreased phosphorylation of protein kinase A (see <a href="/entry/188830">188830</a>) and Akt (see <a href="/entry/164730">164730</a>) substrates, resulting in disruption of Akt and Mtor (see <a href="/entry/601231">601231</a>) signaling. Other phosphorylation profiles were moderately or mildly affected in Cdkl5 -/y brains. <a href="#28" class="mim-tip-reference" title="Wang, I-T. J., Allen, M., Goffin, D., Zhu, X., Fairless, A. H., Brodkin, E. S., Siegel, S. J., Marsh, E. D., Blendy, J. A., Zhou, Z. <strong>Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice.</strong> Proc. Nat. Acad. Sci. 109: 21516-21521, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23236174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23236174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23236174[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.1216988110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23236174">Wang et al. (2012)</a> concluded that CDKL5 plays a critical role in coordinating neural signaling cascades. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23236174" 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="#4" class="mim-tip-reference" title="Della Sala, G., Putignano, E., Chelini, G., Melani, R., Calcagno, E., Ratto, G. M., Amendola, E., Gross, C. T., Giustetto, M., Pizzorusso, T. <strong>Dendritic spine instability in a mouse model of CDKL5 disorder is rescued by insulin-like growth factor 1.</strong> Biol. Psychiat. 80: 302-311, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26452614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26452614</a>] [<a href="https://doi.org/10.1016/j.biopsych.2015.08.028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26452614">Della Sala et al. (2016)</a> found that Cdkl5 -/y mice had reduced synaptic density, impaired long-term potentiation maintenance, and reduced spontaneous excitatory postsynaptic current frequency. Cdkl5 -/y dendritic spines failed to stabilize, possibly due to reduced synaptic Psd95 (DLG4; <a href="/entry/602887">602887</a>) accumulation. Subcutaneous administration of IGF1 (<a href="/entry/147440">147440</a>), an activator of the Akt-Mtor pathway, rescued defective Psd95 expression and normalized spine density and turnover in developing and adult Cdkl5 -/y mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26452614" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Lo Martire, V., Alvente, S., Bastianini, S., Berteotti, C., Silvani, A., Valli, A., Viggiano, R., Ciani, E., Zoccoli, G. <strong>CDKL5 deficiency entails sleep apneas in mice.</strong> J. Sleep Res. 26: 495-497, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28230307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28230307</a>] [<a href="https://doi.org/10.1111/jsr.12512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28230307">Lo Martire et al. (2017)</a> found that Cdkl5-knockout mice showed a higher occurrence of sleep apnea than wildtype mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28230307" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Mazziotti, R., Lupori, L., Sagona, G., Gennaro, M., Della Sala, G., Putignano, E., Pizzorusso, T. <strong>Searching for biomarkers of CDKL5 disorder: early-onset visual impairment in CDKL5 mutant mice.</strong> Hum. Molec. Genet. 26: 2290-2298, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28369421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28369421</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28369421[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddx119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28369421">Mazziotti et al. (2017)</a> found that Cdkl5 -/y male and Cdkl5 +/- female mice developed visual defects by postnatal day 27. Defects included reduced amplitude of light-induced cortical response, abnormal contrast response, and impaired visual acuity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28369421" 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="#26" class="mim-tip-reference" title="Terzic, B., Davatolhagh, M. F., Ho, Y., Tang, S., Liu, Y.-T., Xia, Z., Cui, Y., Fuccillo, M. V., Zhou, Z. <strong>Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder-related deficits.</strong> J. Clin. Invest. 131: e143655, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34651584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34651584</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34651584[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI143655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34651584">Terzic et al. (2021)</a> demonstrated that postdevelopmental knockout of Cdkl5 in male mice at age 6 weeks resulted in deficits in locomotion, sociability, learning, memory, and auditory-evoked event-related potentials (ERPs), similar to what was previously seen in germline Cdkl5 knockout mice. <a href="#26" class="mim-tip-reference" title="Terzic, B., Davatolhagh, M. F., Ho, Y., Tang, S., Liu, Y.-T., Xia, Z., Cui, Y., Fuccillo, M. V., Zhou, Z. <strong>Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder-related deficits.</strong> J. Clin. Invest. 131: e143655, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34651584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34651584</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34651584[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI143655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34651584">Terzic et al. (2021)</a> also found that restoration of Cdkl5 expression in a Cdkl5-deficient mouse through a Cre-lox recombination approach resulted in improvement in anxiety- and hyperactivity-related behaviors. These results demonstrated that CDKL5 is required during both development and adulthood for neurologic function and suggested the possibility of disease treatment after symptom onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34651584" 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=300203[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p>In 2 affected monozygotic twin girls and an affected brother in a family (family 1) with X-linked developmental and epileptic encephalopathy-2 (DEE2; <a href="/entry/300672">300672</a>), <a href="#29" class="mim-tip-reference" title="Weaving, L. S., Christodoulou, J., Williamson, S. L., Friend, K. L., McKenzie, O. L. D., Archer, H., Evans, J., Clarke, A., Pelka, G. J., Tam, P. P. L., Watson, C., Lahooti, H., Ellaway, C. J., Bennetts, B., Leonard, H., Gecz, J. <strong>Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.</strong> Am. J. Hum. Genet. 75: 1079-1093, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15492925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15492925</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15492925[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/10.1086/426462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15492925">Weaving et al. (2004)</a> identified a 1-bp deletion (183delT) in exon 5 of the CDKL5 gene, resulting in a frameshift and premature termination of the protein at amino acid 75. One twin and her brother had onset of infantile spasms as 9 weeks of age and in the neonatal period, respectively, and both developed a mixed seizure disorder. The other twin had a diagnosis of autism; at age 19 years, she had not had any seizures. The brother died at age 16 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15492925" 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 28-year-old woman (family 2) with developmental and epileptic encephalopathy (DEE2; <a href="/entry/300672">300672</a>), <a href="#29" class="mim-tip-reference" title="Weaving, L. S., Christodoulou, J., Williamson, S. L., Friend, K. L., McKenzie, O. L. D., Archer, H., Evans, J., Clarke, A., Pelka, G. J., Tam, P. P. L., Watson, C., Lahooti, H., Ellaway, C. J., Bennetts, B., Leonard, H., Gecz, J. <strong>Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.</strong> Am. J. Hum. Genet. 75: 1079-1093, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15492925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15492925</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15492925[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/10.1086/426462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15492925">Weaving et al. (2004)</a> identified a G-to-A transition in intron 13 of the CDKL5 gene, resulting in a splice site mutation. The patient had onset of severe spasms at about 6 weeks of age and developed intractable seizures during childhood. Her affected half sister with the mutation had a diagnosis of Rett syndrome. She did not have seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15492925" 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=RCV000012251 OR RCV000133370 OR RCV004724734" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012251, RCV000133370, RCV004724734" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012251...</a>
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<p>In a 5-year-old girl (family 1) with developmental and epileptic encephalopathy (DEE2; <a href="/entry/300672">300672</a>), <a href="#25" class="mim-tip-reference" title="Tao, J., Van Esch, H., Hagedorn-Greiwe, M., Hoffmann, K., Moser, B., Raynaud, M., Sperner, J., Fryns, J.-P., Schwinger, E., Gecz, J., Ropers, H.-H., Kalscheuer, V. M. <strong>Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation.</strong> Am. J. Hum. Genet. 75: 1149-1154, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15499549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15499549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15499549[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/10.1086/426460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15499549">Tao et al. (2004)</a> identified a de novo c.455G-T transversion in exon 7 of the CDKL5 gene, resulting in a cys152-to-phe (C152F) substitution. Onset of seizures occurred at age 5 weeks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15499549" 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">rs61749700 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61749700;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=rs61749700" 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=rs61749700" 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=RCV000012252 OR RCV000133372 OR RCV004724735" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012252, RCV000133372, RCV004724735" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012252...</a>
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<p>In female monozygotic twins with developmental and epileptic encephalopathy (DEE2; <a href="/entry/300672">300672</a>), <a href="#25" class="mim-tip-reference" title="Tao, J., Van Esch, H., Hagedorn-Greiwe, M., Hoffmann, K., Moser, B., Raynaud, M., Sperner, J., Fryns, J.-P., Schwinger, E., Gecz, J., Ropers, H.-H., Kalscheuer, V. M. <strong>Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation.</strong> Am. J. Hum. Genet. 75: 1149-1154, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15499549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15499549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15499549[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/10.1086/426460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15499549">Tao et al. (2004)</a> identified a de novo c.525A-T transversion in exon 8 of the CDKL5 gene, resulting in an arg175-to-ser (R175S) substitution. The phenotype included onset of infantile spasms between 2 and 6 weeks of life, severe psychomotor retardation, stereotypic hand movements, mood swings, and episodes of hyperventilation. One twin developed absence seizures later in life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15499549" 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">rs267608433 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608433;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=rs267608433" 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=rs267608433" 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=RCV000133326 OR RCV000170008 OR RCV001068312 OR RCV004724843" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000133326, RCV000170008, RCV001068312, RCV004724843" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000133326...</a>
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<p>In a 9-year-old girl with developmental and epileptic encephalopathy (DEE2; <a href="/entry/300672">300672</a>), <a href="#24" class="mim-tip-reference" title="Scala, E., Ariani, F., Mari, F., Caselli, R., Pescucci, C., Longo, I., Meloni, I., Giachino, D., Bruttini, M., Hayek, G., Zappella, M., Renieri, A. <strong>CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms.</strong> J. Med. Genet. 42: 103-107, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689447</a>] [<a href="https://doi.org/10.1136/jmg.2004.026237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689447">Scala et al. (2005)</a> identified a 4-bp deletion (c.166_169delGAAA) in exon 5 of the CDKL5 gene, resulting in a stop codon at position 74 that interrupts the catalytic domain and results in a markedly truncated, nonfunctional protein. She had onset of seizures at age 1.5 months and some features of Rett syndrome, including acquired microcephaly, hand apraxia, generalized hypotonia, and stereotypic hand motions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15689447" 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 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 2</strong>
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CDKL5, 2-BP DEL, 2636CT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs61753251 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61753251;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=rs61753251" 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=rs61753251" 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=RCV000133357 OR RCV000145535 OR RCV000169918 OR RCV000229531 OR RCV004724867" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000133357, RCV000145535, RCV000169918, RCV000229531, RCV004724867" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000133357...</a>
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<p>In an 8-year-old girl (patient 2) with developmental and epileptic encephalopathy (DEE2; <a href="/entry/300672">300672</a>), <a href="#24" class="mim-tip-reference" title="Scala, E., Ariani, F., Mari, F., Caselli, R., Pescucci, C., Longo, I., Meloni, I., Giachino, D., Bruttini, M., Hayek, G., Zappella, M., Renieri, A. <strong>CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms.</strong> J. Med. Genet. 42: 103-107, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689447</a>] [<a href="https://doi.org/10.1136/jmg.2004.026237" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689447">Scala et al. (2005)</a> identified a 2-bp deletion (c.2636_2637delCT) in exon 18 of the CDKL5 gene, predicted to eliminate a putative signal peptidase I serine active site of the CDKL5 protein. The patient had onset of seizures at 10 days of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15689447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 2</strong>
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CDKL5, GLN834TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs122460158 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122460158;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=rs122460158" 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=rs122460158" 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=RCV000012255 OR RCV000133352 OR RCV003764559 OR RCV004724736" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012255, RCV000133352, RCV003764559, RCV004724736" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012255...</a>
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<p>In a 3-year-old girl with developmental and epileptic encephalopathy (DEE2; <a href="/entry/300672">300672</a>), <a href="#16" class="mim-tip-reference" title="Nectoux, J., Heron, D., Tallot, M., Chelly, J., Bienvenu, T. <strong>Maternal origin of a novel C-terminal truncation mutation in CDKL5 causing a severe atypical form of Rett syndrome.</strong> Clin. Genet. 70: 29-33, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16813600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16813600</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00629.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16813600">Nectoux et al. (2006)</a> identified a heterozygous de novo 2500C-T transition in exon 18 of the CDKL5 gene, resulting in a gln834-to-ter (Q834X) substitution. Further molecular analysis indicated maternal origin, suggesting a maternal germline mutation. RT-PCR analysis did not detect an abnormal mRNA transcript, suggesting the mutated transcript underwent nonsense-mediated decay. The child had a severe phenotype, with seizures at 10 days of age, no speech development, and inability to walk. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16813600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 2</strong>
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CDKL5, IVS6AS, G-T, -1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267608474 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608474;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=rs267608474" 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=rs267608474" 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=RCV000144134 OR RCV000170042 OR RCV005053926" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144134, RCV000170042, RCV005053926" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144134...</a>
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<p>In a 2-year-old girl (patient 2) diagnosed with X-linked infantile spasm syndrome (DEE2; <a href="/entry/300672">300672</a>), <a href="#1" class="mim-tip-reference" title="Archer, H. L., Evans, J., Edwards, S., Colley, J., Newbury-Ecob, R., O'Callaghan, F., Huyton, M., O'Regan, M., Tolmie, J., Sampson, J., Clarke, A., Osborne, J. <strong>CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients.</strong> J. Med. Genet. 43: 729-734, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16611748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16611748</a>] [<a href="https://doi.org/10.1136/jmg.2006.041467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16611748">Archer et al. (2006)</a> identified a splice site mutation in the CDKL5 gene predicted to result in exon 7 skipping (IVS6-1G-T). Onset of seizures occurred at 10 days of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16611748" 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">rs122460159 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122460159;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=rs122460159" 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=rs122460159" 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=RCV000012257 OR RCV000133317 OR RCV000699210 OR RCV001507073 OR RCV001564884" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012257, RCV000133317, RCV000699210, RCV001507073, RCV001564884" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012257...</a>
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<p>In 2 unrelated girls with developmental and epileptic encephalopathy (DEE2; <a href="/entry/300672">300672</a>), <a href="#21" class="mim-tip-reference" title="Rosas-Vargas, H., Bahi-Buisson, N., Philippe, C., Nectoux, J., Girard, B., N'Guyen Morel, M. A., Gitiaux, C., Lazaro, L., Odent, S., Jonveaux, P., Chelly, J., Bienvenu, T. <strong>Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy. (Letter)</strong> J. Med. Genet. 45: 172-178, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17993579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17993579</a>] [<a href="https://doi.org/10.1136/jmg.2007.053504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17993579">Rosas-Vargas et al. (2008)</a> identified a c.119C-T transition in exon 4 of the CDKL5 gene, resulting in an ala40-to-val (A40V) substitution at a highly conserved residue. In vitro functional expression analysis showed that the mutant protein was mislocalized in the cytoplasm and did not reach the nucleus. Onset occurred at age 1 month in 1 patient and at age 6 weeks in the other patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17993579" 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="Nemos, C., Lambert, L., Giuliano, F., Doray, B., Roubertie, A., Goldenberg, A., Delobel, B., Layet, V., N'guyen, M. A., Saunier, A., Verneau, F., Jonveaux, P., Philippe, C. <strong>Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature.</strong> Clin. Genet. 76: 357-371, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19793311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19793311</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01194.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19793311">Nemos et al. (2009)</a> identified a de novo A40V mutation in 2 unrelated girls with DEE2. Onset of seizures occurred at ages 4 and 6 weeks, respectively, but 1 patient had a more severe phenotype with intractable seizures and later epileptic encephalopathy, whereas the other did not. In contrast to the in vitro findings of <a href="#21" class="mim-tip-reference" title="Rosas-Vargas, H., Bahi-Buisson, N., Philippe, C., Nectoux, J., Girard, B., N'Guyen Morel, M. A., Gitiaux, C., Lazaro, L., Odent, S., Jonveaux, P., Chelly, J., Bienvenu, T. <strong>Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy. (Letter)</strong> J. Med. Genet. 45: 172-178, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17993579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17993579</a>] [<a href="https://doi.org/10.1136/jmg.2007.053504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17993579">Rosas-Vargas et al. (2008)</a>, <a href="#17" class="mim-tip-reference" title="Nemos, C., Lambert, L., Giuliano, F., Doray, B., Roubertie, A., Goldenberg, A., Delobel, B., Layet, V., N'guyen, M. A., Saunier, A., Verneau, F., Jonveaux, P., Philippe, C. <strong>Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature.</strong> Clin. Genet. 76: 357-371, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19793311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19793311</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01194.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19793311">Nemos et al. (2009)</a> found that the mutant A40V protein correctly localized to the nucleus in lymphoblastoid cell lines derived from patient lymphoblasts, but was associated with a downregulation of protein levels particularly at the G0/G1 stage of the cell cycle. <a href="#17" class="mim-tip-reference" title="Nemos, C., Lambert, L., Giuliano, F., Doray, B., Roubertie, A., Goldenberg, A., Delobel, B., Layet, V., N'guyen, M. A., Saunier, A., Verneau, F., Jonveaux, P., Philippe, C. <strong>Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature.</strong> Clin. Genet. 76: 357-371, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19793311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19793311</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01194.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19793311">Nemos et al. (2009)</a> emphasized that their own studies more closely represented an in vivo model and suggested that CDKL5 localization is tissue-dependent. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17993579+19793311" 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">rs62641235 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs62641235;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=rs62641235" 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=rs62641235" 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=RCV000012258 OR RCV000080068 OR RCV000169913 OR RCV001385703 OR RCV001507029" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012258, RCV000080068, RCV000169913, RCV001385703, RCV001507029" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012258...</a>
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<p>In a 5-year-old girl with developmental and epileptic encephalopathy (DEE2; <a href="/entry/300672">300672</a>), <a href="#23" class="mim-tip-reference" title="Saletti, V., Canafoglia, L., Cambiaso, P., Russo, S., Marchi, M., Riva, D. <strong>A CDKL5 mutated child with precocious puberty.</strong> Am. J. Med. Genet. 149A: 1046-1051, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396824</a>] [<a href="https://doi.org/10.1002/ajmg.a.32806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396824">Saletti et al. (2009)</a> identified a de novo c.215T-C transition in exon 5 of the CDKL5 gene, resulting in an ile72-to-thr (I72T) substitution in a conserved residue. within the catalytic domain. She had severe mental retardation, microcephaly, diffuse hypotonia, hyperreflexia, no language, numerous refractory seizures since 2 months of age, and stereotypical movement of the hands. At age 5 years, 3 months, she showed signs of precocious puberty, including rapid growth in height, increased sex hormones, and ultrasonic uterine and ovarian changes consistent with the onset of puberty. <a href="#23" class="mim-tip-reference" title="Saletti, V., Canafoglia, L., Cambiaso, P., Russo, S., Marchi, M., Riva, D. <strong>A CDKL5 mutated child with precocious puberty.</strong> Am. J. Med. Genet. 149A: 1046-1051, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19396824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19396824</a>] [<a href="https://doi.org/10.1002/ajmg.a.32806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19396824">Saletti et al. (2009)</a> noted that the onset of precocious puberty had not been reported in association with CDKL5 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19396824" 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">rs267606713 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606713;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=rs267606713" 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=rs267606713" 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=RCV000012259 OR RCV004724737" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012259, RCV004724737" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012259...</a>
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<p>In a 9-year-old Italian boy (patient 2) with developmental and epileptic encephalopathy (DEE2; <a href="/entry/300672">300672</a>), <a href="#5" class="mim-tip-reference" title="Elia, M., Falco, M., Ferri, R., Spalletta, A., Bottitta, M., Calabrese, G., Carotenuto, M., Musumeci, S. A., Lo Giudice, M., Fichera, M. <strong>CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy.</strong> Neurology 71: 997-999, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18809835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18809835</a>] [<a href="https://doi.org/10.1212/01.wnl.0000326592.37105.88" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18809835">Elia et al. (2008)</a> identified a de novo hemizygous c.863C-T transition in the CDKL5 gene, resulting in a thr288-to-ile (T288I) substitution predicted to affect the catalytic domain of the protein. The patient showed psychomotor regression starting at age 8 months, which coincided with onset of seizures. He had loss of speech, ataxia, and progression of refractory seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18809835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 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">rs267606714 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606714;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=rs267606714" 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=rs267606714" 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=RCV000012260 OR RCV001203327 OR RCV002281041" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012260, RCV001203327, RCV002281041" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012260...</a>
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<p>In a 3-year-old Italian boy (patient 3) with developmental and epileptic encephalopathy (DEE2; <a href="/entry/300672">300672</a>), <a href="#5" class="mim-tip-reference" title="Elia, M., Falco, M., Ferri, R., Spalletta, A., Bottitta, M., Calabrese, G., Carotenuto, M., Musumeci, S. A., Lo Giudice, M., Fichera, M. <strong>CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy.</strong> Neurology 71: 997-999, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18809835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18809835</a>] [<a href="https://doi.org/10.1212/01.wnl.0000326592.37105.88" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18809835">Elia et al. (2008)</a> identified a de novo hemizygous c.872G-A transition in the CDKL5 gene, resulting in a cys291-to-tyr (C291Y) substitution predicted to affect the catalytic domain of the protein. He had onset of seizures at age 2 months and mild dysmorphic features including high sloping forehead, hypotelorism, epicanthus, broad nasal bridge, high palate, and large anteverted ears. He later showed profound mental retardation and refractory epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18809835" 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">rs267608546 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608546;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=rs267608546" 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=rs267608546" 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=RCV000012261 OR RCV000133391 OR RCV004724890" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012261, RCV000133391, RCV004724890" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012261...</a>
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<p>In a 6-year-old girl (patient 5) with developmental and epileptic encephalopathy (DEE2; <a href="/entry/300672">300672</a>), <a href="#22" class="mim-tip-reference" title="Russo, S., Marchi, M., Cogliati, F., Bontai, M. T., Pintaudi, M., Veneselli, E., Saletti, V., Balestrini, M., Ben-Zeev, B., Larizza, L. <strong>Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes.</strong> Neurogenetics 10: 241-250, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19241098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19241098</a>] [<a href="https://doi.org/10.1007/s10048-009-0177-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19241098">Russo et al. (2009)</a> identified a heterozygous 2-bp duplication (c.903_904dupGA) in exon 11 of the CDKL5 gene, predicted to result in a frameshift and premature termination just downstream of the N-terminal catalytic domain (Leu302Aspfs49ter). The authors noted that the phenotype was consistent with an Angelman-like syndrome. Onset of seizures began at age 3 weeks. She had absence of speech, severe developmental delay, ataxic gait, hypermotoric behavior, and easily excitable personality with uplifted hand-flapping. She was microcephalic, had intractable seizures, brachycephaly, wide mouth, widely dispersed teeth, and progressive prognathism. She was also autistic but had relatively better motor skills compared to other girls with CDKL5 mutations. The findings broadened the phenotype associated with CDKL5 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19241098" 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">rs267606715 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606715;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=rs267606715" 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=rs267606715" 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=RCV000012262 OR RCV001035195 OR RCV004724751" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012262, RCV001035195, RCV004724751" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012262...</a>
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<p>In a girl (patient 8) with developmental and epileptic encephalopathy (DEE2; <a href="/entry/300672">300672</a>), <a href="#17" class="mim-tip-reference" title="Nemos, C., Lambert, L., Giuliano, F., Doray, B., Roubertie, A., Goldenberg, A., Delobel, B., Layet, V., N'guyen, M. A., Saunier, A., Verneau, F., Jonveaux, P., Philippe, C. <strong>Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature.</strong> Clin. Genet. 76: 357-371, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19793311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19793311</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01194.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19793311">Nemos et al. (2009)</a> identified a de novo heterozygous c.533G-C transversion (c.533G-C, NM_003159.2) in exon 8 of the CDKL5 gene, resulting in an arg178-to-pro (R178P) substitution. The mutant protein correctly localized to the nucleus in lymphoblastoid cell lines derived from patient lymphoblasts, but was associated with a downregulation of protein levels, particularly at the G0/G1 stage of the cell cycle. The patient had onset of seizures at age 4 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19793311" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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Archer, H. L., Evans, J., Edwards, S., Colley, J., Newbury-Ecob, R., O'Callaghan, F., Huyton, M., O'Regan, M., Tolmie, J., Sampson, J., Clarke, A., Osborne, J.
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<strong>CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients.</strong>
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J. Med. Genet. 43: 729-734, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16611748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16611748</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16611748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2006.041467" target="_blank">Full Text</a>]
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Bartnik, M., Derwinska, K., Gos, M., Obersztyn, E., Kolodziejska, K. E., Erez, A., Szpecht-Potocka, A., Fang, P., Terczynska, I., Mierzewska, H., Lohr, N. J., Bellus, G. A., Reimschiesel, T., Bocian, E., Mazurczak, T., Cheung, S. W., Stankiewicz, P.
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<strong>Early-onset seizures due to mosaic exonic deletions of CDKL5 in a male and two females.</strong>
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Genet. Med. 13: 447-452, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21293276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21293276</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21293276" 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/GIM.0b013e31820605f5" target="_blank">Full Text</a>]
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Bienvenu, T., Chelly, J.
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<strong>Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized.</strong>
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Nature Rev. Genet. 7: 415-426, 2006. Note: Erratum: Nature Rev. Genet. 7: 583 only, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16708070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16708070</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16708070" 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/nrg1878" target="_blank">Full Text</a>]
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<a id="Della Sala2016" class="mim-anchor"></a>
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Della Sala, G., Putignano, E., Chelini, G., Melani, R., Calcagno, E., Ratto, G. M., Amendola, E., Gross, C. T., Giustetto, M., Pizzorusso, T.
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<strong>Dendritic spine instability in a mouse model of CDKL5 disorder is rescued by insulin-like growth factor 1.</strong>
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Biol. Psychiat. 80: 302-311, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26452614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26452614</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26452614" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.biopsych.2015.08.028" target="_blank">Full Text</a>]
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Elia, M., Falco, M., Ferri, R., Spalletta, A., Bottitta, M., Calabrese, G., Carotenuto, M., Musumeci, S. A., Lo Giudice, M., Fichera, M.
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<strong>CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy.</strong>
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Neurology 71: 997-999, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18809835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18809835</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18809835" 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.0000326592.37105.88" target="_blank">Full Text</a>]
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Erez, A., Patel, A. J., Wang, X., Xia, Z., Bhatt, S. S., Craigen, W., Cheung, S. W., Lewis, R. A., Fang, P., Davenport, S. L. H., Stankiewicz, P., Lalani, S. R.
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<strong>Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder.</strong>
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Neurogenetics 10: 363-369, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19471977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19471977</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19471977" 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/10.1007/s10048-009-0195-z" target="_blank">Full Text</a>]
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Fichou, Y., Nectoux, J., Bahi-Buisson, N., Chelly, J., Bienvenu, T.
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<strong>An isoform of the severe encephalopathy-related CDKL5 gene, including a novel exon with extremely high sequence conservation, is specifically expressed in brain.</strong>
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J. Hum. Genet. 56: 52-57, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21124335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21124335</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21124335" 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/jhg.2010.143" target="_blank">Full Text</a>]
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<a id="Fraser2019" class="mim-anchor"></a>
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Fraser, H., Goldman, A., Wright, R., Deciphering Developmental Disorders Study, Banka, S.
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<strong>A maternally inherited frameshift CDKL5 variant in a male with global developmental delay and late-onset generalized epilepsy.</strong>
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Am. J. Med. Genet. 179A: 507-511, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30624022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30624022</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30624022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.40661" target="_blank">Full Text</a>]
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<a id="Kalscheuer2003" class="mim-anchor"></a>
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Kalscheuer, V. M., Tao, J., Donnelly, A., Hollway, G., Schwinger, E., Kubart, S., Menzel, C., Hoeltzenbein, M., Tommerup, N., Eyre, H., Harbord, M., Haan, E., Sutherland, G. R., Ropers, H.-H., Gecz, J.
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<strong>Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12736870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12736870</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12736870[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=12736870" 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/10.1086/375538" target="_blank">Full Text</a>]
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<strong>MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome.</strong>
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[<a href="https://doi.org/10.1007/s10038-006-0079-0" target="_blank">Full Text</a>]
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<a id="Lin2005" class="mim-anchor"></a>
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Lin, C., Franco, B., Rosner, M. R.
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<strong>CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders.</strong>
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Hum. Molec. Genet. 14: 3775-3786, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16330482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16330482</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16330482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi391" target="_blank">Full Text</a>]
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</p>
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<p class="mim-text-font">
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[<a href="https://doi.org/10.1111/jsr.12512" target="_blank">Full Text</a>]
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</p>
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<div class="">
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Mari, F., Azimonti, S., Bertani, I., Bolognese, F., Colombo, E., Caselli, R., Scala, E., Longo, I., Grosso, S., Pescucci, C., Ariani, F., Hayek, G., Balestri, P., Bergo, A., Badaracco, G., Zappella, M., Broccoli, V., Renieri, A., Kilstrup-Nielsen, C., Landsberger, N.
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<strong>CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15917271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15917271</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15917271" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi198" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28369421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28369421</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28369421[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=28369421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddx119" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1998.5391" target="_blank">Full Text</a>]
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<strong>Maternal origin of a novel C-terminal truncation mutation in CDKL5 causing a severe atypical form of Rett syndrome.</strong>
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[<a href="https://doi.org/10.1111/j.1399-0004.2006.00629.x" target="_blank">Full Text</a>]
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Nemos, C., Lambert, L., Giuliano, F., Doray, B., Roubertie, A., Goldenberg, A., Delobel, B., Layet, V., N'guyen, M. A., Saunier, A., Verneau, F., Jonveaux, P., Philippe, C.
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<strong>Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature.</strong>
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[<a href="https://doi.org/10.1111/j.1399-0004.2009.01194.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.yebeh.2007.10.010" target="_blank">Full Text</a>]
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<a id="Rademacher2011" class="mim-anchor"></a>
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<strong>Identification of a novel CDKL5 exon and pathogenic mutations in patients with severe mental retardation, early-onset seizures and Rett-like features. (Letter)</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21318334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21318334</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21318334" 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/10.1007/s10048-011-0277-6" target="_blank">Full Text</a>]
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<strong>CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19740913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19740913</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19740913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp426" target="_blank">Full Text</a>]
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<a id="Rosas-Vargas2008" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17993579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17993579</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17993579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2007.053504" target="_blank">Full Text</a>]
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<a id="Russo2009" class="mim-anchor"></a>
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<div class="">
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Russo, S., Marchi, M., Cogliati, F., Bontai, M. T., Pintaudi, M., Veneselli, E., Saletti, V., Balestrini, M., Ben-Zeev, B., Larizza, L.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19241098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19241098</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19241098" 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/10.1007/s10048-009-0177-1" target="_blank">Full Text</a>]
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<a id="Saletti2009" class="mim-anchor"></a>
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Saletti, V., Canafoglia, L., Cambiaso, P., Russo, S., Marchi, M., Riva, D.
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<strong>A CDKL5 mutated child with precocious puberty.</strong>
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Am. J. Med. Genet. 149A: 1046-1051, 2009.
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[<a href="https://doi.org/10.1002/ajmg.a.32806" target="_blank">Full Text</a>]
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<a id="Scala2005" class="mim-anchor"></a>
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<div class="">
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Scala, E., Ariani, F., Mari, F., Caselli, R., Pescucci, C., Longo, I., Meloni, I., Giachino, D., Bruttini, M., Hayek, G., Zappella, M., Renieri, A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689447</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15689447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2004.026237" target="_blank">Full Text</a>]
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Tao, J., Van Esch, H., Hagedorn-Greiwe, M., Hoffmann, K., Moser, B., Raynaud, M., Sperner, J., Fryns, J.-P., Schwinger, E., Gecz, J., Ropers, H.-H., Kalscheuer, V. M.
|
|
<strong>Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation.</strong>
|
|
Am. J. Hum. Genet. 75: 1149-1154, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15499549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15499549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15499549[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=15499549" 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/10.1086/426460" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Terzic2021" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Terzic, B., Davatolhagh, M. F., Ho, Y., Tang, S., Liu, Y.-T., Xia, Z., Cui, Y., Fuccillo, M. V., Zhou, Z.
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|
<strong>Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder-related deficits.</strong>
|
|
J. Clin. Invest. 131: e143655, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34651584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34651584</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34651584[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=34651584" 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/10.1172/JCI143655" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Van Esch2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Van Esch, H., Jansen, A., Bauters, M., Froyen, G., Fryns, J.-P.
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|
<strong>Encephalopathy and bilateral cataract in a boy with an interstitial deletion of Xp22 comprising the CDKL5 and NHS genes.</strong>
|
|
Am. J. Med. Genet. 143A: 364-369, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17256798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17256798</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17256798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31572" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="28" class="mim-anchor"></a>
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<a id="Wang2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, I-T. J., Allen, M., Goffin, D., Zhu, X., Fairless, A. H., Brodkin, E. S., Siegel, S. J., Marsh, E. D., Blendy, J. A., Zhou, Z.
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<strong>Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice.</strong>
|
|
Proc. Nat. Acad. Sci. 109: 21516-21521, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23236174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23236174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23236174[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=23236174" 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/10.1073/pnas.1216988110" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="29" class="mim-anchor"></a>
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<a id="Weaving2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weaving, L. S., Christodoulou, J., Williamson, S. L., Friend, K. L., McKenzie, O. L. D., Archer, H., Evans, J., Clarke, A., Pelka, G. J., Tam, P. P. L., Watson, C., Lahooti, H., Ellaway, C. J., Bennetts, B., Leonard, H., Gecz, J.
|
|
<strong>Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.</strong>
|
|
Am. J. Hum. Genet. 75: 1079-1093, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15492925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15492925</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15492925[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=15492925" 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/10.1086/426462" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="30" class="mim-anchor"></a>
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<a id="Williamson2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Williamson, S. L., Giudici, L., Kilstrup-Nielsen, C., Gold, W., Pelka, G. J., Tam, P. P. L., Grimm, A., Prodi, D., Landsberger, N., Christodoulou, J.
|
|
<strong>A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain.</strong>
|
|
Hum. Genet. 131: 187-200, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21748340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21748340</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21748340" 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/10.1007/s00439-011-1058-x" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Sonja A. Rasmussen - updated : 08/19/2024
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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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Hilary J. Vernon - updated : 04/01/2022<br>Carol A. Bocchini - updated : 10/05/2020<br>Patricia A. Hartz - updated : 02/26/2018<br>Patricia A. Hartz - updated : 9/9/2013<br>Ada Hamosh - updated : 10/1/2012<br>Cassandra L. Kniffin - updated : 6/12/2012<br>Patricia A. Hartz - updated : 8/1/2011<br>Cassandra L. Kniffin - updated : 11/18/2010<br>George E. Tiller - updated : 10/28/2010<br>Cassandra L. Kniffin - updated : 12/11/2009<br>Cassandra L. Kniffin - updated : 11/24/2009<br>Cassandra L. Kniffin - updated : 10/15/2009<br>George E. Tiller - updated : 7/6/2009<br>George E. Tiller - updated : 11/14/2008<br>Cassandra L. Kniffin - updated : 3/18/2008<br>Victor A. McKusick - updated : 9/6/2007<br>Victor A. McKusick - updated : 1/9/2007<br>Cassandra L. Kniffin - updated : 8/24/2006<br>Victor A. McKusick - updated : 7/12/2006<br>Marla J. F. O'Neill - updated : 3/1/2005<br>Victor A. McKusick - updated : 11/12/2004<br>Victor A. McKusick - updated : 5/21/2003
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Jennifer P. Macke : 8/13/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/19/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 04/04/2024<br>carol : 04/01/2022<br>carol : 10/05/2020<br>carol : 03/05/2018<br>mgross : 03/01/2018<br>mgross : 02/26/2018<br>carol : 07/14/2015<br>mcolton : 11/26/2013<br>carol : 9/9/2013<br>mgross : 9/9/2013<br>alopez : 10/3/2012<br>terry : 10/1/2012<br>alopez : 6/18/2012<br>ckniffin : 6/12/2012<br>terry : 3/16/2012<br>joanna : 1/31/2012<br>mgross : 8/25/2011<br>terry : 8/1/2011<br>alopez : 3/30/2011<br>wwang : 12/6/2010<br>ckniffin : 11/18/2010<br>wwang : 11/11/2010<br>terry : 10/28/2010<br>wwang : 2/2/2010<br>wwang : 12/29/2009<br>ckniffin : 12/11/2009<br>wwang : 12/4/2009<br>ckniffin : 11/24/2009<br>wwang : 11/6/2009<br>ckniffin : 10/15/2009<br>alopez : 7/7/2009<br>terry : 7/6/2009<br>wwang : 11/14/2008<br>ckniffin : 7/10/2008<br>carol : 5/9/2008<br>ckniffin : 3/18/2008<br>alopez : 9/6/2007<br>carol : 9/5/2007<br>ckniffin : 8/24/2007<br>alopez : 1/10/2007<br>terry : 1/9/2007<br>wwang : 8/31/2006<br>ckniffin : 8/24/2006<br>terry : 7/12/2006<br>wwang : 3/11/2005<br>wwang : 3/8/2005<br>terry : 3/1/2005<br>alopez : 11/18/2004<br>terry : 11/12/2004<br>carol : 6/4/2003<br>tkritzer : 6/2/2003<br>terry : 5/21/2003<br>alopez : 1/15/2003<br>alopez : 8/13/1999
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 300203
|
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
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|
|
CYCLIN-DEPENDENT KINASE-LIKE 5; CDKL5
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
SERINE/THREONINE PROTEIN KINASE 9; STK9
|
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</span>
|
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: CDKL5</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> 773230003;
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|
|
<strong>ICD10CM:</strong> G40.42;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: Xp22.13
|
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|
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Genomic coordinates <span class="small">(GRCh38)</span> : X:18,425,608-18,653,629 </span>
|
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</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
|
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<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>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
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>
|
|
<td rowspan="1">
|
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<span class="mim-font">
|
|
Xp22.13
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Developmental and epileptic encephalopathy 2
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
300672
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
X-linked dominant
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
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</h4>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</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>During transcriptional mapping in the Xp22 region, Montini et al. (1998) found an exon encoding a product with homology to serine-threonine protein kinases. They cloned the corresponding cDNA, designated STK9, from several adult human tissue cDNA libraries. The STK9 cDNA predicts a protein product of 1,022 or 1,030 amino acids, depending on which initiating methionine is used. Northern blot analysis of human and mouse tissues detected a transcript larger than 9.5 kb expressed in a variety of tissues, and an abundant 3.5-kb transcript expressed only in testis. </p><p>Kalscheuer et al. (2003) reported that the STK9 RNA isoform containing exons 1a and 1b (isoform II) is transcribed at very low levels in human fetal brain and testis but not in lymphoblastoid cell lines, whereas the STK9 RNA isoform containing exon 1 (isoform I) is expressed in a wide range of cells, including human fibroblasts and lymphoblastoid cell lines. </p><p>By RT-PCR of human fibroblast total RNA, Fichou et al. (2011) isolated a CDKL5 splice variant that includes an alternative exon, exon 16b. The 41 residues introduced by exon 16b are inserted in-frame in the C-terminal half of the 1,030-amino acid CDKL5 protein, resulting in a deduced 1,071-amino acid protein. Phylogenetic analysis revealed over 95% sequence similarity in the inserted region in 17 of 24 vertebrate species. RT-PCR analysis of mouse tissues detected high expression of the Cdkl5 variant lacking exon 16b in skeletal muscle, cerebellum, cortex, hippocampus, and olfactory bulb, with low expression in kidney, lung, and heart, and no expression in liver. Expression of the Cdkl5 variant that includes exon 16b was detected almost exclusively in cerebellum, cortex, hippocampus, and olfactory bulb, with low expression in liver, and little to no expression in other tissues examined, including skeletal muscle. </p><p>By RT-PCR analysis on mouse brain RNA, Rademacher et al. (2011) also identified an additional exon in the Cdkl5 gene between exons 16 and 17, which they termed exon 16a. The exon encoded 41 residues and was identical to that identified by Fichou et al. (2011). Expression of the CDKL5 variant with exon 16a was found in human adult and fetal brain, but was barely detectable in lymphoblasts, suggesting tissue-restricted alternative splicing. </p><p>Williamson et al. (2012) identified a splice variant of CDKL5 that includes and terminates in intron 18. The deduced 960-amino acid protein, which the authors designated CKDL5(107) based on its calculated molecular mass, contains the N-terminal kinase domain, but differs in its C terminus, compared with the previously identified full-length protein, CDKL5(115). RT-PCR detected both transcripts in all human tissues and cell lines examined, with highest expression of CDKL5(115) in testis, and highest expression of CDKL5(107) in brain. Fluorescence-tagged CDKL5(115) and CDKL5(107) localized to both the nucleus and cytoplasm in transfected HeLa cells. By database analysis, Williamson et al. (2012) detected orthologs of CDKL5(107) in several vertebrate species, and they identified species-specific variants, including Cdkl5(105) in mice. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>By genomic analysis, Montini et al. (1998) found that STK9 is composed of 20 coding exons. The gene spans the region of marker DXS8000, near the XLRS1 gene (300839). </p><p>Kalscheuer et al. (2003) determined that the STK9 gene contains at least 23 exons; the first 3 exons (1, 1a, and 1b) are untranslated and probably represent 2 transcription start sites. </p><p>Fichou et al. (2011) identified an additional coding exon in the CDKL5 gene that they called 16b due to its location between exons 16 and 17. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</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>During transcriptional mapping in the Xp22 region, Montini et al. (1998) identified the STK9 gene. </p><p>Erez et al. (2009) stated that the CDKL5 gene maps to chromosome Xp22.13. </p>
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</span>
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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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</h4>
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<p>Mari et al. (2005) demonstrated that expression of CDKL5 in mouse brain overlapped with that of MeCP2 (300005) during neural maturation and synaptogenesis. GST pull-down assays, coimmunoprecipitation, and immunoblotting showed that MeCP2 and CDKL5 interacted in vivo and in vitro. CDKL5 possesses kinase activity and is able to autophosphorylate as well as to mediate MeCP2 phosphorylation, suggesting that CDKL5 and MeCP2 may belong to the same molecular pathway. </p><p>Lin et al. (2005) expressed and characterized CDKL5. CDKL5 is a 118-kD protein that is widely distributed in all tissues, with highest levels in brain, thymus, and testis. Whole-mount embryo staining revealed CDKL5 to be ubiquitous. Within cells, CDKL5 was localized primarily in the nucleus. Removal of the C-terminal domain increased CDKL5 expression, enhanced autophosphorylation activity, and caused perinuclear localization, indicating that the C terminus may regulate CDKL5 function. Although MECP2 bound to CDKL5, the results obtained by Lin et al. (2005) suggested that the phosphorylation of MECP2 by CDKL5 reported by Mari et al. (2005) resulted from nonspecific kinases in the immunoprecipitate. The observation that MECP2 is not a direct substrate does not rule out CDKL5 regulation of MECP2 function. Lin et al. (2005) suggested that MECP2 may recruit CDKL5 to a DNA binding complex that contains a functional substrate of the kinase. </p><p>Ricciardi et al. (2009) reported that CDKL5 localized to specific nuclear foci referred to as nuclear speckles in NIH3T3 and HeLa cells and primary mouse hippocampal neurons. CDKL5 overexpression led to nuclear speckle disassembly, and this event was strictly dependent on its kinase activity. Conversely, its downregulation affected nuclear speckle morphology leading to abnormally large and uneven speckles. Similar results were obtained for primary adult fibroblasts isolated from CDKL5-mutated patients. Ricciardi et al. (2009) hypothesized that CDKL5 may control nuclear speckle morphology by regulating the phosphorylation state of splicing regulatory proteins, and may be involved indirectly in pre-mRNA processing, by controlling splicing factor dynamics. </p><p>Using an in vitro kinase assay with epitope-tagged proteins expressed in HEK293 cells, Williamson et al. (2012) found that both CDKL5(115) and CDKL5(107) phosphorylated MECP2 and underwent autophosphorylation. The kinase activity of CDKL5(115) was about twice that of CDKL(107). Inhibitor studies revealed that both isoforms shuttled between the nucleus and cytoplasm and exited the nucleus via the export protein CRM1 (XPO1; 602559). CDKL5(107) was significantly more stable than CDKL5(115). Proteasome inhibition increased the stability of CDKL5(115), but not CDKL5(107). </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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</h4>
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<span class="mim-text-font">
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<p>Van Esch et al. (2007) reported a 10-month-old male infant with severe encephalopathy, congenital cataracts, and tetralogy of Fallot who had a hemizygous de novo 2.8-Mb microdeletion at chromosome Xp22.2-Xp22.13, including the CDKL5 and NHS (300457) genes. He had microphthalmia, refractory myoclonic seizures, and hypotonia. The clinical features were consistent with both DEE2 and the Nance-Horan syndrome (302350), which is caused by mutation in the NHS gene. </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>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Kalscheuer et al. (2003) reported 2 unrelated severely affected girls with developmental and epileptic encephalopathy (DEE2; 300672), diagnosed with infantile spasm syndrome, which was associated with de novo balanced X-autosome translocations, t(X;7)(p22.3;p15) or t(X;6)(p22.3;q14), respectively, that disrupted the STK9 gene. Kalscheuer et al. (2003) showed that STK9 is subject to X inactivation in normal female somatic cells and that the protein was functionally absent in the 2 patients because of preferential inactivation of the normal X chromosome. </p><p>In affected individuals from families with DEE2, Weaving et al. (2004) and Tao et al. (2004) identified mutations in the CDKL5 gene (300203.0001-300203.0004). The disorder had some phenotypic features of atypical Rett syndrome (see 312750). All the patients in the report of Tao et al. (2004) were girls. The family of Weaving et al. (2004) contained 2 twin girls and a brother, who was profoundly affected. The brother had infantile seizures, a mixed seizure disorder, severe global developmental delay with no visual or social responses, spastic quadriparesis, cortical blindness, episodes of hyperventilation, and marked kyphoscoliosis. He died of respiratory failure at the age of 16 years. In the mouse brain, Weaving et al. (2004) showed that Cdkl5 expression overlapped with that of Mecp2 (300005), which is mutated in classic Rett syndrome, and that its expression was unaffected by the loss of Mecp2. In view of the overlapping phenotypic spectrum of CDKL5 and MECP2 mutations, Tao et al. (2004) suggested that these 2 genes may play a role in a common pathogenic process. </p><p>Lin et al. (2005) expressed and characterized CDKL5 mutant forms. All CDKL5 mutations associated with a disease phenotype tested caused loss of kinase activity as assessed by autophosphorylation. </p><p>Bienvenu and Chelly (2006) reported 2 additional mutations in CDKL5 associated with an atypical Rett syndrome phenotype. They stated that at least 12 point mutations and 2 translocations involving this gene had been reported. </p><p>Among 16 Chinese patients diagnosed with Rett syndrome who had no mutation in MECP2, Li et al. (2007) detected 1 synonymous mutation in exon 5 of the CDKL5 gene. </p><p>Archer et al. (2006) searched for CDKL5 mutations in a group of 73 patients referred for CDKL5 analysis, of whom 49 had epileptic seizure onset in the first 6 months of life, and in a group of 26 patients with infantile spasms previously recruited to a clinical trial of that disorder. Seven likely pathogenic mutations were found among female patients from group 1 with epileptic seizure onset in the first 6 months of life, accounting for 7 of the 42 in this group (17%). No mutations other than the already published mutations were found in female patients from group 2, or in any male patient from either study group. All patients with mutations had early signs of developmental delay and most had made little developmental progress. Further clinical information, available for 6 patients, indicated that autistic features and tactile hypersensitivity were common, but only 1 had suggestive Rett-like features. All had a severe epileptic seizure disorder; all but 1 had myoclonic jerks. Archer et al. (2006) suggested that the spectrum of the epileptic seizure disorder and associated EEG changes in patients with CDKL5 mutations is broader than previously reported, and that CDKL5 mutations are a significant cause of infantile spasms and early epileptic seizures in female patients, and of a later intractable seizure disorder. </p><p>In 3 unrelated Italian boys with severe encephalopathy and early-onset intractable seizures, Elia et al. (2008) identified 3 different mutations in the CDKL5 gene (see, e.g., 300203.0011 and 300203.0012). </p><p>Erez et al. (2009) identified variable-sized microdeletions involving exons 1 to 4 of the CDKL5 gene in 3 girls with early-onset seizures. Two of the deletions were flanked by Alu repetitive elements and may have resulted from either nonallelic homologous recombination or a mechanism involving microhomology-mediated fork stalling and template switching/microhomology-mediated break-induced replication. The findings indicated the importance of exon-targeted array CGH analysis for proper analysis of the CDKL5 gene. </p><p>Nemos et al. (2009) screened the CDKL5 gene in a cohort of 177 patients with early-onset seizures, including 30 boys and 10 girls with Aicardi syndrome (AIC; 304050). Eleven girls had 9 different de novo mutations in the CDKL5 gene, including 1 large deletion found by multiplex ligation-dependent probe amplification (MLPA). Studies of genomic DNA extracted from patient peripheral blood lymphocytes showed that all mutations were associated with random X inactivation at the HUMARA locus. Nemos et al. (2009) generated cell lines that exclusively expressed mutant missense mutations (see, e.g., A40V; 300203.0009) and found that the mutant missense proteins properly localized to the nucleus. None of the girls with Aicardi syndrome had a CDKL5 mutation. Nemos et al. (2009) noted that this study brought the number of published CDKL5 mutations to 59, and indicated that CDKL5 mutations account for up to 28% of females with early-onset seizures and intractable epilepsy. </p><p>Rademacher et al. (2011) identified 5 pathogenic mutations in the CDKL5 gene in 5 of 345 female patients with a clinical diagnosis of Rett syndrome, severe infantile seizures, or atypical Rett syndrome. No mutations were identified in the newly identified exon (exon 16a) that is highly expressed in the brain. </p><p>Bartnik et al. (2011) used CGH with a custom-designed clinical oligonucleotide array targeting exons of selected disease and candidate genes, including CDKL5, and identified mosaic exonic deletions of this gene in 1 male and 2 females with developmental delay and medically intractable seizures. These 3 mosaic changes represented 60% of all deletions detected in 12,000 patients analyzed by array CGH and involving the exonic portion of CDKL5. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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In a 13-year-old boy with severely impaired intellectual development and late-onset generalized epilepsy, Fraser et al. (2019) identified a 1-bp insertion (c.2809_2810insA, ENST00000379996.7) in exon 20 the CDKL5 gene, resulting in a cys937-to-ter (C937X) substitution. The mutation was identified by trio whole-exome sequencing; no other likely pathogenic variants were identified. The variant was inherited from the boy's mother, who was asymptomatic with no intellectual or neurologic problems, and X-inactivation studies showed random X-inactivation in peripheral DNA. An asymptomatic maternal aunt also carried the variant. Two asymptomatic boys who were at risk of inheriting the variant were tested and did not carry the variant; thus, segregation analysis was consistent with X-linked recessive inheritance. </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>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>Russo et al. (2009) identified 7 different mutations in the CDKL5 gene in 6 of 93 patients with classic or atypical Rett syndrome and in 1 of 17 patients with Angelman/Angelman-like patients (see 105830). Two of the patients were reported by Pintaudi et al. (2008) and 1 by Saletti et al. (2009). All were girls, and all except 1 showed progressive microcephaly during the first 2 years of life. All girls had severe intellectual disability, limited hand skills, hypotonia, lack of eye contact, and the absence of speech and walking, except for 1. Only 2 patients showed a clear regressive stage. Seizures appeared by the second week of life: 3 patients had drug-resistant seizures, 3 had some response, and 1 had spontaneous resolution of seizures at 6 months. The patient with features consistent with an Angelman-like syndrome, resulting from a 2-bp insertion (903insGA; 300203.0013) had absence of speech, severe developmental delay, ataxic gait, hypermotoric behavior, and easily excitable personality with uplifted hand-flapping. She was also autistic but had relatively better motor skills than the other girls. Overall, the CDKL5 mutations included 2 missense, 2 splicing, 1 in-frame deletion, 1 nonsense mutation, and 1 insertion. Four of the mutations affected the predicted N-terminal catalytic domain. Nonsense mutation carriers tended to have a milder phenotype than those with missense or splicing mutations. </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>Wang et al. (2012) found that male Cdkl5 -/y mice and female Cdkl5 +/- mice were viable and fertile, with normal appearance, growth, and overall brain morphology. Cdkl5 -/y males were hyperactive, showed motor, learning, memory, and social impairments, and had reduced anxiety relative to wildtype mice. Compared with wildtype, Cdkl5 -/y brains showed decreased phosphorylation of protein kinase A (see 188830) and Akt (see 164730) substrates, resulting in disruption of Akt and Mtor (see 601231) signaling. Other phosphorylation profiles were moderately or mildly affected in Cdkl5 -/y brains. Wang et al. (2012) concluded that CDKL5 plays a critical role in coordinating neural signaling cascades. </p><p>Della Sala et al. (2016) found that Cdkl5 -/y mice had reduced synaptic density, impaired long-term potentiation maintenance, and reduced spontaneous excitatory postsynaptic current frequency. Cdkl5 -/y dendritic spines failed to stabilize, possibly due to reduced synaptic Psd95 (DLG4; 602887) accumulation. Subcutaneous administration of IGF1 (147440), an activator of the Akt-Mtor pathway, rescued defective Psd95 expression and normalized spine density and turnover in developing and adult Cdkl5 -/y mice. </p><p>Lo Martire et al. (2017) found that Cdkl5-knockout mice showed a higher occurrence of sleep apnea than wildtype mice. </p><p>Mazziotti et al. (2017) found that Cdkl5 -/y male and Cdkl5 +/- female mice developed visual defects by postnatal day 27. Defects included reduced amplitude of light-induced cortical response, abnormal contrast response, and impaired visual acuity. </p><p>Terzic et al. (2021) demonstrated that postdevelopmental knockout of Cdkl5 in male mice at age 6 weeks resulted in deficits in locomotion, sociability, learning, memory, and auditory-evoked event-related potentials (ERPs), similar to what was previously seen in germline Cdkl5 knockout mice. Terzic et al. (2021) also found that restoration of Cdkl5 expression in a Cdkl5-deficient mouse through a Cre-lox recombination approach resulted in improvement in anxiety- and hyperactivity-related behaviors. These results demonstrated that CDKL5 is required during both development and adulthood for neurologic function and suggested the possibility of disease treatment after symptom onset. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>14 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 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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CDKL5, 1-BP DEL, 183T
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<br />
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SNP: rs62643608,
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ClinVar: RCV000133332, RCV000170012, RCV000170013, RCV004724849
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 affected monozygotic twin girls and an affected brother in a family (family 1) with X-linked developmental and epileptic encephalopathy-2 (DEE2; 300672), Weaving et al. (2004) identified a 1-bp deletion (183delT) in exon 5 of the CDKL5 gene, resulting in a frameshift and premature termination of the protein at amino acid 75. One twin and her brother had onset of infantile spasms as 9 weeks of age and in the neonatal period, respectively, and both developed a mixed seizure disorder. The other twin had a diagnosis of autism; at age 19 years, she had not had any seizures. The brother died at age 16 years. </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 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 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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CDKL5, IVSAS13, G-A, -1
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<br />
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SNP: rs267608650,
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ClinVar: RCV000144124, RCV000170016, RCV001385706, RCV001849177, RCV004724896
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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 28-year-old woman (family 2) with developmental and epileptic encephalopathy (DEE2; 300672), Weaving et al. (2004) identified a G-to-A transition in intron 13 of the CDKL5 gene, resulting in a splice site mutation. The patient had onset of severe spasms at about 6 weeks of age and developed intractable seizures during childhood. Her affected half sister with the mutation had a diagnosis of Rett syndrome. She did not have seizures. </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 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 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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CDKL5, CYS152PHE
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<br />
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SNP: rs122460157,
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ClinVar: RCV000012251, RCV000133370, RCV004724734
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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 5-year-old girl (family 1) with developmental and epileptic encephalopathy (DEE2; 300672), Tao et al. (2004) identified a de novo c.455G-T transversion in exon 7 of the CDKL5 gene, resulting in a cys152-to-phe (C152F) substitution. Onset of seizures occurred at age 5 weeks. </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 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 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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CDKL5, ARG175SER
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<br />
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SNP: rs61749700,
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ClinVar: RCV000012252, RCV000133372, RCV004724735
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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 female monozygotic twins with developmental and epileptic encephalopathy (DEE2; 300672), Tao et al. (2004) identified a de novo c.525A-T transversion in exon 8 of the CDKL5 gene, resulting in an arg175-to-ser (R175S) substitution. The phenotype included onset of infantile spasms between 2 and 6 weeks of life, severe psychomotor retardation, stereotypic hand movements, mood swings, and episodes of hyperventilation. One twin developed absence seizures later in life. </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 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 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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CDKL5, 4-BP DEL, 166GAAA
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<br />
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SNP: rs267608433,
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ClinVar: RCV000133326, RCV000170008, RCV001068312, RCV004724843
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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 9-year-old girl with developmental and epileptic encephalopathy (DEE2; 300672), Scala et al. (2005) identified a 4-bp deletion (c.166_169delGAAA) in exon 5 of the CDKL5 gene, resulting in a stop codon at position 74 that interrupts the catalytic domain and results in a markedly truncated, nonfunctional protein. She had onset of seizures at age 1.5 months and some features of Rett syndrome, including acquired microcephaly, hand apraxia, generalized hypotonia, and stereotypic hand motions. </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>.0006 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 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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CDKL5, 2-BP DEL, 2636CT
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<br />
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SNP: rs61753251,
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ClinVar: RCV000133357, RCV000145535, RCV000169918, RCV000229531, RCV004724867
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an 8-year-old girl (patient 2) with developmental and epileptic encephalopathy (DEE2; 300672), Scala et al. (2005) identified a 2-bp deletion (c.2636_2637delCT) in exon 18 of the CDKL5 gene, predicted to eliminate a putative signal peptidase I serine active site of the CDKL5 protein. The patient had onset of seizures at 10 days of life. </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 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 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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CDKL5, GLN834TER
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<br />
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SNP: rs122460158,
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ClinVar: RCV000012255, RCV000133352, RCV003764559, RCV004724736
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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-year-old girl with developmental and epileptic encephalopathy (DEE2; 300672), Nectoux et al. (2006) identified a heterozygous de novo 2500C-T transition in exon 18 of the CDKL5 gene, resulting in a gln834-to-ter (Q834X) substitution. Further molecular analysis indicated maternal origin, suggesting a maternal germline mutation. RT-PCR analysis did not detect an abnormal mRNA transcript, suggesting the mutated transcript underwent nonsense-mediated decay. The child had a severe phenotype, with seizures at 10 days of age, no speech development, and inability to walk. </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>.0008 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 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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CDKL5, IVS6AS, G-T, -1
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<br />
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SNP: rs267608474,
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ClinVar: RCV000144134, RCV000170042, RCV005053926
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 2-year-old girl (patient 2) diagnosed with X-linked infantile spasm syndrome (DEE2; 300672), Archer et al. (2006) identified a splice site mutation in the CDKL5 gene predicted to result in exon 7 skipping (IVS6-1G-T). Onset of seizures occurred at 10 days of life. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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CDKL5, ALA40VAL
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<br />
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|
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SNP: rs122460159,
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|
|
ClinVar: RCV000012257, RCV000133317, RCV000699210, RCV001507073, RCV001564884
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated girls with developmental and epileptic encephalopathy (DEE2; 300672), Rosas-Vargas et al. (2008) identified a c.119C-T transition in exon 4 of the CDKL5 gene, resulting in an ala40-to-val (A40V) substitution at a highly conserved residue. In vitro functional expression analysis showed that the mutant protein was mislocalized in the cytoplasm and did not reach the nucleus. Onset occurred at age 1 month in 1 patient and at age 6 weeks in the other patient. </p><p>Nemos et al. (2009) identified a de novo A40V mutation in 2 unrelated girls with DEE2. Onset of seizures occurred at ages 4 and 6 weeks, respectively, but 1 patient had a more severe phenotype with intractable seizures and later epileptic encephalopathy, whereas the other did not. In contrast to the in vitro findings of Rosas-Vargas et al. (2008), Nemos et al. (2009) found that the mutant A40V protein correctly localized to the nucleus in lymphoblastoid cell lines derived from patient lymphoblasts, but was associated with a downregulation of protein levels particularly at the G0/G1 stage of the cell cycle. Nemos et al. (2009) emphasized that their own studies more closely represented an in vivo model and suggested that CDKL5 localization is tissue-dependent. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CDKL5, ILE72THR
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs62641235,
|
|
|
|
|
|
|
|
ClinVar: RCV000012258, RCV000080068, RCV000169913, RCV001385703, RCV001507029
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 5-year-old girl with developmental and epileptic encephalopathy (DEE2; 300672), Saletti et al. (2009) identified a de novo c.215T-C transition in exon 5 of the CDKL5 gene, resulting in an ile72-to-thr (I72T) substitution in a conserved residue. within the catalytic domain. She had severe mental retardation, microcephaly, diffuse hypotonia, hyperreflexia, no language, numerous refractory seizures since 2 months of age, and stereotypical movement of the hands. At age 5 years, 3 months, she showed signs of precocious puberty, including rapid growth in height, increased sex hormones, and ultrasonic uterine and ovarian changes consistent with the onset of puberty. Saletti et al. (2009) noted that the onset of precocious puberty had not been reported in association with CDKL5 mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CDKL5, THR288ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606713,
|
|
|
|
|
|
|
|
ClinVar: RCV000012259, RCV004724737
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 9-year-old Italian boy (patient 2) with developmental and epileptic encephalopathy (DEE2; 300672), Elia et al. (2008) identified a de novo hemizygous c.863C-T transition in the CDKL5 gene, resulting in a thr288-to-ile (T288I) substitution predicted to affect the catalytic domain of the protein. The patient showed psychomotor regression starting at age 8 months, which coincided with onset of seizures. He had loss of speech, ataxia, and progression of refractory seizures. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CDKL5, CYS291TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606714,
|
|
|
|
|
|
|
|
ClinVar: RCV000012260, RCV001203327, RCV002281041
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-year-old Italian boy (patient 3) with developmental and epileptic encephalopathy (DEE2; 300672), Elia et al. (2008) identified a de novo hemizygous c.872G-A transition in the CDKL5 gene, resulting in a cys291-to-tyr (C291Y) substitution predicted to affect the catalytic domain of the protein. He had onset of seizures at age 2 months and mild dysmorphic features including high sloping forehead, hypotelorism, epicanthus, broad nasal bridge, high palate, and large anteverted ears. He later showed profound mental retardation and refractory epilepsy. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CDKL5, 2-BP DUP, 903GA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267608546,
|
|
|
|
|
|
|
|
ClinVar: RCV000012261, RCV000133391, RCV004724890
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6-year-old girl (patient 5) with developmental and epileptic encephalopathy (DEE2; 300672), Russo et al. (2009) identified a heterozygous 2-bp duplication (c.903_904dupGA) in exon 11 of the CDKL5 gene, predicted to result in a frameshift and premature termination just downstream of the N-terminal catalytic domain (Leu302Aspfs49ter). The authors noted that the phenotype was consistent with an Angelman-like syndrome. Onset of seizures began at age 3 weeks. She had absence of speech, severe developmental delay, ataxic gait, hypermotoric behavior, and easily excitable personality with uplifted hand-flapping. She was microcephalic, had intractable seizures, brachycephaly, wide mouth, widely dispersed teeth, and progressive prognathism. She was also autistic but had relatively better motor skills compared to other girls with CDKL5 mutations. The findings broadened the phenotype associated with CDKL5 mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CDKL5, ARG178PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606715,
|
|
|
|
|
|
|
|
ClinVar: RCV000012262, RCV001035195, RCV004724751
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl (patient 8) with developmental and epileptic encephalopathy (DEE2; 300672), Nemos et al. (2009) identified a de novo heterozygous c.533G-C transversion (c.533G-C, NM_003159.2) in exon 8 of the CDKL5 gene, resulting in an arg178-to-pro (R178P) substitution. The mutant protein correctly localized to the nucleus in lymphoblastoid cell lines derived from patient lymphoblasts, but was associated with a downregulation of protein levels, particularly at the G0/G1 stage of the cell cycle. The patient had onset of seizures at age 4 months. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Archer, H. L., Evans, J., Edwards, S., Colley, J., Newbury-Ecob, R., O'Callaghan, F., Huyton, M., O'Regan, M., Tolmie, J., Sampson, J., Clarke, A., Osborne, J.
|
|
<strong>CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients.</strong>
|
|
J. Med. Genet. 43: 729-734, 2006.
|
|
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|
|
[PubMed: 16611748]
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|
|
[Full Text: https://doi.org/10.1136/jmg.2006.041467]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bartnik, M., Derwinska, K., Gos, M., Obersztyn, E., Kolodziejska, K. E., Erez, A., Szpecht-Potocka, A., Fang, P., Terczynska, I., Mierzewska, H., Lohr, N. J., Bellus, G. A., Reimschiesel, T., Bocian, E., Mazurczak, T., Cheung, S. W., Stankiewicz, P.
|
|
<strong>Early-onset seizures due to mosaic exonic deletions of CDKL5 in a male and two females.</strong>
|
|
Genet. Med. 13: 447-452, 2011.
|
|
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|
|
|
[PubMed: 21293276]
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|
|
[Full Text: https://doi.org/10.1097/GIM.0b013e31820605f5]
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Bienvenu, T., Chelly, J.
|
|
<strong>Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized.</strong>
|
|
Nature Rev. Genet. 7: 415-426, 2006. Note: Erratum: Nature Rev. Genet. 7: 583 only, 2006.
|
|
|
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|
|
[PubMed: 16708070]
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|
|
[Full Text: https://doi.org/10.1038/nrg1878]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Della Sala, G., Putignano, E., Chelini, G., Melani, R., Calcagno, E., Ratto, G. M., Amendola, E., Gross, C. T., Giustetto, M., Pizzorusso, T.
|
|
<strong>Dendritic spine instability in a mouse model of CDKL5 disorder is rescued by insulin-like growth factor 1.</strong>
|
|
Biol. Psychiat. 80: 302-311, 2016.
|
|
|
|
|
|
[PubMed: 26452614]
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|
|
[Full Text: https://doi.org/10.1016/j.biopsych.2015.08.028]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Elia, M., Falco, M., Ferri, R., Spalletta, A., Bottitta, M., Calabrese, G., Carotenuto, M., Musumeci, S. A., Lo Giudice, M., Fichera, M.
|
|
<strong>CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy.</strong>
|
|
Neurology 71: 997-999, 2008.
|
|
|
|
|
|
[PubMed: 18809835]
|
|
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|
|
[Full Text: https://doi.org/10.1212/01.wnl.0000326592.37105.88]
|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
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Sonja A. Rasmussen - updated : 08/19/2024<br>Hilary J. Vernon - updated : 04/01/2022<br>Carol A. Bocchini - updated : 10/05/2020<br>Patricia A. Hartz - updated : 02/26/2018<br>Patricia A. Hartz - updated : 9/9/2013<br>Ada Hamosh - updated : 10/1/2012<br>Cassandra L. Kniffin - updated : 6/12/2012<br>Patricia A. Hartz - updated : 8/1/2011<br>Cassandra L. Kniffin - updated : 11/18/2010<br>George E. Tiller - updated : 10/28/2010<br>Cassandra L. Kniffin - updated : 12/11/2009<br>Cassandra L. Kniffin - updated : 11/24/2009<br>Cassandra L. Kniffin - updated : 10/15/2009<br>George E. Tiller - updated : 7/6/2009<br>George E. Tiller - updated : 11/14/2008<br>Cassandra L. Kniffin - updated : 3/18/2008<br>Victor A. McKusick - updated : 9/6/2007<br>Victor A. McKusick - updated : 1/9/2007<br>Cassandra L. Kniffin - updated : 8/24/2006<br>Victor A. McKusick - updated : 7/12/2006<br>Marla J. F. O'Neill - updated : 3/1/2005<br>Victor A. McKusick - updated : 11/12/2004<br>Victor A. McKusick - updated : 5/21/2003
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Jennifer P. Macke : 8/13/1999
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carol : 08/19/2024<br>alopez : 04/04/2024<br>carol : 04/01/2022<br>carol : 10/05/2020<br>carol : 03/05/2018<br>mgross : 03/01/2018<br>mgross : 02/26/2018<br>carol : 07/14/2015<br>mcolton : 11/26/2013<br>carol : 9/9/2013<br>mgross : 9/9/2013<br>alopez : 10/3/2012<br>terry : 10/1/2012<br>alopez : 6/18/2012<br>ckniffin : 6/12/2012<br>terry : 3/16/2012<br>joanna : 1/31/2012<br>mgross : 8/25/2011<br>terry : 8/1/2011<br>alopez : 3/30/2011<br>wwang : 12/6/2010<br>ckniffin : 11/18/2010<br>wwang : 11/11/2010<br>terry : 10/28/2010<br>wwang : 2/2/2010<br>wwang : 12/29/2009<br>ckniffin : 12/11/2009<br>wwang : 12/4/2009<br>ckniffin : 11/24/2009<br>wwang : 11/6/2009<br>ckniffin : 10/15/2009<br>alopez : 7/7/2009<br>terry : 7/6/2009<br>wwang : 11/14/2008<br>ckniffin : 7/10/2008<br>carol : 5/9/2008<br>ckniffin : 3/18/2008<br>alopez : 9/6/2007<br>carol : 9/5/2007<br>ckniffin : 8/24/2007<br>alopez : 1/10/2007<br>terry : 1/9/2007<br>wwang : 8/31/2006<br>ckniffin : 8/24/2006<br>terry : 7/12/2006<br>wwang : 3/11/2005<br>wwang : 3/8/2005<br>terry : 3/1/2005<br>alopez : 11/18/2004<br>terry : 11/12/2004<br>carol : 6/4/2003<br>tkritzer : 6/2/2003<br>terry : 5/21/2003<br>alopez : 1/15/2003<br>alopez : 8/13/1999
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