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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="DEPDC5-Related Epilepsy" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2023/03/09" /><meta name="citation_author" content="Stéphanie Baulac" /><meta name="citation_author" content="Sara Baldassari" /><meta name="citation_pmid" content="27683934" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK385626/" /><meta name="citation_keywords" content="DEPDC5-Related Familial Focal Epilepsy with Variable Foci (FFEVF)" /><meta name="citation_keywords" content="DEPDC5-Related Autosomal Dominant Sleep-Related Hypermotor Epilepsy (ADSHE) (Autosomal Dominant Nocturnal Frontal Lobe Epilepsy [ADNFLE])" /><meta name="citation_keywords" content="DEPDC5-Related Familial Mesial Temporal Lobe Epilepsy (FMTLE)" /><meta name="citation_keywords" content="DEPDC5-Related Autosomal Dominant Epilepsy with Auditory Features (ADEAF)" /><meta name="citation_keywords" content="DEPDC5-Related Infantile Spasms" /><meta name="citation_keywords" content="DEPDC5-Related Developmental Encephalopathy with Macrocephaly and Polymicrogyria" /><meta name="citation_keywords" content="DEPDC5-Related Focal Cortical Dysplasia" /><meta name="citation_keywords" content="DEPDC5-Related Hemimegalencephaly" /><meta name="citation_keywords" content="GATOR1 complex protein DEPDC5" /><meta name="citation_keywords" content="DEPDC5" /><meta name="citation_keywords" content="DEPDC5-Related Epilepsy" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="DEPDC5-Related Epilepsy" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Stéphanie Baulac" /><meta name="DC.Contributor" content="Sara Baldassari" /><meta name="DC.Date" content="2023/03/09" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK385626/" /><meta name="description" content="DEPDC5-related epilepsy encompasses a range of epilepsy syndromes, almost all of which are characterized by focal seizures, with seizure onset in a discrete area of the brain. While most individuals with DEPDC5-related epilepsy have a normal brain MRI, some have epilepsy associated with a cortical malformation, usually focal cortical dysplasia or hemimegalencephaly. Seizure syndromes include familial focal epilepsy with variable foci (FFEVF), autosomal dominant sleep-related hypermotor epilepsy (ADSHE), familial mesial temporal lobe epilepsies (FMTLE), autosomal dominant epilepsy with auditory features (ADEAF), infantile spasms, and severe developmental encephalopathy. Although psychomotor development is usually normal, developmental delays, intellectual disability, or autism spectrum disorder have been reported in some individuals." /><meta name="og:title" content="DEPDC5-Related Epilepsy" /><meta name="og:type" content="book" /><meta name="og:description" content="DEPDC5-related epilepsy encompasses a range of epilepsy syndromes, almost all of which are characterized by focal seizures, with seizure onset in a discrete area of the brain. While most individuals with DEPDC5-related epilepsy have a normal brain MRI, some have epilepsy associated with a cortical malformation, usually focal cortical dysplasia or hemimegalencephaly. Seizure syndromes include familial focal epilepsy with variable foci (FFEVF), autosomal dominant sleep-related hypermotor epilepsy (ADSHE), familial mesial temporal lobe epilepsies (FMTLE), autosomal dominant epilepsy with auditory features (ADEAF), infantile spasms, and severe developmental encephalopathy. Although psychomotor development is usually normal, developmental delays, intellectual disability, or autism spectrum disorder have been reported in some individuals." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK385626/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/gene/depdc5-epilepsy/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK385626/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script><meta name="book-collection" content="NONE" />
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK385626_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK385626_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/ddx41-mds/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/dfna2/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK385626_"><span class="title" itemprop="name"><i>DEPDC5</i>-Related Epilepsy</span></h1><p class="contrib-group"><span itemprop="author">Stéphanie Baulac</span>, PhD and <span itemprop="author">Sara Baldassari</span>, PhD.</p><a data-jig="ncbitoggler" href="#__NBK385626_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK385626_ai__"><div class="contrib half_rhythm"><span itemprop="author">Stéphanie Baulac</span>, PhD<div class="affiliation small">Institut du Cerveau (ICM)<br />Paris Brain Institute<br />Paris, France<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.etutitsni-mci@caluab.einahpets" class="oemail">gro.etutitsni-mci@caluab.einahpets</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Sara Baldassari</span>, PhD<div class="affiliation small">Institut du Cerveau (ICM)<br />Paris Brain Institute<br />Paris, France<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.etutitsni-mci@irassadlab.aras" class="oemail">gro.etutitsni-mci@irassadlab.aras</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">September 29, 2016</span>; Last Update: <span itemprop="dateModified">March 9, 2023</span>.</p><p><em>Estimated reading time: 31 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="depdc5-epilepsy.Summary" itemprop="description"><h2 id="_depdc5-epilepsy_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>DEPDC5-</i>related epilepsy encompasses a range of epilepsy syndromes, almost all of which are characterized by focal seizures, with seizure onset in a discrete area of the brain. While most individuals with <i>DEPDC5</i>-related epilepsy have a normal brain MRI, some have epilepsy associated with a cortical malformation, usually focal cortical dysplasia or hemimegalencephaly. Seizure syndromes include <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/familial/" ref="pagearea=abstract&targetsite=external&targetcat=link&targettype=uri">familial</a> focal epilepsy with variable foci (FFEVF), <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> sleep-related hypermotor epilepsy (ADSHE), familial mesial temporal lobe epilepsies (FMTLE), autosomal dominant epilepsy with auditory features (ADEAF), infantile spasms, and severe developmental encephalopathy. Although psychomotor development is usually normal, developmental delays, intellectual disability, or autism spectrum disorder have been reported in some individuals.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <i>DEPDC5</i>-related epilepsy is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with suggestive findings and at least one <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>DEPDC5</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>. Some affected individuals have <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> variants in <i>DEPDC5</i>, and some have a second mosaic (or <a class="def" href="/books/n/gene/glossary/def-item/postzygotic/">postzygotic</a>) <i>DEPDC5</i> variant within the brain.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> The response to anti-seizure medication (ASM) is variable. While some individuals respond well to first-line ASMs, others are more refractory to treatment. There is currently no evidence that seizures respond better to one specific ASM. In individuals with hemimegalencephaly or focal cortical dysplasia and refractory epilepsy, resective epilepsy surgery should be explored early in the disease course. Standard treatment for developmental delay / intellectual disability and autism spectrum disorders.</p><p><i>Surveillance:</i> Assess for new or ongoing neurologic manifestations (such as new-onset seizures or changes in seizure symptoms), predictive factors for sudden unexpected death in epilepsy, and developmental progress at each visit. Repeat EEG as appropriate when seizure frequency increases or when seizures of new symptomatology occur. Repeat brain MRI with a higher-resolution technique in individuals with treatment-resistant seizures whose first brain MRI was normal to rule out subtle cortical dysplasia.</p><p><i>Evaluation of relatives at risk:</i> It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify those who are at risk for developing seizures as early as possible. This typically entails targeted <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> for the known <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>(s) in the family.</p><p><i>Pregnancy management:</i> Pregnant women should receive counseling regarding the risks and benefits of using ASM during pregnancy; the advantages and disadvantages of increasing maternal periconceptional folic acid supplementation to 4,000 µg daily; the effects of pregnancy on ASM metabolism; and the effect of pregnancy on maternal seizure control.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>DEPDC5</i>-related epilepsy is an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> disorder; however, affected individuals with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants have been rarely reported. All probands reported to date with biallelic <i>DEPDC5</i> variants inherited variants from their <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parents. In these families, heterozygous parents may or may not have manifestations of <i>DEPDC5</i>-related epilepsy. The risk to the sibs of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> depends on the genetic status of the proband's parents. If one parent of the proband has a <i>DEPDC5</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the risk to the sibs of inheriting the pathogenic variant is 50%. If both parents of a proband have a <i>DEPDC5</i> pathogenic variant, sibs have a 75% chance of inheriting one or two pathogenic variants and a 25% chance of inheriting neither pathogenic variant and not being affected. Once the <i>DEPDC5</i> pathogenic variant(s) have been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p></div></div><div id="depdc5-epilepsy.GeneReview_Scope"><h2 id="_depdc5-epilepsy_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><div id="depdc5-epilepsy.T.depdc5related_epilepsy" class="table"><div class="caption"><p><i>DEPDC5</i>-Related Epilepsy: Phenotypic Spectrum <sup>1</sup></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385626/table/depdc5-epilepsy.T.depdc5related_epilepsy/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__depdc5-epilepsy.T.depdc5related_epilepsy_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Phenotypes <sup>1</sup></th><th id="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorders</th></tr></thead><tbody><tr><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Epilepsy phenotypes</b>
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</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Familial focal epilepsy with variable foci (FFEVF)</div></li><li class="half_rhythm"><div>Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) (previously termed <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> nocturnal frontal lobe epilepsy [ADNFLE])</div></li><li class="half_rhythm"><div>Familial mesial temporal lobe epilepsy (FMTLE)</div></li><li class="half_rhythm"><div>Autosomal dominant epilepsy with auditory features (ADEAF)</div></li><li class="half_rhythm"><div>Infantile spasms</div></li><li class="half_rhythm"><div>Developmental encephalopathy with macrocephaly and polymicrogyria</div></li></ul>
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</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Brain malformation phenotypes</b>
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</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Focal cortical dysplasia</div></li><li class="half_rhythm"><div>Hemimegalencephaly</div></li></ul>
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</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">For synonyms and outdated names, see <a href="#depdc5-epilepsy.Nomenclature">Nomenclature</a>.</p></div></dd><dt>1. </dt><dd><div id="depdc5-epilepsy.TF.d.1"><p class="no_margin">For other genetic causes of these phenotypes, see <a href="#depdc5-epilepsy.Differential_Diagnosis">Differential Diagnosis</a>.</p></div></dd></dl></div></div></div></div><div id="depdc5-epilepsy.Diagnosis"><h2 id="_depdc5-epilepsy_Diagnosis_">Diagnosis</h2><p>No consensus clinical diagnostic criteria for <i>DEPDC5</i>-related epilepsy have been published to date.</p><div id="depdc5-epilepsy.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>DEPDC5</i>-related epilepsy <b>should be suspected</b> in individuals with the following clinical, neuroimaging, EEG, and family history findings.</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Epilepsy (<a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> or <a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a>), which may include:</div><ul><li class="half_rhythm"><div>Focal epilepsy (emerging from any cortical region but predominantly from the frontal lobe), variable epilepsy foci (temporal, parietal), or hypermotor seizures</div></li><li class="half_rhythm"><div>Nocturnal or sleep-related seizures</div></li><li class="half_rhythm"><div>Drug-resistant epilepsy</div></li><li class="half_rhythm"><div>Infantile spasms</div></li></ul></li><li class="half_rhythm"><div>Otherwise normal neurologic examination</div></li><li class="half_rhythm"><div>Normal psychomotor development and cognition in most, although developmental delay, intellectual disability, and/or neuropsychiatric features (autism spectrum disorder, attention-deficit/hyperactivity disorder) have been described rarely.</div></li><li class="half_rhythm"><div>Sudden unexpected death in epilepsy</div></li></ul><p>
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<b>Neuroimaging/EEG findings</b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm">Brain MRI may demonstrate focal cortical dysplasia, hemimegalencephaly, or rarely other malformations (polymicrogyria, pachygyria, heterotopia, hypoplasia of corpus callosum)</div><div class="half_rhythm">Note: A normal brain MRI does not preclude the diagnosis.</div></li><li class="half_rhythm"><div class="half_rhythm">Interictal EEG may show focal (frontal, temporal, parietal, or occipital) epileptiform abnormalities that remain constant over time, typically with a background EEG that is normal.</div></li></ul><p><b>Family history</b> is typically consistent with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> inheritance (e.g., affected males and females in multiple generations), although a few affected individuals have <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants [<a class="bk_pop" href="#depdc5-epilepsy.REF.ververi.2023.580">Ververi et al 2023</a>]. Absence of a known family history does not preclude the diagnosis.</p></div><div id="depdc5-epilepsy.Establishing_the_Diagnos"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>DEPDC5</i>-related epilepsy is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with <a href="#depdc5-epilepsy.Suggestive_Findings">suggestive findings</a> and at least one <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variant in <i>DEPDC5</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK385626/table/depdc5-epilepsy.T.molecular_genetic_test/?report=objectonly" target="object" rid-ob="figobdepdc5epilepsyTmoleculargenetictest">Table 1</a>). Some rare affected individuals have <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants in <i>DEPDC5.</i></p><p>Notes: (1) Per ACMG/AMP variant interpretation guidelines, the terms "<a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [<a class="bk_pop" href="#depdc5-epilepsy.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>DEPDC5</i> variant of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> does not establish or rule out the diagnosis of the disorder. (3) While most individuals with <i>DEPDC5</i>-related epilepsy have only a heterozygous <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> (i.e., constitutional) pathogenic variant, some individuals with cortical malformations (most frequently focal cortical dysplasia or hemimegalencephaly) have been reported to have a brain-specific <a class="def" href="/books/n/gene/glossary/def-item/postzygotic/">postzygotic</a> (or mosaic) pathogenic variant in <i>DEPDC5</i> on the non-mutated <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> (i.e., a second pathogenic variant or "second hit") in addition to a heterozygous constitutional pathogenic variant (see <a href="#depdc5-epilepsy.Molecular_Genetics">Molecular Genetics</a>).</p><p>Gene-targeted testing requires that the clinician determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved, whereas <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing does not. As the differential diagnosis for genetic causes of epilepsy and brain malformations is broad, single-gene testing (<a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> of <i>DEPDC5</i>, followed by gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>) is rarely useful and typically NOT recommended.</p><p>Molecular genetic testing approaches typically include a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> or <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>).</p><p>Note: As some <i>DEDPC5</i> pathogenic variants are <a class="def" href="/books/n/gene/glossary/def-item/postzygotic/">postzygotic</a> (or mosaic), deep sequencing of surgical resected brain tissue (from epilepsy surgery) could be considered in the diagnostic evaluation of an affected individual if there is a high suspicion for this condition and a surgical brain tissue resection is either planned or a brain tissue sample is available.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes genes associated with epilepsy with or without brain malformations (e.g., <i>AKT3</i>, <i>CHRNA2</i>, <i>CHRNA4</i>, <i>CHRNB2</i>, <i>DEPDC5</i>, <i>KCNT1</i>, <i>MTOR</i>, <i>NPRL2</i>, <i>NPRL3</i>, <i>PIK3CA</i>, <i>PTEN</i>, <i>RHEB</i>) may be considered. Notes: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests. (5) As brain-specific mosaic pathogenic variants of <i>DEPDC5</i> have been identified in some individuals, the depth of sequencing of a multigene panel and sample type may determine the yield of molecular diagnostic testing using these panels.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> is likely involved. <b>Exome sequencing</b> is most commonly used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible. If no <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is found in <i>DEPDC5</i>, <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> with methods to detect <a class="def" href="/books/n/gene/glossary/def-item/somatic-mosaicism/">somatic mosaicism</a> could be considered (see above).</div><div class="half_rhythm">For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>.</div></li></ul><div id="depdc5-epilepsy.T.molecular_genetic_test" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>DEPDC5</i>-Related Epilepsy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385626/table/depdc5-epilepsy.T.molecular_genetic_test/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__depdc5-epilepsy.T.molecular_genetic_test_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_depdc5-epilepsy.T.molecular_genetic_test_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_depdc5-epilepsy.T.molecular_genetic_test_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_depdc5-epilepsy.T.molecular_genetic_test_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_depdc5-epilepsy.T.molecular_genetic_test_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>DEPDC5</i>
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</td><td headers="hd_h_depdc5-epilepsy.T.molecular_genetic_test_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_depdc5-epilepsy.T.molecular_genetic_test_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~96% <sup>4</sup></td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.molecular_genetic_test_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>5</sup></td><td headers="hd_h_depdc5-epilepsy.T.molecular_genetic_test_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~4% <sup>4</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="depdc5-epilepsy.TF.1.1"><p class="no_margin">See <a href="/books/NBK385626/#depdc5-epilepsy.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>2. </dt><dd><div id="depdc5-epilepsy.TF.1.2"><p class="no_margin">See <a href="#depdc5-epilepsy.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>3. </dt><dd><div id="depdc5-epilepsy.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="depdc5-epilepsy.TF.1.4"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bk_pop" href="#depdc5-epilepsy.REF.stenson.2020.1197">Stenson et al 2020</a>] as well as the following references: <a class="bk_pop" href="#depdc5-epilepsy.REF.dibbens.2013.546">Dibbens et al [2013]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ishida.2013.552">Ishida et al [2013]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.lal.2014.788">Lal et al [2014]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.martin.2014.570">Martin et al [2014]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.picard.2014.2101">Picard et al [2014]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.scheffer.2014.782">Scheffer et al [2014]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baulac.2015.675">Baulac et al [2015]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.carvill.2015.e17">Carvill et al [2015]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.dgama.2015.720">D'Gama et al [2015]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.nascimento.2015.e28">Nascimento et al [2015]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.pippucci.2015.e5">Pippucci et al [2015]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.scerri.2015.575">Scerri et al [2015]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.striano.2015.e168">Striano et al [2015]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.bagnall.2016.522">Bagnall et al [2016]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ricos.2016.120">Ricos et al [2016]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.weckhuysen.2016.994">Weckhuysen et al [2016]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baldassari.2019b.885">Baldassari et al [2019b]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.sim.2019.901">Sim et al [2019]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.krenn.2020.624">Krenn et al [2020]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.liu.2020.821">Liu et al [2020]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.benova.2021.88">Benova et al [2021]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.wang.2021.40">Wang et al [2021]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.zhang.2021.641019">Zhang et al [2021]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.arenascabrera.2022.11795735211060114">Arenas-Cabrera et al [2022]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.bacq.2022.101">Bacq et al [2022]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ververi.2023.580">Ververi et al [2023]</a></p></div></dd><dt>5. </dt><dd><div id="depdc5-epilepsy.TF.1.5"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd></dl></div></div></div></div></div><div id="depdc5-epilepsy.Clinical_Characteristics"><h2 id="_depdc5-epilepsy_Clinical_Characteristics_">Clinical Characteristics</h2><div id="depdc5-epilepsy.Clinical_Description"><h3>Clinical Description</h3><p><i>DEPDC5-</i>related epilepsy encompasses a range of epilepsy syndromes, almost all of which are characterized by focal seizures, with seizure onset in a discrete area of the brain. While about 60% of individuals with <i>DEPDC5</i>-related epilepsy have a normal brain MRI [<a class="bk_pop" href="#depdc5-epilepsy.REF.baldassari.2019a.398">Baldassari et al 2019a</a>], some have epilepsy associated with a cortical malformation, usually focal cortical dysplasia type II or hemimegalencephaly. Most affected individuals have a family history of focal epilepsy.</p><p>To date, nearly 200 symptomatic individuals have been identified with a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>DEPDC5</i> [<a class="bk_pop" href="#depdc5-epilepsy.REF.dibbens.2013.546">Dibbens et al 2013</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ishida.2013.552">Ishida et al 2013</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.lal.2014.788">Lal et al 2014</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.martin.2014.570">Martin et al 2014</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.picard.2014.2101">Picard et al 2014</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.scheffer.2014.782">Scheffer et al 2014</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baulac.2015.675">Baulac et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.carvill.2015.e17">Carvill et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.dgama.2015.720">D'Gama et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.nascimento.2015.e28">Nascimento et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.pippucci.2015.e5">Pippucci et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.scerri.2015.575">Scerri et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.striano.2015.e168">Striano et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.bagnall.2016.522">Bagnall et al 2016</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ricos.2016.120">Ricos et al 2016</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.weckhuysen.2016.994">Weckhuysen et al 2016</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baldassari.2019b.885">Baldassari et al 2019b</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.sim.2019.901">Sim et al 2019</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.krenn.2020.624">Krenn et al 2020</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.liu.2020.821">Liu et al 2020</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.benova.2021.88">Benova et al 2021</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.wang.2021.40">Wang et al 2021</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.zhang.2021.641019">Zhang et al 2021</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.arenascabrera.2022.11795735211060114">Arenas-Cabrera et al 2022</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.bacq.2022.101">Bacq et al 2022</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ververi.2023.580">Ververi et al 2023</a>]. The following description of the phenotypic features associated with this condition is based on these reports.</p><div id="depdc5-epilepsy.T.depdc5related_epilepsy_1" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p><i>DEPDC5</i>-Related Epilepsy: Frequency of Select Features in Symptomatic Individuals <sup>1</sup></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385626/table/depdc5-epilepsy.T.depdc5related_epilepsy_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__depdc5-epilepsy.T.depdc5related_epilepsy_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature Subtype (if applicable)</th><th id="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons w/Feature <sup>2</sup></th><th id="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Epilepsy & related complications</b>
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</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">All types</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% <sup>3</sup></td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Most commonly frontal lobe seizures / sleep-related hypermotor epilepsy (30%)</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Infantile spasms</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">6%</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">SUDEP</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10%</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Brain malformations</b>
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</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">All types</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">20%</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Focal cortical dysplasia</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">17%</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mostly type II</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Hemimegalencephaly</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2%</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Polymicrogyria</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><1%</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">One person was reported w/bilateral polymicrogyria. <sup>4</sup></td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Developmental/learning issues</b>
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</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental delays (language, motor)</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">8%</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Intellectual disability</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12%</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Most reported persons w/ID have FCD/focal epilepsy or drug-resistant epilepsy.</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Developmental delay</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7%</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Autism spectrum disorder</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5%</td><td headers="hd_h_depdc5-epilepsy.T.depdc5related_epilepsy_1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">FCD = focal cortical dysplasia; SUDEP = sudden unexpected death in epilepsy</p></div></dd><dt>1. </dt><dd><div id="depdc5-epilepsy.TF.2.1"><p class="no_margin">Asymptomatic heterozygotes are common in families with <i>DEPDC5</i>-related epilepsy. Penetrance is therefore reduced and may be as low as 60% [<a class="bk_pop" href="#depdc5-epilepsy.REF.dibbens.2013.546">Dibbens et al 2013</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ishida.2013.552">Ishida et al 2013</a>].</p></div></dd><dt>2. </dt><dd><div id="depdc5-epilepsy.TF.2.2"><p class="no_margin">Percentages are based on nearly 200 reported symptomatic individuals with <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variants only and do not include individuals with <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>DEPDC5</i>.</p></div></dd><dt>3. </dt><dd><div id="depdc5-epilepsy.TF.2.3"><p class="no_margin">Most symptomatic individuals are diagnosed because they have epilepsy, so this percentage is biased toward those individuals who have epilepsy as a feature.</p></div></dd><dt>4. </dt><dd><div id="depdc5-epilepsy.TF.2.4"><p class="no_margin">
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<a class="bk_pop" href="#depdc5-epilepsy.REF.ricos.2016.120">Ricos et al [2016]</a>
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</p></div></dd></dl></div></div></div><p><b>Epilepsy.</b> In general, the age of seizure onset can range from infancy to adulthood. However, not every person with a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>DEPDC5</i> will develop epilepsy (see <a href="#depdc5-epilepsy.Penetrance">Penetrance</a>). A variety of epilepsy phenotypes have been described in affected individuals/families.</p><ul><li class="half_rhythm"><div><b>Familial focal epilepsy with variable foci (FFEVF)</b> is characterized by focal seizures that arise from different cortical regions of the brain in members of the same family. However, each affected individual in the family has one specific focal seizure type.</div><ul><li class="half_rhythm"><div>Average age of seizure onset is 4.5 years, and seizure symptomatology depend on the focal region of the brain in which the seizures originate.</div></li><li class="half_rhythm"><div>Frontal lobe and temporal lobe seizures are most common; parietal and occipital lobe seizures are also seen.</div></li><li class="half_rhythm"><div>Age of onset, seizure frequency, and drug response may vary considerably within a family.</div></li><li class="half_rhythm"><div>EEGs may show focal interictal abnormalities that typically stay constant in a given individual.</div></li></ul></li><li class="half_rhythm"><div><b>Autosomal dominant sleep-related hypermotor epilepsy (ADSHE)</b> is characterized by clusters of nocturnal motor seizures, which are often stereotyped and brief (lasting from a few seconds to a few minutes). They vary from simple arousals from sleep to dramatic, often bizarre, hyperkinetic events with tonic or dystonic features. Affected individuals may experience an aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures.</div><ul><li class="half_rhythm"><div>About 80% of individuals develop ADSHE within the first two decades of life, with a mean age of onset of about 5 years.</div></li><li class="half_rhythm"><div>Clinical neurologic examination is usually normal and intellect preserved, but intellectual disability, cognitive deficits, or psychiatric comorbidity may occur.</div></li><li class="half_rhythm"><div>Within a family, the manifestations of the disorder may vary considerably; however, seizures have a consistent onset within the frontal region.</div></li><li class="half_rhythm"><div>ADSHE is lifelong but not progressive. As an individual reaches middle age, seizures may become milder and less frequent.</div></li></ul></li><li class="half_rhythm"><div><b>Familial temporal lobe epilepsy</b> has rarely been described [<a class="bk_pop" href="#depdc5-epilepsy.REF.ishida.2013.552">Ishida et al 2013</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.krenn.2020.624">Krenn et al 2020</a>] and includes two subtypes.</div><ul><li class="half_rhythm"><div class="half_rhythm">Familial mesial temporal lobe epilepsy (FMTLE) is characterized by focal seizures with ictal mesial temporal lobe symptomatology, including psychic symptoms such as déjà vu and fear or autonomic symptoms such as nausea. Hippocampal sclerosis is commonly observed, as are febrile seizures preceding focal seizures.</div></li><li class="half_rhythm"><div class="half_rhythm">Autosomal dominant epilepsy with auditory features (ADEAF) is characterized by focal seizures with auditory auras and symptoms suggesting lateral temporal onset. It is considered a mild syndrome, with onset in adolescence or adulthood, low seizure frequency, and only rare secondarily generalized seizures.</div><div class="half_rhythm">It is unclear if ADEAF is part of <i>DEPDC5</i>-related epilepsy. While a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>DEPDC5</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> can be found in individuals with seizures with auditory features, to date heterozygous <i>DEPDC5</i> pathogenic variants have not been identified in larger families with the classic ADEAF <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> [<a class="bk_pop" href="#depdc5-epilepsy.REF.bisulli.2016.335">Bisulli et al 2016</a>].</div></li></ul></li><li class="half_rhythm"><div><b>Infantile spasms</b> have been reported as the initial seizure type in 10 unrelated individuals with <i>DEPDC5</i> pathogenic variants [<a class="bk_pop" href="#depdc5-epilepsy.REF.carvill.2015.e17">Carvill et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.tsang.2018.63">Tsang et al 2018</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baldassari.2019a.398">Baldassari et al 2019a</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.lee.2019.1338">Lee et al 2019</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.sim.2019.901">Sim et al 2019</a>], all but one of whom had some degree of developmental delay [<a class="bk_pop" href="#depdc5-epilepsy.REF.carvill.2015.e17">Carvill et al 2015</a>].</div><ul><li class="half_rhythm"><div>Focal seizures occurred later in most affected individuals; four had focal cortical dysplasia.</div></li><li class="half_rhythm"><div>In individuals with infantile spasms, hypsarrhythmia can be seen.</div></li></ul></li><li class="half_rhythm"><div><b>Sudden unexpected death in epilepsy (SUDEP)</b> has been described in about 10% of families with pathogenic <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>DEPDC5</i> variants in one study and has been reported in several individuals with <i>DEPDC5</i>-related epilepsy in case reports or small case series [<a class="bk_pop" href="#depdc5-epilepsy.REF.nascimento.2015.e28">Nascimento et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.bagnall.2016.522">Bagnall et al 2016</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baldassari.2019a.398">Baldassari et al 2019a</a>]. SUDEP may occur in heterozygous individuals without cognitive or developmental issue and without exposure to polytherapy. Therefore, affected individuals should be monitored regularly for known predictive factors of SUDEP, such as frequency of generalized tonic-clonic seizures (see <a href="#depdc5-epilepsy.Management">Management</a>) [<a class="bk_pop" href="#depdc5-epilepsy.REF.bacq.2022.101">Bacq et al 2022</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.samanta.2022.108678">Samanta 2022</a>]. Further evidence from larger studies is needed to confirm to what extent individuals with <i>DEPDC5</i>-related epilepsy have an increased risk for SUDEP.</div></li></ul><p><b>Neurodevelopment and behavior</b> is usually normal, although a minority of affected individuals have been reported to have intellectual disability (ID) or autism spectrum disorder [<a class="bk_pop" href="#depdc5-epilepsy.REF.dibbens.2013.546">Dibbens et al 2013</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ricos.2016.120">Ricos et al 2016</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baldassari.2019a.398">Baldassari et al 2019a</a>], particularly if they have a history of infantile spasms or brain malformations. Individuals with ID who do not have infantile spasms typically have mild ID, while those with a history of infantile spasms have severe-to-profound ID.</p><p><b>Neuroimaging/histopathology.</b> Brain MRI is normal in most individuals; however, about 20% of individuals have a cortical malformation detected on MRI and/or histopathologic examination [<a class="bk_pop" href="#depdc5-epilepsy.REF.scheffer.2014.782">Scheffer et al 2014</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baulac.2015.675">Baulac et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.dgama.2015.720">D'Gama et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.mirzaa.2016.836">Mirzaa et al 2016</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ricos.2016.120">Ricos et al 2016</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.weckhuysen.2016.994">Weckhuysen et al 2016</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baldassari.2019a.398">Baldassari et al 2019a</a>].</p><ul><li class="half_rhythm"><div>Most reported individuals had focal cortical dysplasia type IIa (characterized by cortical dyslamination frequently associated with the presence of <a class="def" href="/books/n/gene/glossary/def-item/dysmorphic/">dysmorphic</a> neurons) associated with early-onset drug-resistant seizures.</div></li><li class="half_rhythm"><div>Hemimegalencephaly (characterized typically by enlargement and dysplasia of one cerebral hemisphere) has been reported in several affected individuals.</div></li><li class="half_rhythm"><div>Other reported findings seen in a few individuals include the following:</div><ul><li class="half_rhythm"><div>Bilateral symmetric perisylvian polymicrogyria</div></li><li class="half_rhythm"><div>Pachygyria</div></li><li class="half_rhythm"><div>Subtle band heterotopia</div></li><li class="half_rhythm"><div>Hypoplasia of the corpus callosum in addition to focal cortical dysplasia</div></li></ul></li></ul><p><b>Biallelic pathogenic variants in <i>DEPDC5.</i></b> A more severe <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> has been described in nine individuals with <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> constitutional (non-mosaic) <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants in <i>DEPDC5</i> [<a class="bk_pop" href="#depdc5-epilepsy.REF.ververi.2023.580">Ververi et al 2023</a>]. The phenotype consisted of progressive developmental encephalopathy, early-onset refractory epilepsy with multifocal seizures, bilateral polymicrogyria, and <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> macrocephaly. The presence of multisystemic features involving eye and cardiac defects has also been reported in these individuals.</p></div><div id="depdc5-epilepsy.GenotypePhenotype_Correl"><h3>Genotype-Phenotype Correlations</h3><p>No definitive <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a> have been identified.</p><ul><li class="half_rhythm"><div>In general, individuals with a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a> or frameshift <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> leading to a premature stop codon are more likely to have brain malformations (focal cortical dysplasia or hemimegalencephaly) [<a class="bk_pop" href="#depdc5-epilepsy.REF.scheffer.2014.782">Scheffer et al 2014</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baulac.2015.675">Baulac et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.dgama.2015.720">D'Gama et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.scerri.2015.575">Scerri et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ricos.2016.120">Ricos et al 2016</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.weckhuysen.2016.994">Weckhuysen et al 2016</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baldassari.2019b.885">Baldassari et al 2019b</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.sim.2019.901">Sim et al 2019</a>].</div></li><li class="half_rhythm"><div>Individuals with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants and a severe multisystemic <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> are very rare (only a few individuals have been reported), and therefore no definite <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a>-phenotype associations can be defined (see <a href="#depdc5-epilepsy.Clinical_Description">Clinical Description</a>).</div></li></ul></div><div id="depdc5-epilepsy.Penetrance"><h3>Penetrance</h3><p>Asymptomatic heterozygotes are common in families with <i>DEPDC5</i>-related epilepsy. Penetrance is therefore reduced and may be as low as 60% [<a class="bk_pop" href="#depdc5-epilepsy.REF.dibbens.2013.546">Dibbens et al 2013</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ishida.2013.552">Ishida et al 2013</a>].</p></div><div id="depdc5-epilepsy.Nomenclature"><h3>Nomenclature</h3><p>Familial focal epilepsy with variable foci (FFEVF) [<a class="bk_pop" href="#depdc5-epilepsy.REF.dibbens.2013.546">Dibbens et al 2013</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ishida.2013.552">Ishida et al 2013</a>] was previously referred to as <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> partial epilepsy with variable foci.</p></div><div id="depdc5-epilepsy.Prevalence"><h3>Prevalence</h3><p>The prevalence of <i>DEPDC5</i>-related epilepsy is unknown. Nearly 200 unrelated probands with <i>DEPDC5</i>-related epilepsy have been reported to date.</p></div></div><div id="depdc5-epilepsy.Genetically_Related_Alle"><h2 id="_depdc5-epilepsy_Genetically_Related_Alle_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with pathogenic variants in <i>DEPDC5</i>.</p></div><div id="depdc5-epilepsy.Differential_Diagnosis"><h2 id="_depdc5-epilepsy_Differential_Diagnosis_">Differential Diagnosis</h2><p>The differential diagnosis for <i>DEPDC5</i>-related epilepsy includes other focal epilepsy syndromes as well as other genetic causes of (<a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a>) focal epilepsy and focal cortical dysplasia (see <a href="/books/NBK385626/table/depdc5-epilepsy.T.genes_of_interest_in_t/?report=objectonly" target="object" rid-ob="figobdepdc5epilepsyTgenesofinterestint">Table 3</a>). Of note, <i>DEPDC5</i> is the most frequently involved <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> among genetic focal epilepsies.</p><div id="depdc5-epilepsy.T.genes_of_interest_in_t" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genes of Interest in the Differential Diagnosis of <i>DEPDC5</i>-Related Epilepsy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385626/table/depdc5-epilepsy.T.genes_of_interest_in_t/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__depdc5-epilepsy.T.genes_of_interest_in_t_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_2" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Clinical Features of Differential Diagnosis Disorder</th></tr><tr><th headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4" id="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/<i>DEPDC5</i>-related epilepsy</th><th headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4" id="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from <i>DEPDC5</i>-related epilepsy</th></tr></thead><tbody><tr><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CHRNA2</i>
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<br />
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<i>CHRNA4</i>
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<br />
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<i>CHRNB2</i>
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<br />
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<i>CRH</i>
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</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>CHRNA2</i>-, <i>CHRNA4</i>, <i>CHRNB2</i>-, & <i>CRH</i>-related <a href="/books/n/gene/adnfle/">ADSHE</a></td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frontal lobe seizures <sup>1</sup></td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frontal lobe seizures in <i>DEPDC5</i>-related ADSHE occur more frequently during wakefulness & less frequently in clusters; no cortical malformations in <i>CHRNA2</i>-, <i>CHRNA4</i>, <i>CHRNB2</i>-, & <i>CRH</i>-related ADSHE to date. <sup>2</sup></td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>KCNT1</i>
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</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/kcnt1-epilepsy/"><i>KCNT1</i>-related epilepsy</a>
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</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">EIMFS & ADSHE</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Persons w/<i>KCNT1</i>-related ADSHE are more likely to develop seizures at a younger age, have cognitive comorbidity, & display psychiatric & behavioral issues than those w/ADSHE from other causes.</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<br />
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<i>LGI1</i>
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<br />
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<i>RELN</i>
|
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</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>LGI1</i>- & <i>RELN</i>-related <a href="/books/n/gene/peaf/">ADEAF</a> <sup>3</sup></td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Focal epilepsy syndrome in which auditory symptoms &/or receptive aphasia are prominent ictal manifestations. Affected persons have focal seizures ± altered consciousness; most typical features are auras consisting of humming or buzzing, or more complex auditory hallucinations. Most affected persons also have secondarily generalized seizures, but these are rare.</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ADEAF is more commonly assoc w/pathogenic variants in <i>LGI1</i> & <i>RELN</i> than w/pathogenic variants in <i>DEPDC5</i>.</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>NPRL2</i><br /><i>NPRL3</i> <sup>4</sup></td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>NPRL2</i>- & <i>NPRL3</i>-related focal epilepsy (OMIM <a href="https://omim.org/entry/617116" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">617116</a> & <a href="https://omim.org/entry/617118" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">617118</a>)</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Familial focal epilepsies incl families w/ADSHE or FFEVF, of which some family members can have FCD type II <sup>5</sup></td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>NPRL2</i>- & <i>NPRL3</i>-related epilepsies are similar to <i>DEPDC5</i>-related epilepsies. <i>DEPDC5</i> & <i>NPRL2/3</i> are part of the same complex, GATOR1, <sup>4</sup> a repressor of the amino acid-sensing branch of the mTOR pathway. To date, 35 persons have been reported w/<i>NPRL2</i> or <i>NPRL3</i> pathogenic variants.</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MTOR</i>
|
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</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">FCD (OMIM <a href="https://omim.org/entry/607341" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">607341</a>) & Smith-Kingsmore syndrome (OMIM <a href="https://omim.org/entry/616638" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">616638</a>)</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD or<br />somatic</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Focal epilepsy, FCD type II, hemimegalencephaly, polymicrogyria</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hyperpigmented macules, macrocephaly. Germline pathogenic <i>MTOR</i> variants cause Smith-Kingsmore syndrome. Persons w/<a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> <i>MTOR</i> pathogenic variants typically represent <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> cases (i.e., only affected family member). Somatic <i>MTOR</i> variants cause hemimegalencephaly & FCD.</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>AKT3</i>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">FCD, hemimegalencephaly, & <i>AKT3-</i>related <a href="/books/n/gene/mpph/">megalencephaly-polydactyly-polymicrogyria-hydrocephalus syndrome</a> <sup>6</sup></td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD or<br />somatic</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Focal epilepsy, FCD type II, hemimegalencephaly, polymicrogyria</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Macrocephaly, vascular malformations. Persons w/<i>AKT3</i> pathogenic variants typically represent <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> cases (i.e., only affected family member).</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PIK3CA</i>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<a href="/books/n/gene/pik3ca-overgrowth/"><i>PIK3CA</i>-related overgrowth spectrum</a>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Somatic</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Focal epilepsy, FCD type II, hemimegalencephaly, polymicrogyria</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Macrocephaly, somatic overgrowth, polydactyly, syndactyly, vascular/lymphatic malformations</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>RHEB</i>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">FCD & hemimegalencephaly <sup>7</sup></td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Somatic</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Focal epilepsy, FCD type II, hemimegalencephaly</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Somatic mutations</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<i>PIK3C2B</i>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Focal epilepsy <sup>8</sup></td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Focal epilepsy</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To date, all persons w/<i>PIK3C2B</i> pathogenic variants have represented <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> cases (i.e., only affected family member).</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>PTEN</i> <sup>9</sup></td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Megalencephaly, hemimegalencephaly</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Somatic</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Focal epilepsy, FCD type II, hemimegalencephaly</td><td headers="hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_1_4 hd_h_depdc5-epilepsy.T.genes_of_interest_in_t_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Macrocephaly, overgrowth, hamartomas, <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> cancer</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; ADEAF = autosomal dominant epilepsy with auditory features; ADSHE = autosomal dominant sleep-related epilepsy; AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>; EIMFS = epilepsy of infancy with migrating focal seizures; FCD = focal cortical dysplasia; FFEVF = <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> focal epilepsy with variable foci; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a></p></div></dd><dt>1. </dt><dd><div id="depdc5-epilepsy.TF.3.1"><p class="no_margin">
|
||
<a class="bk_pop" href="#depdc5-epilepsy.REF.picard.2014.2101">Picard et al [2014]</a>
|
||
</p></div></dd><dt>2. </dt><dd><div id="depdc5-epilepsy.TF.3.2"><p class="no_margin"><a class="bk_pop" href="#depdc5-epilepsy.REF.scheffer.2014.782">Scheffer et al [2014]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baulac.2015.675">Baulac et al [2015]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baldassari.2019a.398">Baldassari et al [2019a]</a></p></div></dd><dt>3. </dt><dd><div id="depdc5-epilepsy.TF.3.3"><p class="no_margin">Previously referred to as <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> partial epilepsy with auditory features (ADPEAF) or autosomal dominant lateral temporal lobe epilepsy (ADTLE) [<a class="bk_pop" href="#depdc5-epilepsy.REF.bisulli.2021.115">Bisulli et al 2021</a>]</p></div></dd><dt>4. </dt><dd><div id="depdc5-epilepsy.TF.3.4"><p class="no_margin">NPRL2 and NPRL3, together with DEPDC5, form a complex called GATOR1 (<i>G</i>AP <i>a</i>ctivity <i>to</i>wards <i>R</i>ags) complex.</p></div></dd><dt>5. </dt><dd><div id="depdc5-epilepsy.TF.3.5"><p class="no_margin"><a class="bk_pop" href="#depdc5-epilepsy.REF.korenke.2016.e60">Korenke et al [2016]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ricos.2016.120">Ricos et al [2016]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.sim.2016.132">Sim et al [2016]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.weckhuysen.2016.994">Weckhuysen et al [2016]</a></p></div></dd><dt>6. </dt><dd><div id="depdc5-epilepsy.TF.3.6"><p class="no_margin">
|
||
<a class="bk_pop" href="#depdc5-epilepsy.REF.poduri.2012.41">Poduri et al [2012]</a>
|
||
</p></div></dd><dt>7. </dt><dd><div id="depdc5-epilepsy.TF.3.7"><p class="no_margin"><a class="bk_pop" href="#depdc5-epilepsy.REF.baldassari.2019b.885">Baldassari et al [2019b]</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.lee.2021.485">Lee et al [2021]</a></p></div></dd><dt>8. </dt><dd><div id="depdc5-epilepsy.TF.3.8"><p class="no_margin">
|
||
<a class="bk_pop" href="#depdc5-epilepsy.REF.gozzelino.2022.2313">Gozzelino et al [2022]</a>
|
||
</p></div></dd><dt>9. </dt><dd><div id="depdc5-epilepsy.TF.3.9"><p class="no_margin">
|
||
<a class="bk_pop" href="#depdc5-epilepsy.REF.macken.2019.591">Macken et al [2019]</a>
|
||
</p></div></dd></dl></div></div></div></div><div id="depdc5-epilepsy.Management"><h2 id="_depdc5-epilepsy_Management_">Management</h2><p>No clinical practice guidelines for <i>DEPDC5</i>-related epilepsy have been published.</p><div id="depdc5-epilepsy.Evaluations_Following_In"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <i>DEPDC5</i>-related epilepsy, the evaluations summarized in <a href="/books/NBK385626/table/depdc5-epilepsy.T.recommended_evaluation/?report=objectonly" target="object" rid-ob="figobdepdc5epilepsyTrecommendedevaluation">Table 4</a> (if not performed as part of the evaluation that led to diagnosis) are recommended.</p><div id="depdc5-epilepsy.T.recommended_evaluation" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with <i>DEPDC5</i>-Related Epilepsy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385626/table/depdc5-epilepsy.T.recommended_evaluation/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__depdc5-epilepsy.T.recommended_evaluation_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment by neurologist for eval of suspected seizures, as indicated</td><td headers="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl EEG & high-resolution brain MRI to evaluate for focal cortical dysplasia or other brain malformations</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Assessment for predictive factors for SUDEP <sup>1</sup></td><td headers="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Development</b>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To incl motor, adaptive, cognitive, & speech-language eval</div></li><li class="half_rhythm"><div>Eval for early intervention / special education</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genetic counseling</b>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>2</sup></td><td headers="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & their families re nature, MOI, & implications of <i>DEPDC5-</i>related disorders to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family support</b>
|
||
<br />
|
||
<b>& resources</b>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess need for:
|
||
<ul><li class="half_rhythm"><div>Community or <a href="#depdc5-epilepsy.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>;</div></li><li class="half_rhythm"><div>Social work involvement for parental support.</div></li></ul>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.recommended_evaluation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; SUDEP = sudden unexpected death in epilepsy</p></div></dd><dt>1. </dt><dd><div id="depdc5-epilepsy.TF.4.1"><p class="no_margin">Predictive factors may include frequent generalized clonic-tonic seizures.</p></div></dd><dt>2. </dt><dd><div id="depdc5-epilepsy.TF.4.2"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="depdc5-epilepsy.Treatment_of_Manifestati"><h3>Treatment of Manifestations</h3><p>There is no specific cure for <i>DEPDC5</i>-related epilepsy.</p><p><b>Supportive care</b> to improve quality of life, maximize function, and reduce complications is recommended (see <a href="/books/NBK385626/table/depdc5-epilepsy.T.treatment_of_manifesta/?report=objectonly" target="object" rid-ob="figobdepdc5epilepsyTtreatmentofmanifesta">Table 5</a>).</p><div id="depdc5-epilepsy.T.treatment_of_manifesta" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with <i>DEPDC5</i>-Related Epilepsy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385626/table/depdc5-epilepsy.T.treatment_of_manifesta/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__depdc5-epilepsy.T.treatment_of_manifesta_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Epilepsy</b>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standardized treatment w/ASM by experienced neurologist</td><td headers="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.</div></li><li class="half_rhythm"><div>Education of parents/caregivers <sup>1</sup></div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Brain malformations</b>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Resective epilepsy surgery may be considered in persons w/focal epilepsy that is refractory to medical therapy.</td><td headers="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>In those w/FCD or hemimegalencephaly, epilepsy surgery should be explored early in disease course.</div></li><li class="half_rhythm"><div>Surgical outcomes have been variable. <sup>2</sup></div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Developmental delay /</b>
|
||
<br />
|
||
<b>Intellectual disability</b>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment, which may incl supportive developmental therapies (OT, PT, ST) to address specific delayed areas</td><td headers="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/neurodevelopmental specialist may be considered.</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Autism spectrum disorder</b>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment, which may incl ABA therapy</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family/Community</b>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ensure appropriate social work involvement to connect families w/local resources & support.</td><td headers="hd_h_depdc5-epilepsy.T.treatment_of_manifesta_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ABA = applied behavior analysis; ASM = anti-seizure medication; FCD = focal cortical dysplasia; OT = occupational therapy; PT = physical therapy; ST = speech therapy</p></div></dd><dt>1. </dt><dd><div id="depdc5-epilepsy.TF.5.1"><p class="no_margin">Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see <a href="https://www.epilepsy.com/tools-resources/forms-resources#Epilepsy-Foundation-Toolbox" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Epilepsy Foundation Toolbox</a>.</p></div></dd><dt>2. </dt><dd><div id="depdc5-epilepsy.TF.5.2"><p class="no_margin">In one study, four of five unrelated individuals who underwent epilepsy surgery with resection of the focal cortical dysplasia had a favorable postoperative outcome [<a class="bk_pop" href="#depdc5-epilepsy.REF.baulac.2015.675">Baulac et al 2015</a>]. In contrast, another study reported a poor surgical outcome in four individuals [<a class="bk_pop" href="#depdc5-epilepsy.REF.benova.2021.88">Benova et al 2021</a>].</p></div></dd></dl></div></div></div></div><div id="depdc5-epilepsy.Surveillance"><h3>Surveillance</h3><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in <a href="/books/NBK385626/table/depdc5-epilepsy.T.recommended_surveillan/?report=objectonly" target="object" rid-ob="figobdepdc5epilepsyTrecommendedsurveillan">Table 6</a> are recommended.</p><div id="depdc5-epilepsy.T.recommended_surveillan" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with <i>DEPDC5</i>-Related Epilepsy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385626/table/depdc5-epilepsy.T.recommended_surveillan/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__depdc5-epilepsy.T.recommended_surveillan_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency/Indication</th></tr></thead><tbody><tr><td headers="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic</b>
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</td><td headers="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for new or ongoing manifestations, such as new-onset seizures &/or changes in seizures or tone.</td><td headers="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Assess for predictive factors for SUDEP. <sup>1</sup></td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Repeat brain MRI (incl higher-resolution brain MRI).</td><td headers="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For those w/treatment-resistant seizures whose first brain MRI was normal</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Repeat EEG.</td><td headers="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To address any ↑ in seizure frequency or new seizure symptomatology</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Development</b>
|
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</td><td headers="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor developmental progress.</td><td headers="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Family/Community</b>
|
||
</td><td headers="hd_h_depdc5-epilepsy.T.recommended_surveillan_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assess family need for social work support, care coordination, or follow-up <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> if new questions arise (e.g., family planning).</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">SUDEP = sudden unexpected death in epilepsy</p></div></dd><dt>1. </dt><dd><div id="depdc5-epilepsy.TF.6.1"><p class="no_margin">Predictive factors may include frequent generalized clonic-tonic seizures.</p></div></dd></dl></div></div></div></div><div id="depdc5-epilepsy.Evaluation_of_Relatives"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify those who are at risk for the development of seizures as early as possible. This typically entails targeted <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> for the known <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>(s) in the family.</p><p>See <a href="#depdc5-epilepsy.Related_Genetic_Counseli">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="depdc5-epilepsy.Pregnancy_Management"><h3>Pregnancy Management</h3><p>In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medications (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, ASM to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [<a class="bk_pop" href="#depdc5-epilepsy.REF.sarma.2016.467">Sarma et al 2016</a>].</p><p>See <a href="https://www.mothertobaby.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MotherToBaby</a> for further information on medication use during pregnancy.</p></div><div id="depdc5-epilepsy.Therapies_Under_Investig"><h3>Therapies Under Investigation</h3><p>Loss-of-function pathogenic variants in <i>DEPDC5</i> lead to hyperactivation of the mTORC1 pathway (see <a href="#depdc5-epilepsy.Molecular_Genetics">Molecular Genetics</a>). Therefore, mTORC1 inhibitors including rapamycin (or everolimus) have been proposed as a potential targeted treatment option. Animal model studies, notably <i>Depdc5</i> knockout rodent models, have shown that mTOR inhibitors reduce the frequency of seizures [<a class="bk_pop" href="#depdc5-epilepsy.REF.marsan.2016.180">Marsan et al 2016</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ribierre.2018.2452">Ribierre et al 2018</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.yuskaitis.2019.2952">Yuskaitis et al 2019</a>]. So far, the clinical use of mTORC1 inhibitors has only been studied in the more severe mTORopathy <a href="/books/n/gene/tuberous-sclerosis/">tuberous sclerosis complex</a> [<a class="bk_pop" href="#depdc5-epilepsy.REF.wiegand.2021.111">Wiegand et al 2021</a>], and in focal cortical dysplasia type II [<a class="bk_pop" href="#depdc5-epilepsy.REF.kato.2022.181">Kato et al 2022</a>] with mitigated results. Further studies are needed to determine whether (subsets of) individuals with <i>DEPDC5</i> could benefit from treatment with this class of drugs.</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="depdc5-epilepsy.Genetic_Counseling"><h2 id="_depdc5-epilepsy_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="depdc5-epilepsy.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>DEPDC5</i>-related epilepsy is typically inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner. In rare cases <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> inheritance of <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants has been reported in association with a severe multisystemic <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> (five families, including three <a class="def" href="/books/n/gene/glossary/def-item/consanguineous/">consanguineous</a> families) [<a class="bk_pop" href="#depdc5-epilepsy.REF.ververi.2023.580">Ververi et al 2023</a>].</p></div><div id="depdc5-epilepsy.Autosomal_Dominant_Inher"><h3>Autosomal Dominant Inheritance – Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>Many individuals diagnosed with <i>DEPDC5</i>-related epilepsy inherited a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> from a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parent [<a class="bk_pop" href="#depdc5-epilepsy.REF.dibbens.2013.546">Dibbens et al 2013</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ishida.2013.552">Ishida et al 2013</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baldassari.2019a.398">Baldassari et al 2019a</a>]. Because asymptomatic heterozygotes are common in families with <i>DEPDC5</i>-related epilepsy, a heterozygous parent may or may not have manifestations of <i>DEPDC5</i>-related epilepsy.</div></li><li class="half_rhythm"><div>A <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with <i>DEPDC5</i>-related epilepsy may have the disorder as the result of a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. The overall proportion of individuals with <i>DEPDC5</i>-related epilepsy caused by a <i>de novo</i> pathogenic variant is unknown [<a class="bk_pop" href="#depdc5-epilepsy.REF.dibbens.2013.546">Dibbens et al 2013</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.carvill.2015.e17">Carvill et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.mirzaa.2016.836">Mirzaa et al 2016</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ricos.2016.120">Ricos et al 2016</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baldassari.2019a.398">Baldassari et al 2019a</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.liu.2020.821">Liu et al 2020</a>].</div></li><li class="half_rhythm"><div>Some individuals with <i>DEPDC5</i>-related epilepsy and cortical malformations have a <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> (i.e., constitutional) <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and a second <i>DEPDC5</i> pathogenic variant that is mosaic and only present in brain tissue (i.e., a second mutational event).</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> appears to be the only affected family member (i.e., a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case), <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> for the constitutional <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> counseling.</div></li><li class="half_rhythm"><div>If the constitutional <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> inherited a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> from a parent with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> or gonosomal <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a> [<a class="bk_pop" href="#depdc5-epilepsy.REF.baulac.2015.675">Baulac et al 2015</a>]. Note: Testing of parental leukocyte DNA may not detect all instances of <a class="def" href="/books/n/gene/glossary/def-item/somatic-mosaicism/">somatic mosaicism</a> and will not detect a pathogenic variant that is present in the germ cells only.</div></li></ul></li><li class="half_rhythm"><div>The family history of some individuals diagnosed with <i>DEPDC5</i>-related epilepsy may appear to be negative because of a milder <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>, reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a>, or late onset of the disorder in <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> family members. Therefore, an apparently negative family history cannot be confirmed unless <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> has demonstrated that neither parent is heterozygous for the <i>DEPDC5</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</div></li></ul><p><b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The risk to the sibs of the proband depends on the genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is affected and/or is known to have the <i>DEPDC5</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.</div></li><li class="half_rhythm"><div>Reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> and intrafamilial <a class="def" href="/books/n/gene/glossary/def-item/variable-expressivity/">variable expressivity</a> are observed in <i>DEPDC5</i>-related epilepsy. Sibs who inherit a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>:</div><ul><li class="half_rhythm"><div>May or may not have manifestations of <i>DEPDC5</i>-related epilepsy – asymptomatic heterozygotes are common in families with <i>DEPDC5</i>-related epilepsy, and <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> may be as low as 60% (see <a href="#depdc5-epilepsy.Penetrance">Penetrance</a>);</div></li><li class="half_rhythm"><div>May have different phenotypic manifestations of <i>DEPDC5</i>-related epilepsy than other affected family members – the age of seizure onset, seizure type, seizure severity, drug response, and presence of cortical malformations can vary between affected family members (see <a href="#depdc5-epilepsy.GenotypePhenotype_Correl">Genotype-Phenotype Correlations</a>).</div></li></ul></li><li class="half_rhythm"><div>If the <i>DEPDC5</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> cannot be detected in the leukocyte DNA of either parent, the <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> to sibs is slightly greater than that of the general population because of the possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>. Parental gonosomal mosaicism has been reported in one family [<a class="bk_pop" href="#depdc5-epilepsy.REF.baulac.2015.675">Baulac et al 2015</a>].</div></li><li class="half_rhythm"><div>If the parents have not been tested for the <i>DEPDC5</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> but are clinically unaffected, sibs are still presumed to be at increased risk for <i>DEPDC5</i>-related epilepsy because of the possibility of reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> in a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parent or parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>.</div></li></ul><p>
|
||
<b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>Each child of an individual with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> <i>DEPDC5</i>-related epilepsy is at a 50% risk of inheriting the constitutional <i>DEPDC5</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>The specific <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>, age of onset, and disease severity cannot be predicted accurately in offspring who inherit a <i>DEPDC5</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> because of reduced <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> and <a class="def" href="/books/n/gene/glossary/def-item/variable-expressivity/">variable expressivity</a>.</div></li></ul><p><b>Other family members.</b> The risk to other family members depends on the status of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents: if a parent has the <i>DEPDC5</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the parent's family members may be at risk.</p></div><div id="depdc5-epilepsy.Autosomal_Recessive_Inhe"><h3>Autosomal Recessive Inheritance – Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>The parents of an affected child are presumed to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>DEPDC5</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> to confirm that both parents are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>DEPDC5</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and to allow reliable <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> assessment.</div></li><li class="half_rhythm"><div>If a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> occurred as a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> event in the proband or as a <a class="def" href="/books/n/gene/glossary/def-item/postzygotic/">postzygotic</a> <i>de novo</i> event in a mosaic parent [<a class="bk_pop" href="#depdc5-epilepsy.REF.j_nsson.2017.519">Jónsson et al 2017</a>]. If the proband appears to have <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:</div><ul><li class="half_rhythm"><div>A single- or multiexon <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> that was not detected by <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> and that resulted in the artifactual appearance of homozygosity;</div></li><li class="half_rhythm"><div>Uniparental isodisomy for the parental <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> with the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> that resulted in homozygosity for the pathogenic variant in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</div></li></ul></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Heterozygous parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> <i>DEPDC5</i>-related epilepsy may be at risk of developing epilepsy based on one report [<a class="bk_pop" href="#depdc5-epilepsy.REF.ververi.2023.580">Ververi et al 2023</a>].</div></li></ul><p><b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> If both parents are known to be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>DEPDC5</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a>, and a 25% chance of being unaffected and not a carrier.</p><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> To date, it is unknown whether individuals with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> severe <i>DEPDC5</i>-related epilepsy are able to reproduce.</p><p><b>Other family members.</b> Each sib of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents is at a 50% risk of being a <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> of a <i>DEPDC5</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p><p><b>Carrier detection.</b> Carrier testing for at-risk relatives requires prior identification of the <i>DEPDC5</i> pathogenic variants in the family.</p></div><div id="depdc5-epilepsy.Related_Genetic_Counseli"><h3>Related Genetic Counseling Issues</h3><p><b>Predictive testing for <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> <i>DEPDC5</i>-related epilepsy.</b> Predictive testing for at-risk asymptomatic adult family members requires prior identification of the <i>DEPDC5</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in the family.</p><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.</div></li></ul></div><div id="depdc5-epilepsy.Prenatal_Testing_and_Pre"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>DEPDC5</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>(s) have been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk for <i>DEPDC5</i>-related epilepsy and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible. Note, however, that the specific <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>, age of onset, and disease severity cannot be accurately predicted on the basis of <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> results.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="depdc5-epilepsy.Resources"><h2 id="_depdc5-epilepsy_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>American Epilepsy Society</b>
|
||
</div><div>
|
||
<a href="https://www.aesnet.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">aesnet.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Canadian Epilepsy Alliance</b>
|
||
</div><div>Canada</div><div><b>Phone:</b> 1-866-EPILEPSY (1-866-374-5377)</div><div>
|
||
<a href="https://www.canadianepilepsyalliance.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">canadianepilepsyalliance.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Epilepsy Foundation</b>
|
||
</div><div><b>Phone:</b> 800-332-1000; 866-748-8008</div><div>
|
||
<a href="https://www.epilepsy.com/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">epilepsy.com</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>National Institute of Neurological Disorders and Stroke (NINDS)</b>
|
||
</div><div><b>Phone:</b> 800-352-9424</div><div>
|
||
<a href="https://www.ninds.nih.gov/Disorders/All-Disorders/Epilepsy-Information-Page" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Epilepsy and Seizures</a>
|
||
</div></li></ul>
|
||
</div><div id="depdc5-epilepsy.Molecular_Genetics"><h2 id="_depdc5-epilepsy_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="depdc5-epilepsy.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>DEPDC5-Related Epilepsy: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385626/table/depdc5-epilepsy.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__depdc5-epilepsy.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_depdc5-epilepsy.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_depdc5-epilepsy.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_depdc5-epilepsy.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_depdc5-epilepsy.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_depdc5-epilepsy.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_depdc5-epilepsy.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/9681" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>DEPDC5</i>
|
||
</a>
|
||
</td><td headers="hd_b_depdc5-epilepsy.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=9681" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">22q12<wbr style="display:inline-block"></wbr>.2-q12.3</a>
|
||
</td><td headers="hd_b_depdc5-epilepsy.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/O75140" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GATOR1 complex protein DEPDC5</a>
|
||
</td><td headers="hd_b_depdc5-epilepsy.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=DEPDC5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">DEPDC5</a>
|
||
</td><td headers="hd_b_depdc5-epilepsy.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=DEPDC5[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">DEPDC5</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="depdc5-epilepsy.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="depdc5-epilepsy.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for DEPDC5-Related Epilepsy (<a href="/omim/604364,614191" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385626/table/depdc5-epilepsy.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__depdc5-epilepsy.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/604364" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">604364</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 1; FFEVF1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/614191" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">614191</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DEP DOMAIN-CONTAINING PROTEIN 5; DEPDC5</td></tr></tbody></table></div></div><div id="depdc5-epilepsy.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>DEPDC5</i> encodes a ubiquitously expressed protein of 1,603 amino acids, GATOR complex protein DEPDC5 (DEPDC5). The 3D structure was recently resolved and identified five domains (NTD, SABA, SHEN, DEP, and CTD) [<a class="bk_pop" href="#depdc5-epilepsy.REF.shen.2018.64">Shen et al 2018</a>]. DEPDC5 acts as a GTPase-activating protein for RagA/B and, together with NPRL2 and NPRL3, is part of the GATOR1 complex that inhibits the mechanistic target of the rapamycin complex 1 (mTORC1) pathway in response to low amino acid cellular levels [<a class="bk_pop" href="#depdc5-epilepsy.REF.barpeled.2013.1100">Bar-Peled et al 2013</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.panchaud.2013.ra42">Panchaud et al 2013</a>]. A role of DEPDC5 in the signaling pathway has been confirmed in vivo in a <i>Depdc5</i> knockout rat [<a class="bk_pop" href="#depdc5-epilepsy.REF.marsan.2016.180">Marsan et al 2016</a>]. Rapamycin complex 1 has serine-threonine kinase activity that phosphorylates several downstream proteins, regulating essential cellular functions like protein synthesis, cell growth, migration, and proliferation [<a class="bk_pop" href="#depdc5-epilepsy.REF.lasarge.2014.18">Lasarge & Danzer 2014</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.liu.2020.183">Liu & Sabatini 2020</a>]. Most pathogenic variants are likely to lead to a loss of function. Several <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a> pathogenic variants have been shown to be targeted by nonsense-mediated <a class="def" href="/books/n/gene/glossary/def-item/mrna/">mRNA</a> decay [<a class="bk_pop" href="#depdc5-epilepsy.REF.ishida.2013.552">Ishida et al 2013</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.picard.2014.2101">Picard et al 2014</a>].</p><p>Preliminary in vitro functional studies investigated the effect on mTORC1 signaling of ten <i>DEPDC5</i> variants identified in individuals with focal epilepsy: seven <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants, two <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a> variants, and one <a class="def" href="/books/n/gene/glossary/def-item/in-frame/">in-frame</a> <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a>. The two nonsense variants and the 3-bp deletion clearly disrupted the DEPDC5-dependent inhibition of mTORC1, while none of the seven missense variants had this effect [<a class="bk_pop" href="#depdc5-epilepsy.REF.van_kranenburg.2015.200">van Kranenburg et al 2015</a>].</p><p>Some individuals with cortical malformations (most frequently focal cortical dysplasia type II or hemimegalencephaly) have been reported to have a brain-specific mosaic (or <a class="def" href="/books/n/gene/glossary/def-item/postzygotic/">postzygotic</a>) <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>DEPDC5</i> on the normal (or non-mutated) <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> (i.e., a "second hit") in addition to a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> constitutional pathogenic variant [<a class="bk_pop" href="#depdc5-epilepsy.REF.baulac.2015.675">Baulac et al 2015</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.dgama.2017.3754">D'Gama et al 2017</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.ribierre.2018.2452">Ribierre et al 2018</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baldassari.2019b.885">Baldassari et al 2019b</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.sim.2019.901">Sim et al 2019</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.lee.2020.27">Lee et al 2020</a>]. In addition, somatic copy-neutral <a class="def" href="/books/n/gene/glossary/def-item/loss-of-heterozygosity/">loss of heterozygosity</a> of the <i>DEPDC5</i> non-mutated allele may also occur [<a class="bk_pop" href="#depdc5-epilepsy.REF.mirzaa.2016.836">Mirzaa et al 2016</a>, <a class="bk_pop" href="#depdc5-epilepsy.REF.baldassari.2019b.885">Baldassari et al 2019b</a>], leading to brain tissues with <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic <i>DEPDC5</i> variants.</p><p><b>Mechanism of disease causation.</b> Loss of function</p><p><b><i>DEPDC5</i>-specific laboratory technical considerations – targeted testing for <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a>.</b> Sequence analysis of DNA derived from affected brain tissues (whether visibly affected or not) may detect a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> that is not present in DNA isolated from peripheral blood or other peripheral tissues (e.g., saliva). Note: Sensitivity to detect low-level mosaicism of a mosaic pathogenic variant is greatest using <a class="def" href="/books/n/gene/glossary/def-item/next-generation-sequencing/">next-generation sequencing</a> in tissues other than blood and has a high yield when analyzing affected (brain) tissues in particular.</p></div></div><div id="depdc5-epilepsy.Chapter_Notes"><h2 id="_depdc5-epilepsy_Chapter_Notes_">Chapter Notes</h2><div id="depdc5-epilepsy.Author_Notes"><h3>Author Notes</h3><p>Dr Stéphanie Baulac is a neurogeneticist, research director, and group leader at ICM (Paris Brain Institute) working on the genetics and neurobiology of focal epilepsies with brain malformations.</p><p>Dr Sara Baldassari is a neurogeneticist and principal investigator working at the ICM (Paris Brain Institute) on the genetics and physiopathology of focal epilepsies with brain malformations.</p><p>To volunteer for research contact:</p><p>Stéphanie Baulac<br />Institut du Cerveau (ICM)-Paris Brain Institute<br />Pitié-Salpêtrière Hospital<br />47 bd de l'Hôpital<br />75013 Paris, France<br />Email: <a href="mailto:dev@null" data-email="gro.etutitsni-mci@caluab.einahpets" class="oemail">gro.etutitsni-mci@caluab.einahpets</a></p></div><div id="depdc5-epilepsy.Author_History"><h3>Author History</h3><p>Sara Baldassari, PhD (2023-present)<br />Stéphanie Baulac, PhD (2016-2023)<br />Sarah Weckhuysen, MD, PhD; Vlaams Instituut voor Biotechnologie (2016-2023)</p></div><div id="depdc5-epilepsy.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>9 March 2023 (gm) Comprehensive update posted live</div></li><li class="half_rhythm"><div>29 September 2016 (bp) Review posted live</div></li><li class="half_rhythm"><div>23 December 2015 (sb) Original submission</div></li></ul></div></div><div id="depdc5-epilepsy.References"><h2 id="_depdc5-epilepsy_References_">References</h2><div id="depdc5-epilepsy.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="depdc5-epilepsy.REF.arenascabrera.2022.11795735211060114">Arenas-Cabrera C, Baena-Palomino P, Sánchez-García J, Oliver-Romero M, Chocrón-González Y, Caballero-Martínez M. 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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div><div class="small"><span class="label">Bookshelf ID: NBK385626</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/27683934" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">27683934</a></span></div><div style="margin-top:2em" class="bk_noprnt"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/ddx41-mds/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/dfna2/" title="Next page in this title">Next ></a></div></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK385626/?report=reader">PubReader</a></li><li><a href="/books/NBK385626/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK385626" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK385626" style="display:none" title="Cite this Page"><div class="bk_tt">Baulac S, Baldassari S. DEPDC5-Related Epilepsy. 2016 Sep 29 [Updated 2023 Mar 9]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK385626/pdf/Bookshelf_NBK385626.pdf">PDF version of this page</a> (560K)</li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this GeneReview</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#depdc5-epilepsy.Summary" ref="log$=inpage&link_id=inpage">Summary</a></li><li><a href="#depdc5-epilepsy.GeneReview_Scope" ref="log$=inpage&link_id=inpage"><i>GeneReview</i> Scope</a></li><li><a href="#depdc5-epilepsy.Diagnosis" ref="log$=inpage&link_id=inpage">Diagnosis</a></li><li><a href="#depdc5-epilepsy.Clinical_Characteristics" ref="log$=inpage&link_id=inpage">Clinical Characteristics</a></li><li><a href="#depdc5-epilepsy.Genetically_Related_Alle" ref="log$=inpage&link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#depdc5-epilepsy.Differential_Diagnosis" ref="log$=inpage&link_id=inpage">Differential Diagnosis</a></li><li><a href="#depdc5-epilepsy.Management" ref="log$=inpage&link_id=inpage">Management</a></li><li><a href="#depdc5-epilepsy.Genetic_Counseling" ref="log$=inpage&link_id=inpage">Genetic Counseling</a></li><li><a href="#depdc5-epilepsy.Resources" ref="log$=inpage&link_id=inpage">Resources</a></li><li><a href="#depdc5-epilepsy.Molecular_Genetics" ref="log$=inpage&link_id=inpage">Molecular Genetics</a></li><li><a href="#depdc5-epilepsy.Chapter_Notes" ref="log$=inpage&link_id=inpage">Chapter Notes</a></li><li><a href="#depdc5-epilepsy.References" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://ftp.ncbi.nlm.nih.gov/pub/litarch/ca/84/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download GeneReviews data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>GeneReviews Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/gene/advanced/"><i>GeneReviews</i> Advanced Search</a></li><li><a href="/books/n/gene/glossary/"><i>GeneReviews</i> Glossary</a></li><li><a href="/books/n/gene/resource_mats/">Resource Materials</a> <span class="bk_hlight1">NEW FEATURE</span></li><li><a href="/books/n/gene/updates/">New in <i>GeneReviews</i></a></li><li><a href="/books/n/gene/authors/">Author List</a></li><li><a href="/books/n/gene/prospective_authors/">For Current/Prospective Authors</a></li><li><a href="/books/n/gene/GRpersonnel/"><i>GeneReviews</i> Personnel</a></li><li><a href="/books/n/gene/howto_linkin/">Download/Link to <i>GeneReviews</i></a></li><li><a href="/books/n/gene/contact_us/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Tests in GTR by Gene</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li>
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<a href="https://www.ncbi.nlm.nih.gov/gtr/tests/?term=9681[geneid]" ref="pagearea=document-links&targetsite=external&targetcat=link&targettype=uri&link_id=tests_in_gtr_by_gene">DEPDC5</a>
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</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=omim&DbFrom=books&Cmd=Link&LinkName=books_omim&IdsFromResult=4326126" ref="log$=recordlinks">OMIM</a><div class="brieflinkpop offscreen_noflow">Related OMIM records</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=4326126" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=4326126" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=gene&DbFrom=books&Cmd=Link&LinkName=books_gene&IdsFromResult=4326126" ref="log$=recordlinks">Gene</a><div class="brieflinkpop offscreen_noflow">Locus Links</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/37200470" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> TET3-Related Beck-Fahrner Syndrome.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> TET3-Related Beck-Fahrner Syndrome.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Fahrner JA. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/24851285" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> KCNQ3-Related Disorders.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> KCNQ3-Related Disorders.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Miceli F, Soldovieri MV, Weckhuysen S, Cooper EC, Taglialatela M. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/34081427" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> SCN3A-Related Neurodevelopmental Disorder.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> SCN3A-Related Neurodevelopmental Disorder.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Helbig KL, Goldberg EM. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301377" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Phelan-McDermid Syndrome-SHANK3 Related.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Phelan-McDermid Syndrome-SHANK3 Related.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Phelan K, Rogers RC, Boccuto L. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301348" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Kurahashi H, Hirose S. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=27683934" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=27683934" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=1" href="/portal/utils/pageresolver.fcgi?recordid=67d2ab13a68b6b5afc7adf9a">DEPDC5-Related Epilepsy - 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