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<!DOCTYPE html><html lang="en"><head><title data-react-helmet="true">High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies</title> <meta data-react-helmet="true" name="viewport" content="width=device-width, initial-scale=1, maximum-scale=5, viewport-fit=cover"/><meta data-react-helmet="true" property="og:site_name" content="scite.ai"/><meta data-react-helmet="true" property="og:type" content="website"/><meta data-react-helmet="true" property="twitter:card" content="summary_large_image"/><meta data-react-helmet="true" name="twitter:site" content="@scite"/><meta data-react-helmet="true" property="title" content="High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies"/><meta data-react-helmet="true" property="og:title" content="High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies"/><meta data-react-helmet="true" property="twitter:title" content="High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies"/><meta data-react-helmet="true" property="og:image" content="http://image.thum.io/get/ogImage/https://scite.ai/reports/high-rate-of-recurrent-de-J1P4bEw?bannerClosed=true&onboardingOff=true&paywallOff=true&v=2"/><meta data-react-helmet="true" property="twitter:image" content="http://image.thum.io/get/ogImage/https://scite.ai/reports/high-rate-of-recurrent-de-J1P4bEw?bannerClosed=true&onboardingOff=true&paywallOff=true&v=2"/><meta data-react-helmet="true" name="description" content="Supporting: 24, Contrasting: 1, Mentioning: 380 - Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy."/><meta data-react-helmet="true" property="og:description" content="Supporting: 24, Contrasting: 1, Mentioning: 380 - Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy."/><meta data-react-helmet="true" property="twitter:description" content="Supporting: 24, Contrasting: 1, Mentioning: 380 - Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy."/><meta data-react-helmet="true" property="og:url" content="https://scite.ai/reports/high-rate-of-recurrent-de-J1P4bEw"/><meta data-react-helmet="true" name="citation_title" content="High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies"/><meta data-react-helmet="true" name="citation_doi" content="10.1016/j.ajhg.2017.09.008"/><meta data-react-helmet="true" name="citation_author" content="Hamdan, Fadi F."/><meta data-react-helmet="true" name="citation_author" content="Myers, Candace T."/><meta data-react-helmet="true" name="citation_author" content="Cossette, Patrick"/><meta data-react-helmet="true" name="citation_author" content="Lemay, Philippe"/><meta data-react-helmet="true" name="citation_author" content="Spiegelman, Dan"/><meta data-react-helmet="true" name="citation_author" content="Laporte, Alexandre D."/><meta data-react-helmet="true" name="citation_author" content="Nassif, Christina"/><meta data-react-helmet="true" name="citation_author" content="Diallo, Ousmane"/><meta data-react-helmet="true" name="citation_author" content="Monlong, Jean"/><meta data-react-helmet="true" name="citation_author" content="Cadieux‐Dion, Maxime"/><meta data-react-helmet="true" name="citation_author" content="Dobrzeniecka, Sylvia"/><meta data-react-helmet="true" name="citation_author" content="Meloche, Caroline"/><meta data-react-helmet="true" name="citation_author" content="Retterer, Kyle"/><meta data-react-helmet="true" name="citation_author" content="Cho, Megan T."/><meta data-react-helmet="true" name="citation_author" content="Rosenfeld, Jill A."/><meta data-react-helmet="true" name="citation_author" content="Bi, Weimin"/><meta data-react-helmet="true" name="citation_author" content="Massicotte, Christine"/><meta data-react-helmet="true" name="citation_author" content="Miguet, Marguerite"/><meta data-react-helmet="true" name="citation_author" content="Brunga, Ledia"/><meta data-react-helmet="true" name="citation_author" content="Regan, Brigid M."/><meta data-react-helmet="true" name="citation_author" content="Mo, Kelly"/><meta data-react-helmet="true" name="citation_author" content="Tam, Cory"/><meta data-react-helmet="true" name="citation_author" content="Schneider, Amy L."/><meta data-react-helmet="true" name="citation_author" content="Hollingsworth, Georgie"/><meta data-react-helmet="true" name="citation_author" content="Fitzpatrick, David"/><meta data-react-helmet="true" name="citation_author" content="Donaldson, Alan"/><meta data-react-helmet="true" name="citation_author" content="Canham, Natalie"/><meta data-react-helmet="true" name="citation_author" content="Blair, Edward"/><meta data-react-helmet="true" name="citation_author" content="Kerr, Bronwyn"/><meta data-react-helmet="true" name="citation_author" content="Fry, Andrew E."/><meta data-react-helmet="true" name="citation_author" content="Thomas, Rhys H."/><meta data-react-helmet="true" name="citation_author" content="Shelagh, Joss"/><meta data-react-helmet="true" name="citation_author" content="Hurst, Jane A."/><meta data-react-helmet="true" name="citation_author" content="Brittain, Helen"/><meta data-react-helmet="true" name="citation_author" content="Blyth, Moira"/><meta data-react-helmet="true" name="citation_author" content="Lebel, Robert Roger"/><meta data-react-helmet="true" name="citation_author" content="Gerkes, Erica H."/><meta data-react-helmet="true" name="citation_author" content="Davis‐Keppen, Laura"/><meta data-react-helmet="true" name="citation_author" content="Stein, Quinn"/><meta data-react-helmet="true" name="citation_author" content="Chung, Wendy K."/><meta data-react-helmet="true" name="citation_author" content="Dorison, Sara J."/><meta data-react-helmet="true" name="citation_author" content="Benke, Paul J."/><meta data-react-helmet="true" name="citation_author" content="Fassi, Emily"/><meta data-react-helmet="true" name="citation_author" content="Corsten‐Janssen, Nicole"/><meta data-react-helmet="true" name="citation_author" content="Kamsteeg, Erik‐Jan"/><meta data-react-helmet="true" name="citation_author" content="Mau‐Them, Frédéric Tran"/><meta data-react-helmet="true" name="citation_author" content="Bruel, Ange‐Line"/><meta data-react-helmet="true" name="citation_author" content="Verloès, Alain"/><meta data-react-helmet="true" name="citation_author" content="Õunap, Katrin"/><meta data-react-helmet="true" name="citation_author" content="Wojcik, Monica H."/><meta data-react-helmet="true" name="citation_author" content="Albert, Dara V.F."/><meta data-react-helmet="true" name="citation_author" content="Venkateswaran, Sunita"/><meta data-react-helmet="true" name="citation_author" content="Ware, Tyson L."/><meta data-react-helmet="true" name="citation_author" content="Jones, Dean"/><meta data-react-helmet="true" name="citation_author" content="Liu, Y. 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The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy."/><meta data-react-helmet="true" name="citation_public_url" content="https://doi.org/10.1016/j.ajhg.2017.09.008"/> <link data-react-helmet="true" rel="preconnect" href="https://cdn.scite.ai" crossorigin="true"/><link data-react-helmet="true" rel="preconnect" href="https://fonts.googleapis.com"/><link data-react-helmet="true" rel="preconnect" href="https://fonts.gstatic.com" crossorigin="true"/><link data-react-helmet="true" rel="shortcut icon" href="https://cdn.scite.ai/assets/images/favicon.ico"/><link data-react-helmet="true" rel="stylesheet preload prefetch" as="style" href="https://cdn.scite.ai/assets/css/line-awesome-font-awesome.min.css?v=2"/><link data-react-helmet="true" rel="preload" as="style" href="https://fonts.googleapis.com/css2?family=IBM+Plex+Sans:wght@200;300;400;500;600&display=swap"/><link data-react-helmet="true" rel="stylesheet" as="style" href="https://fonts.googleapis.com/css2?family=IBM+Plex+Sans:wght@200;300;400;500;600&display=swap" media="print" onload="this.media='all'"/><link data-react-helmet="true" rel="canonical" href="https://scite.ai/reports/high-rate-of-recurrent-de-J1P4bEw"/> <script data-react-helmet="true" src="https://www.recaptcha.net/recaptcha/api.js?render=6LcnMGsqAAAAAJLHdGuust5QwzLk-asKPW5MWbAx"></script><script data-react-helmet="true" type="application/ld+json">{"@context":"http://schema.org","@graph":[{"@id":"#issue","@type":"PublicationIssue","issueNumber":"5","datePublished":2017,"isPartOf":{"@id":"#periodical","@type":["PublicationVolume","Periodical"],"name":"The American Journal of Human Genetics","issn":["0002-9297"],"volumeNumber":"101","publisher":"Elsevier BV"}},{"@type":"ScholarlyArticle","isPartOf":"#issue","description":"Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.","abstract":"Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.","sameAs":"https://doi.org/10.1016/j.ajhg.2017.09.008","pagination":"664-685","name":"High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies","headline":"High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies","author":["Fadi F. Hamdan","Candace T. Myers","Patrick Cossette","Philippe Lemay","Dan Spiegelman","Alexandre D. 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Michaud"],"publisher":{"@type":"Organization","name":"Elsevier BV"},"datePublished":2017}]}</script> <link data-chunk="main" rel="stylesheet" href="https://cdn.scite.ai/assets/dist/main.2a4a881c9257077826c8.css"> <link data-chunk="Report" rel="stylesheet" href="https://cdn.scite.ai/assets/dist/6901.5555e2c3b29dc5d88f29.css"> <link data-chunk="Report" rel="stylesheet" href="https://cdn.scite.ai/assets/dist/6392.ee3f7fe674ceac954f77.css"> </head> <body><div id="scite-app"><!--$--><div class="ReportApp__layout___ljMuO"><div><nav class="NavBar__navBarContainer___skQfv"><div class="NavBar__navBar___ELwVq NavBar__notStatic___bzily" style="transform:translate3d(0,0%,0)"><div class="NavBar__navContents___X2u7r"><a class="NavBar__logo___aYKoi" href="/"><img alt="scite logo" width="115px" height="38px" class="NavBar__logoDesktop___Cwo_2" style="filter:contrast(2.15)" src="https://cdn.scite.ai/assets/images/logo-blue.svg"/><img alt="scite logo" width="64px" height="38px" 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href="/journals/the-american-journal-of-human-vJYyO">The American Journal of Human Genetics</a></span></div></span><span class="Reference__pubYear___BW5ev"> <!-- -->2017<!-- --> </span><div class="Reference__doiContainer___kZXiq"><span>DOI: <!-- -->10.1016/j.ajhg.2017.09.008</span><div class="Reference__tooltip___Nu3gD Tooltip__reference___hgPSY"><i class="copy fa fa-copy fa-lg"></i></div><span> |</span><a class="Reference__fullTextLink___p92ic Link__link___plGt2 Link__blueLink___BhE5_ Link__underline___K1Y7j Reference__fullTextLink___p92ic" href="https://doi.org/10.1016/j.ajhg.2017.09.008" tabindex="0" role="link" target="_blank" rel="noopener noreferrer nofollow">View full text</a><span> |</span><a class="Reference__fullTextLink___p92ic Link__link___plGt2 Link__blueLink___BhE5_ Link__underline___K1Y7j Reference__fullTextLink___p92ic" tabindex="0" role="button">Cite</a></div></span></span><div class="TitlePaper__widgetContainer___xNQUF"><div 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class="SocialIcon__socialIcon___gm1fE SharingWidget__icon___Rek8d Link__link___plGt2 SocialIcon__socialIcon___gm1fE SharingWidget__icon___Rek8d" href="https://www.facebook.com/sharer/sharer.php?u=" tabindex="0" role="link" target="_blank" rel="noopener noreferrer" aria-label="https://facebook.com/sciteai"><i class="icon icon-facebook-new"></i></a><a class="SocialIcon__socialIcon___gm1fE SharingWidget__icon___Rek8d Link__link___plGt2 SocialIcon__socialIcon___gm1fE SharingWidget__icon___Rek8d" href="https://www.linkedin.com/sharing/share-offsite/?url=" tabindex="0" role="link" target="_blank" rel="noopener noreferrer" aria-label="https://www.linkedin.com/company/sciteai/"><i class="icon icon-linkedin-new"></i></a></div></div><div class="TitlePaper__paperTitle___zucih"><span><h1 class="Header__h1___YjMd5 TitlePaper__paperTitleHeader___p1alj">High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies</h1></span></div><div class="Authors__authors___uWMEz"><div class="Authors__author___TTnHS"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/authors/fadi-f-hamdan-ka0km5"><span>Fadi F. Hamdan</span></a><div class="Tooltip__reference___hgPSY"><sup class="Authors__affiliationSup___Vvflj"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/affiliations/centre-hospitalier-universitaire-sainte-justine-KWA1">1</a></sup></div><span>, </span></div><div class="Authors__author___TTnHS"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/authors/candace-t-myers-dvZ0Wb"><span>Candace T. Myers</span></a><div class="Tooltip__reference___hgPSY"><sup class="Authors__affiliationSup___Vvflj"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/affiliations/university-of-washington-5JeG">2</a></sup></div><span>, </span></div><div class="Authors__author___TTnHS"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/authors/patrick-cossette-0Gwz60"><span>Patrick Cossette</span></a><div class="Tooltip__reference___hgPSY"><sup class="Authors__affiliationSup___Vvflj"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/affiliations/centre-hospitalier-de-l-universite-de-Wx80g">3</a></sup></div><span> </span></div><span class="Authors__link___k07oy">et al.</span></div><div class="TitlePaper__abstractWrapper___S7D_F"><span><h2 class="Header__h2___MuBOH TitlePaper__abstract___GrSZl"><strong>Abstract:</strong> <!-- --> <!-- --> <span>Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. 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class=" css-1wy0on6"><style data-emotion="css 1u9des2-indicatorSeparator">.css-1u9des2-indicatorSeparator{-webkit-align-self:stretch;-ms-flex-item-align:stretch;align-self:stretch;width:1px;background-color:hsl(0, 0%, 80%);margin-bottom:8px;margin-top:8px;box-sizing:border-box;}</style><span class=" css-1u9des2-indicatorSeparator"></span><style data-emotion="css 1xc3v61-indicatorContainer">.css-1xc3v61-indicatorContainer{display:-webkit-box;display:-webkit-flex;display:-ms-flexbox;display:flex;-webkit-transition:color 150ms;transition:color 150ms;color:hsl(0, 0%, 80%);padding:8px;box-sizing:border-box;}.css-1xc3v61-indicatorContainer:hover{color:hsl(0, 0%, 60%);}</style><div class=" css-1xc3v61-indicatorContainer" aria-hidden="true"><style data-emotion="css 8mmkcg">.css-8mmkcg{display:inline-block;fill:currentColor;line-height:1;stroke:currentColor;stroke-width:0;}</style><svg height="20" width="20" viewBox="0 0 20 20" aria-hidden="true" focusable="false" class="css-8mmkcg"><path d="M4.516 7.548c0.436-0.446 1.043-0.481 1.576 0l3.908 3.747 3.908-3.747c0.533-0.481 1.141-0.446 1.574 0 0.436 0.445 0.408 1.197 0 1.615-0.406 0.418-4.695 4.502-4.695 4.502-0.217 0.223-0.502 0.335-0.787 0.335s-0.57-0.112-0.789-0.335c0 0-4.287-4.084-4.695-4.502s-0.436-1.17 0-1.615z"></path></svg></div></div></div></div><div class="CheckRowCount__sectionRow___vyiE6"><label class="CheckRow__checkRow___Wumpa"><input class="fa fa-lg fa-check Checkbox__checkbox___dGd5x " type="checkbox"/><span class="CheckRow__checkRowLabel___ax_ST">Discussion</span></label><span><span>3</span></span></div><div class="CheckRowCount__sectionRow___vyiE6"><label class="CheckRow__checkRow___Wumpa"><input class="fa fa-lg fa-check Checkbox__checkbox___dGd5x " type="checkbox"/><span class="CheckRow__checkRowLabel___ax_ST">Introduction</span></label><span><span>2</span></span></div></div></div></div><div class="FilterCard__filterCard___bZEVP"><div class="FilterCard__noInput___lsgWM"><div class="FilterCard__filterCardHeader___puB2k" role="button" tabindex="0" aria-label="Expand Citation Types"><div class="FilterCard__tooltip___q395i Tooltip__reference___hgPSY"><p class="FilterCard__header___dRl1u Paragraph__body____m5FY Paragraph__bold___PhFOq">Citation Types<!-- --> </p><i class="FilterCard__icon___iqNMr fa fa-info-circle"></i></div></div><div class=""><div class="Classification__row___s1V6w"><div class="Classification__rowLeft___VoLlX"><label class="CheckRow__checkRow___Wumpa"><input class="fa fa-lg fa-check Checkbox__checkbox___dGd5x " type="checkbox"/><span class="CheckRow__checkRowLabel___ax_ST">Supporting</span></label><div class="Classification__rowType___282g8"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--supporting___ru3vm icon-supporting"></i></div></div><div class="Classification__rowRight___Zxitp"><span class="Classification__count___Y86vw">24</span></div></div><div class="Classification__row___s1V6w"><div class="Classification__rowLeft___VoLlX"><label class="CheckRow__checkRow___Wumpa"><input class="fa fa-lg fa-check Checkbox__checkbox___dGd5x " type="checkbox"/><span class="CheckRow__checkRowLabel___ax_ST">Mentioning</span></label><div class="Classification__rowType___282g8"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--mentioning___zHr8j icon-mentioning"></i></div></div><div class="Classification__rowRight___Zxitp"><span class="Classification__count___Y86vw">380</span></div></div><div class="Classification__row___s1V6w"><div class="Classification__rowLeft___VoLlX"><label class="CheckRow__checkRow___Wumpa"><input class="fa fa-lg fa-check Checkbox__checkbox___dGd5x " type="checkbox"/><span class="CheckRow__checkRowLabel___ax_ST">Contrasting</span></label><div class="Classification__rowType___282g8"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--contradicting___BpYwd icon-contradicting"></i></div></div><div class="Classification__rowRight___Zxitp"><span class="Classification__count___Y86vw">1</span></div></div><div class="Classification__row___s1V6w"><div class="Classification__rowLeft___VoLlX"><label class="CheckRow__checkRow___Wumpa"><input class="fa fa-lg fa-check Checkbox__checkbox___dGd5x " type="checkbox"/><span class="CheckRow__checkRowLabel___ax_ST">Unclassified</span></label><div class="Classification__rowType___282g8"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--unclassified___Wc9aa icon-unclassified"></i></div></div><div class="Classification__rowRight___Zxitp"><span class="Classification__count___Y86vw">5</span></div></div></div></div></div><div class="FilterCard__filterCard___bZEVP"><div class="FilterCard__noInput___lsgWM"><div class="FilterCard__filterCardHeader___puB2k" role="button" tabindex="0" aria-label="Expand Year Published"><p class="FilterCard__header___dRl1u Paragraph__body____m5FY Paragraph__bold___PhFOq">Year Published<!-- --> </p></div><div class="Filters__yearRange___mtpTm"><div class="CitationsYearBarChart__barChartContainer___fOCtc"><div class="CitationsYearBarChart__barChart___J1Zgl"><div class="CitationsYearBarChart__bar___QB0KQ" style="width:14.285714285714286%"><div class="CitationsYearBarChart__barContainer___A2gcx Tooltip__reference___hgPSY"><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__supporting___iMyv8" style="height:NaNrem"></div><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__contradicting___ZRgkC" style="height:NaNrem"></div><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__mentioning___rfif5" style="height:4.8rem"></div></div></div><div class="CitationsYearBarChart__bar___QB0KQ" style="width:14.285714285714286%"><div class="CitationsYearBarChart__barContainer___A2gcx Tooltip__reference___hgPSY"><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__supporting___iMyv8" style="height:NaNrem"></div><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__contradicting___ZRgkC" style="height:NaNrem"></div><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__mentioning___rfif5" style="height:4.8rem"></div></div></div><div class="CitationsYearBarChart__bar___QB0KQ" style="width:14.285714285714286%"><div class="CitationsYearBarChart__barContainer___A2gcx Tooltip__reference___hgPSY"><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__supporting___iMyv8" style="height:NaNrem"></div><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__contradicting___ZRgkC" style="height:NaNrem"></div><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__mentioning___rfif5" style="height:0rem"></div></div></div><div class="CitationsYearBarChart__bar___QB0KQ" style="width:14.285714285714286%"><div class="CitationsYearBarChart__barContainer___A2gcx Tooltip__reference___hgPSY"><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__supporting___iMyv8" style="height:NaNrem"></div><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__contradicting___ZRgkC" style="height:NaNrem"></div><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__mentioning___rfif5" style="height:2.4rem"></div></div></div><div class="CitationsYearBarChart__bar___QB0KQ" style="width:14.285714285714286%"><div class="CitationsYearBarChart__barContainer___A2gcx Tooltip__reference___hgPSY"><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__supporting___iMyv8" style="height:NaNrem"></div><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__contradicting___ZRgkC" style="height:NaNrem"></div><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__mentioning___rfif5" style="height:2.4rem"></div></div></div><div class="CitationsYearBarChart__bar___QB0KQ" style="width:14.285714285714286%"><div class="CitationsYearBarChart__barContainer___A2gcx Tooltip__reference___hgPSY"><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__supporting___iMyv8" style="height:NaNrem"></div><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__contradicting___ZRgkC" style="height:NaNrem"></div><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__mentioning___rfif5" style="height:0rem"></div></div></div><div class="CitationsYearBarChart__bar___QB0KQ" style="width:14.285714285714286%"><div class="CitationsYearBarChart__barContainer___A2gcx Tooltip__reference___hgPSY"><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__supporting___iMyv8" style="height:NaNrem"></div><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__contradicting___ZRgkC" style="height:NaNrem"></div><div class="CitationsYearBarChart__barPart___aKZ37 CitationsYearBarChart__mentioning___rfif5" style="height:3.8039100017307743rem"></div></div></div></div></div><div><div aria-disabled="false" class="undefined InputRangeFilter__range___i8qUt"><span class="InputRangeFilter__hide___cvWG2 input-range__label--min"><span class="input-range__label-container InputRangeFilter__labelContainer___UOzQG">2018</span></span><div class="InputRangeFilter__track___Fdwrd input-range__track--background"><div style="left:0%;width:100%" class="InputRangeFilter__track___Fdwrd InputRangeFilter__activeTrack___Xb3wK"></div><span class="input-range__slider-container" style="position:absolute;left:0%"><span class="InputRangeFilter__label___uyn35 InputRangeFilter__labelValue___vCEiN InputRangeFilter__labelBottom___LxO3k"><span class="input-range__label-container InputRangeFilter__labelContainer___UOzQG">2018</span></span><div aria-valuemax="2024" aria-valuemin="2018" aria-valuenow="2018" class="InputRangeFilter__slider___CpeJ9" draggable="false" role="slider" tabindex="0"></div></span><span class="input-range__slider-container" style="position:absolute;left:100%"><span class="InputRangeFilter__label___uyn35 InputRangeFilter__labelValue___vCEiN InputRangeFilter__labelBottom___LxO3k"><span class="input-range__label-container InputRangeFilter__labelContainer___UOzQG">2024</span></span><div aria-valuemax="2024" aria-valuemin="2018" aria-valuenow="2024" class="InputRangeFilter__slider___CpeJ9" draggable="false" role="slider" tabindex="0"></div></span></div><span class="InputRangeFilter__hide___cvWG2 input-range__label--max"><span class="input-range__label-container InputRangeFilter__labelContainer___UOzQG">2024</span></span></div></div></div></div></div><div class="FilterCard__filterCard___bZEVP"><div class="FilterCard__noInput___lsgWM"><div class="FilterCard__filterCardHeader___puB2k" role="button" tabindex="0" aria-label="Expand Publication Types"><p class="FilterCard__header___dRl1u Paragraph__body____m5FY Paragraph__bold___PhFOq">Publication Types<!-- --> </p></div><div><style data-emotion="css b62m3t-container">.css-b62m3t-container{position:relative;box-sizing:border-box;}</style><div class=" css-b62m3t-container"><style data-emotion="css 7pg0cj-a11yText">.css-7pg0cj-a11yText{z-index:9999;border:0;clip:rect(1px, 1px, 1px, 1px);height:1px;width:1px;position:absolute;overflow:hidden;padding:0;white-space:nowrap;}</style><span id="react-select-201596-live-region" class="css-7pg0cj-a11yText"></span><span aria-live="polite" aria-atomic="false" aria-relevant="additions text" class="css-7pg0cj-a11yText"></span><style data-emotion="css 13cymwt-control">.css-13cymwt-control{-webkit-align-items:center;-webkit-box-align:center;-ms-flex-align:center;align-items:center;cursor:default;display:-webkit-box;display:-webkit-flex;display:-ms-flexbox;display:flex;-webkit-box-flex-wrap:wrap;-webkit-flex-wrap:wrap;-ms-flex-wrap:wrap;flex-wrap:wrap;-webkit-box-pack:justify;-webkit-justify-content:space-between;justify-content:space-between;min-height:38px;outline:0!important;position:relative;-webkit-transition:all 100ms;transition:all 100ms;background-color:hsl(0, 0%, 100%);border-color:hsl(0, 0%, 80%);border-radius:4px;border-style:solid;border-width:1px;box-sizing:border-box;}.css-13cymwt-control:hover{border-color:hsl(0, 0%, 70%);}</style><div class=" css-13cymwt-control"><style data-emotion="css hlgwow">.css-hlgwow{-webkit-align-items:center;-webkit-box-align:center;-ms-flex-align:center;align-items:center;display:grid;-webkit-flex:1;-ms-flex:1;flex:1;-webkit-box-flex-wrap:wrap;-webkit-flex-wrap:wrap;-ms-flex-wrap:wrap;flex-wrap:wrap;-webkit-overflow-scrolling:touch;position:relative;overflow:hidden;padding:2px 8px;box-sizing:border-box;}</style><div class=" css-hlgwow"><style data-emotion="css 1jqq78o-placeholder">.css-1jqq78o-placeholder{grid-area:1/1/2/3;color:hsl(0, 0%, 50%);margin-left:2px;margin-right:2px;box-sizing:border-box;}</style><div class=" css-1jqq78o-placeholder" id="react-select-201596-placeholder">Select...</div><style data-emotion="css 19bb58m">.css-19bb58m{visibility:visible;-webkit-flex:1 1 auto;-ms-flex:1 1 auto;flex:1 1 auto;display:inline-grid;grid-area:1/1/2/3;grid-template-columns:0 min-content;margin:2px;padding-bottom:2px;padding-top:2px;color:hsl(0, 0%, 20%);box-sizing:border-box;}.css-19bb58m:after{content:attr(data-value) " ";visibility:hidden;white-space:pre;grid-area:1/2;font:inherit;min-width:2px;border:0;margin:0;outline:0;padding:0;}</style><div class=" css-19bb58m" data-value=""><input class="" style="label:input;color:inherit;background:0;opacity:1;width:100%;grid-area:1 / 2;font:inherit;min-width:2px;border:0;margin:0;outline:0;padding:0" autoCapitalize="none" autoComplete="off" autoCorrect="off" id="react-select-201596-input" spellcheck="false" tabindex="0" type="text" aria-autocomplete="list" aria-expanded="false" aria-haspopup="true" role="combobox" aria-describedby="react-select-201596-placeholder" value=""/></div></div><style data-emotion="css 1wy0on6">.css-1wy0on6{-webkit-align-items:center;-webkit-box-align:center;-ms-flex-align:center;align-items:center;-webkit-align-self:stretch;-ms-flex-item-align:stretch;align-self:stretch;display:-webkit-box;display:-webkit-flex;display:-ms-flexbox;display:flex;-webkit-flex-shrink:0;-ms-flex-negative:0;flex-shrink:0;box-sizing:border-box;}</style><div class=" css-1wy0on6"><style data-emotion="css 1u9des2-indicatorSeparator">.css-1u9des2-indicatorSeparator{-webkit-align-self:stretch;-ms-flex-item-align:stretch;align-self:stretch;width:1px;background-color:hsl(0, 0%, 80%);margin-bottom:8px;margin-top:8px;box-sizing:border-box;}</style><span class=" css-1u9des2-indicatorSeparator"></span><style data-emotion="css 1xc3v61-indicatorContainer">.css-1xc3v61-indicatorContainer{display:-webkit-box;display:-webkit-flex;display:-ms-flexbox;display:flex;-webkit-transition:color 150ms;transition:color 150ms;color:hsl(0, 0%, 80%);padding:8px;box-sizing:border-box;}.css-1xc3v61-indicatorContainer:hover{color:hsl(0, 0%, 60%);}</style><div class=" css-1xc3v61-indicatorContainer" aria-hidden="true"><style data-emotion="css 8mmkcg">.css-8mmkcg{display:inline-block;fill:currentColor;line-height:1;stroke:currentColor;stroke-width:0;}</style><svg height="20" width="20" viewBox="0 0 20 20" aria-hidden="true" focusable="false" class="css-8mmkcg"><path d="M4.516 7.548c0.436-0.446 1.043-0.481 1.576 0l3.908 3.747 3.908-3.747c0.533-0.481 1.141-0.446 1.574 0 0.436 0.445 0.408 1.197 0 1.615-0.406 0.418-4.695 4.502-4.695 4.502-0.217 0.223-0.502 0.335-0.787 0.335s-0.57-0.112-0.789-0.335c0 0-4.287-4.084-4.695-4.502s-0.436-1.17 0-1.615z"></path></svg></div></div></div></div><div class="CheckRowCount__sectionRow___vyiE6"><label class="CheckRow__checkRow___Wumpa"><input class="fa fa-lg fa-check Checkbox__checkbox___dGd5x " type="checkbox"/><span class="CheckRow__checkRowLabel___ax_ST">Article</span></label><span><span>9</span></span></div><div class="CheckRowCount__sectionRow___vyiE6"><label class="CheckRow__checkRow___Wumpa"><input class="fa fa-lg fa-check Checkbox__checkbox___dGd5x " type="checkbox"/><span class="CheckRow__checkRowLabel___ax_ST">Other</span></label><span><span>1</span></span></div></div></div></div><div class="FilterCard__filterCard___bZEVP"><div class="FilterCard__noInput___lsgWM"><div class="FilterCard__filterCardHeader___puB2k" role="button" tabindex="0" aria-label="Expand Relationship"><p class="FilterCard__header___dRl1u Paragraph__body____m5FY Paragraph__bold___PhFOq">Relationship<!-- --> </p></div><div><div class="CheckRowCount__sectionRow___vyiE6"><label class="CheckRow__checkRow___Wumpa"><input class="fa fa-lg fa-check Checkbox__checkbox___dGd5x " type="checkbox"/><span class="CheckRow__checkRowLabel___ax_ST">Self Cite</span></label><span><span>3</span></span></div><div class="CheckRowCount__sectionRow___vyiE6"><label class="CheckRow__checkRow___Wumpa"><input class="fa fa-lg fa-check Checkbox__checkbox___dGd5x " type="checkbox"/><span class="CheckRow__checkRowLabel___ax_ST">Independent</span></label><span><span>7</span></span></div></div></div></div><div class="FilterCard__filterCard___bZEVP"><div class="FilterCard__noInput___lsgWM"><div class="FilterCard__filterCardHeader___puB2k" role="button" tabindex="0" aria-label="Expand Authors"><p class="FilterCard__header___dRl1u Paragraph__body____m5FY Paragraph__bold___PhFOq">Authors<!-- --> </p><div class="OpenerIcon__folder___jiKx6 false undefined"><i class="OpenerIcon__angleDown___QHC0i icon icon-down-carret"></i></div></div></div></div><div class="FilterCard__filterCard___bZEVP"><div class="FilterCard__noInput___lsgWM"><div class="FilterCard__filterCardHeader___puB2k" role="button" tabindex="0" aria-label="Expand Journals"><p class="FilterCard__header___dRl1u Paragraph__body____m5FY Paragraph__bold___PhFOq">Journals<!-- --> </p><div class="OpenerIcon__folder___jiKx6 false undefined"><i class="OpenerIcon__angleDown___QHC0i icon icon-down-carret"></i></div></div></div></div><div class="FiltersSubmit__mobileSpacer___Zot7B"></div><div class="FiltersSubmit__mobileButtons___q8V7A"><button class="FiltersSubmit__button___JlyTu Button__btn___k1xtO Button__btn--transparent___XnBIC Button__size--medium___yX63r">OK</button></div></div></div><div class="ReportPanel__reportButtons___XerGy"><button class="Citations__reportExport___KlHrC Button__btn___k1xtO Button__btn--transparent___XnBIC Button__size--medium___yX63r"><img alt="Export report" src="https://cdn.scite.ai/assets/images/icons/reports/download-csv.svg" width="16px" height="16px"/><span class="Citations__reportExportText___fPVDL">Export report</span></button><div class="ReportPanel__reportButton___fQ0Q4 AddReportToDashboardButton__link___U95EJ"><button class="AddReportToDashboardButton__button___GSCqY Button__btn___k1xtO Button__btn--blue___FBSR2 Button__size--medium___yX63r"><i class="AddReportToDashboardButton__icon___GnVvr fa fa-book-open"></i><span class="AddReportToDashboardButton__text___fO21o">Add to dashboard</span></button></div></div></div><div class="ReportPanel__citationsWrapper___Ik9b3"><div class="Citations__citations___rsiM2"><div class="CitationsHeader__citationsSort___VxgmK"><div class="CitationsHeader__citationsHeader___uQ15D"><div class="CitationsHeader__citeCount___gEx9I CitationsHeader__selected___eJOwX" tabindex="0" role="button"><div class="CitationsHeader__imageTooltip____m9Gf Tooltip__reference___hgPSY"><img class="CitationsHeader__citationsImg___lK2Tq" alt="citations" src="https://cdn.scite.ai/assets/images/icons/citations-icon.svg" height="32px" width="32px"/><h5 class="Header__h5___YDSW4 CitationsHeader__citeHeader___q7Gw4">Cited by <!-- -->396<!-- --> publication<!-- -->s</h5><div class="CitationsHeader__citeHeaderLabel___Zhzp2"> <!-- -->(<!-- -->410<!-- --> citation statement<!-- -->s<!-- -->)</div></div></div><div tabindex="0" role="button" class="CitationsHeader__referencesCount___tubVv"><div class="CitationsHeader__imageTooltip____m9Gf Tooltip__reference___hgPSY"><img class="CitationsHeader__citationsImg___lK2Tq" alt="references" src="https://cdn.scite.ai/assets/images/icons/references-icon.svg" height="32px" width="32px"/><h5 class="Header__h5___YDSW4 CitationsHeader__citeHeader___q7Gw4">References <!-- -->79<!-- --> publication<!-- -->s</h5></div></div></div><div class="CitationsHeader__mobileFilters___xqr8O"><div class="CitationsHeader__mobileClassificationfilter___w6IKl"><div class="Classification__row___s1V6w"><div class="Classification__rowLeft___VoLlX"><label class="CheckRow__checkRow___Wumpa"><input class="fa fa-lg fa-check Checkbox__checkbox___dGd5x " type="checkbox"/><span class="CheckRow__checkRowLabel___ax_ST">Supporting</span></label><div class="Classification__rowType___282g8"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--supporting___ru3vm icon-supporting"></i></div></div><div class="Classification__rowRight___Zxitp"><span class="Classification__count___Y86vw">24</span></div></div><div class="Classification__row___s1V6w"><div class="Classification__rowLeft___VoLlX"><label class="CheckRow__checkRow___Wumpa"><input class="fa fa-lg fa-check Checkbox__checkbox___dGd5x " type="checkbox"/><span class="CheckRow__checkRowLabel___ax_ST">Mentioning</span></label><div class="Classification__rowType___282g8"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--mentioning___zHr8j icon-mentioning"></i></div></div><div class="Classification__rowRight___Zxitp"><span class="Classification__count___Y86vw">380</span></div></div><div class="Classification__row___s1V6w"><div class="Classification__rowLeft___VoLlX"><label class="CheckRow__checkRow___Wumpa"><input class="fa fa-lg fa-check Checkbox__checkbox___dGd5x " type="checkbox"/><span class="CheckRow__checkRowLabel___ax_ST">Contrasting</span></label><div class="Classification__rowType___282g8"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--contradicting___BpYwd icon-contradicting"></i></div></div><div class="Classification__rowRight___Zxitp"><span class="Classification__count___Y86vw">1</span></div></div><div class="Classification__row___s1V6w"><div class="Classification__rowLeft___VoLlX"><label class="CheckRow__checkRow___Wumpa"><input class="fa fa-lg fa-check Checkbox__checkbox___dGd5x " type="checkbox"/><span class="CheckRow__checkRowLabel___ax_ST">Unclassified</span></label><div class="Classification__rowType___282g8"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--unclassified___Wc9aa icon-unclassified"></i></div></div><div class="Classification__rowRight___Zxitp"><span class="Classification__count___Y86vw">5</span></div></div></div><div class="CitationsHeader__searchCitesMobileLayout___Ai7i2"><div class="SearchCites__layout___vB255"><form class="SearchInput__searchInput___ze14_ SearchCites__search___Y_Yhp"><input aria-label="search citations" data-showdropdown="true" autoComplete="off" class="SearchInput__input___D08BX SearchCites__input___dC99x" type="text" placeholder="Context, author(s), title etc." value=""/><div class="SearchInput__button___L2ljx" aria-label="search-button" role="button" tabindex="0"><i class="icon icon-search SearchInput__icon___sEZb9"></i></div></form></div></div><div class="CitationsHeader__sortCitesMobileLayout___FB0xB"><style data-emotion="css b62m3t-container">.css-b62m3t-container{position:relative;box-sizing:border-box;}</style><div class=" css-b62m3t-container"><style data-emotion="css 7pg0cj-a11yText">.css-7pg0cj-a11yText{z-index:9999;border:0;clip:rect(1px, 1px, 1px, 1px);height:1px;width:1px;position:absolute;overflow:hidden;padding:0;white-space:nowrap;}</style><span id="react-select-201597-live-region" class="css-7pg0cj-a11yText"></span><span aria-live="polite" aria-atomic="false" aria-relevant="additions text" class="css-7pg0cj-a11yText"></span><style data-emotion="css 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0-1.615z"></path></svg></div></div></div></div></div></div><div class="CitationsHeader__settingsButtonLayout___SCS1l"><button class="SettingsButton__btn___P6KmW Button__btn___k1xtO Button__btn--transparent___XnBIC Button__size--medium___yX63r Button__tiny___hya9X" aria-label="Settings button"><i class="SettingsButton__icon___w15lK fa fa-sliders-h"></i><span>Settings</span></button></div></div><div class="PapersList__citationList___nW0RR"><div style="opacity:1;pointer-events:auto"><div class="PaperCard__paperCard___Tkx_L PaperCard__card___rYfBl"><div><div><div class="Citation__citation___I7BGj Citation__citationGrid___yNzom"><div class="Citation__rightCol___rqdSW"><div class="Citation__snippetLayout___VCTXv"><div class="Snippet__snippetWrapper___pL8c1"><span><span><div>“…Similarly, Romaniello et al<cite data-doi="10.1097/wnr.0000000000000337"></cite> reported the case of a 9‐year‐old girl with the STXBP1 mutation c.1217G>A who presented with Rett syndrome following the onset of epilepsy. All the clinical features of the patients included in this study justify the definition of developmental and EE, emphasizing a genetic component in the mechanisms of both the developmental delay and epilepsy <cite class="target" data-doi="10.1016/j.ajhg.2017.09.008"></cite>. Furthermore, Hamdan et al<cite data-doi="10.1002/ana.21625"></cite> reported 2 cases with de novo mutations, p.R388X and c.169 + 1G>A presenting with mental retardation and nonsyndromic epilepsy.…”</div></span></span></div></div><div class="Citation__citeInfo___v24kU"><span class="Citation__section___YjAW3"><b>Section</b>: <!-- -->Discussion</span><span class="Citation__typeInfo___s7iNF"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--mentioning___zHr8j icon-mentioning"></i><span class="Citation__citationType___LuRbr">mentioning</span><div class="Tooltip__reference___hgPSY"><div class="Citation__classificationDetails___xRtK5"><span class="Citation__classificationDetail___vPtBx">confidence: <!-- -->56%</span></div></div></span></div></div><div class="Citation__actions___STMoF"><div class="Tooltip__reference___hgPSY"><i class="CopyButton__copyButton___I1ybw fa fa-copy" role="button" tabindex="0"></i></div><div class=""><i class="fa fa-2x fa-ellipsis-h DropdownMenu__dropdownMenuIcon___LGAcI"></i></div></div></div></div><div aria-hidden="true" class="PaperCard__expandingWrapper___JmHu_" style="overflow:hidden;height:0;opacity:0"><div style="width:fit-content"></div></div></div><div class="PaperCard__grid___NMQAD"><div class="PaperCard__abstractWrapper___Yq394"><div class="Paper__paper___CWi0y"><a class="Paper__title___WkJQP Link__link___plGt2 Link__bold___JGJNO Paper__title___WkJQP" href="https://scite.ai/reports/de-novo-mutations-of-i-stxbp1-i-4LDD2JP" tabindex="0" role="link" target="_blank" rel="noopener noreferrer"><h3 class="Paper__title___WkJQP">De novo mutations of <i>STXBP1</i> in Chinese children with early onset epileptic encephalopathy</h3></a><div class="Paper__referenceLine___quVTP"><div class="Authors__authors___uWMEz Paper__lineItem___FXrg7"><div class="Authors__author___TTnHS"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/authors/tingsong-li-6My56r"><span>Li</span></a><div class="Tooltip__reference___hgPSY"><sup class="Authors__affiliationSup___Vvflj"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/affiliations/china-international-science-and-technology-lXdYk">1</a></sup></div><span>, </span></div><div class="Authors__author___TTnHS"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/authors/m-l-cheng-9MOPA2"><span>Cheng</span></a><div class="Tooltip__reference___hgPSY"><sup class="Authors__affiliationSup___Vvflj"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/affiliations/children-s-hospital-of-chongqing-medical-K62kp">2</a></sup></div><span>, </span></div><div class="Authors__author___TTnHS"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/authors/j-wang-5MvR22"><span>Wang</span></a><div class="Tooltip__reference___hgPSY"><sup class="Authors__affiliationSup___Vvflj"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/affiliations/chongqing-medical-university-w2Vz">3</a></sup></div><span> </span></div><span class="Authors__link___k07oy">et al.</span><span> <!-- -->2018</span></div><span class="Paper__lineItem___FXrg7"><span class="Reference__reference___AIzFu"><span><a class="Link__link___plGt2 Link__underline___K1Y7j" tabindex="0" href="/journals/genes-brain-behavior-8GXV3"><em>Genes Brain and Behavior</em></a></span></span></span></div><div class="Paper__tallyLayout___k19c4"><a class="HorizontalTally__horizontalTally___gMrpx" href="/reports/de-novo-mutations-of-i-stxbp1-i-4LDD2JP"><div class="HorizontalTally__inner___AzKR8"><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--publications___MBaqU icon-publications"></i><span class="HorizontalTally__count___ZuxQA">28</span></div></div><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--supporting___ru3vm icon-supporting"></i><span class="HorizontalTally__count___ZuxQA">2</span></div></div><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--mentioning___zHr8j icon-mentioning"></i><span class="HorizontalTally__count___ZuxQA">23</span></div></div><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--contradicting___BpYwd icon-contradicting"></i><span class="HorizontalTally__count___ZuxQA">0</span></div></div></div></a></div><div class="Paper__linksLayout___Ql9Qd"><a class="Paper__link___YsYPi Link__link___plGt2 Link__blueLink___BhE5_ Link__underline___K1Y7j Paper__link___YsYPi" href="https://doi.org/10.1111/gbb.12492" tabindex="0" role="link" target="_blank" rel="noopener noreferrer nofollow">View full text</a><a class="Paper__link___YsYPi Link__link___plGt2 Link__blueLink___BhE5_ Link__underline___K1Y7j Paper__link___YsYPi" tabindex="0" role="button">Add to dashboard</a><a class="Paper__link___YsYPi Link__link___plGt2 Link__blueLink___BhE5_ Link__underline___K1Y7j Paper__link___YsYPi" tabindex="0" role="button">Cite</a></div></div><div aria-hidden="true" style="overflow:hidden;height:0;opacity:0"><div style="width:auto"><p class="Abstract__abstract___V8wNr PaperCard__abstract___lR5RS Paragraph__body____m5FY"><span><span>To detect syntaxin-binding protein 1 (STXBP1) mutations in Chinese patients with early onset epileptic encephalopathy (EOEE) of unknown etiology. Targeted next-generation sequencing was used to identify STXBP1 mutations in 143 Chinese patients with EOEE of unknown etiology. A filtering process was applied to prioritize rare variants of potential functional significance. Then Sanger sequencing was employed to validate the parental origin of the variants. Detailed clinical and genetic data were collected for 9 STXBP1-positive patients. Eight de novo heterozygous STXBP1 mutations were identified in 9 patients; 5 were novel mutations (c.1155delC, c.1030-1G>A, c.217G>C, c.268G>C, c.1480_1481 insT) and 3 were previously reported (c.1216C> T, c.1217G>A [2 cases], c.875G>A). Two patients had Ohtahara syndrome and 1 had West syndrome at onset, whereas the other 6 presented with EOEE that did not fit a specific recognized epilepsy syndrome. Six of these patients later evolved to West syndrome. All but 2 cases were prescribed more than 2 antiepileptic drugs (AEDs) plus other regimens. Four subjects showed good responses to levetiracetam (LEV) alone or in combination with other AEDs, and one case (1/3) achieved complete freedom from seizures with a ketogenic diet (KD). All patients exhibited severe to profound global developmental delay. Five novel heterozygous de novo STXBP1 mutations were discovered in patients with EOEE from China. STXBP1 mutational analysis should be performed in cases of EOEE of unknown etiology. LEV as monotherapy or adjunctive therapy with other regimens, as well as KD should be considered for management of this patient group.</span></span></p></div></div></div><div class="PaperCard__menu___wXkM0"><a class="PaperCard__textButton___ncs_Z" tabindex="0">show abstract</a><div class=""><i class="fa fa-2x fa-ellipsis-h DropdownMenu__dropdownMenuIcon___LGAcI"></i></div></div></div></div><div class="PapersList__paywalledCites___XIuJQ"><div class="PapersList__paperCardsLayout___dtzN9"><div class="PaperCard__paperCard___Tkx_L PaperCard__card___rYfBl"><div><div><div class="Citation__citation___I7BGj Citation__citationGrid___yNzom"><div class="Citation__rightCol___rqdSW"><div class="Citation__snippetLayout___VCTXv"><div class="Snippet__snippetWrapper___pL8c1"><span><span><div>“…Similarly, Romaniello et al<cite data-doi="10.1097/wnr.0000000000000337"></cite> reported the case of a 9‐year‐old girl with the STXBP1 mutation c.1217G>A who presented with Rett syndrome following the onset of epilepsy. All the clinical features of the patients included in this study justify the definition of developmental and EE, emphasizing a genetic component in the mechanisms of both the developmental delay and epilepsy <cite class="target" data-doi="10.1016/j.ajhg.2017.09.008"></cite>. Furthermore, Hamdan et al<cite data-doi="10.1002/ana.21625"></cite> reported 2 cases with de novo mutations, p.R388X and c.169 + 1G>A presenting with mental retardation and nonsyndromic epilepsy.…”</div></span></span></div></div><div class="Citation__citeInfo___v24kU"><span class="Citation__section___YjAW3"><b>Section</b>: <!-- -->Discussion</span><span class="Citation__typeInfo___s7iNF"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--mentioning___zHr8j icon-mentioning"></i><span class="Citation__citationType___LuRbr">mentioning</span><div class="Tooltip__reference___hgPSY"><div class="Citation__classificationDetails___xRtK5"><span class="Citation__classificationDetail___vPtBx">confidence: <!-- -->56%</span></div></div></span></div></div><div class="Citation__actions___STMoF"><div class="Tooltip__reference___hgPSY"><i class="CopyButton__copyButton___I1ybw fa fa-copy" role="button" tabindex="0"></i></div><div class=""><i class="fa fa-2x fa-ellipsis-h DropdownMenu__dropdownMenuIcon___LGAcI"></i></div></div></div></div><div aria-hidden="true" class="PaperCard__expandingWrapper___JmHu_" style="overflow:hidden;height:0;opacity:0"><div style="width:fit-content"></div></div></div><div class="PaperCard__grid___NMQAD"><div class="PaperCard__abstractWrapper___Yq394"><div class="Paper__paper___CWi0y"><a class="Paper__title___WkJQP Link__link___plGt2 Link__bold___JGJNO Paper__title___WkJQP" href="https://scite.ai/reports/de-novo-mutations-of-i-stxbp1-i-4LDD2JP" tabindex="0" role="link" target="_blank" rel="noopener noreferrer"><h3 class="Paper__title___WkJQP">De novo mutations of <i>STXBP1</i> in Chinese children with early onset epileptic encephalopathy</h3></a><div class="Paper__referenceLine___quVTP"><div class="Authors__authors___uWMEz Paper__lineItem___FXrg7"><div class="Authors__author___TTnHS"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/authors/tingsong-li-6My56r"><span>Li</span></a><div class="Tooltip__reference___hgPSY"><sup class="Authors__affiliationSup___Vvflj"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/affiliations/china-international-science-and-technology-lXdYk">1</a></sup></div><span>, </span></div><div class="Authors__author___TTnHS"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/authors/m-l-cheng-9MOPA2"><span>Cheng</span></a><div class="Tooltip__reference___hgPSY"><sup class="Authors__affiliationSup___Vvflj"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/affiliations/children-s-hospital-of-chongqing-medical-K62kp">2</a></sup></div><span>, </span></div><div class="Authors__author___TTnHS"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/authors/j-wang-5MvR22"><span>Wang</span></a><div class="Tooltip__reference___hgPSY"><sup class="Authors__affiliationSup___Vvflj"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/affiliations/chongqing-medical-university-w2Vz">3</a></sup></div><span> </span></div><span class="Authors__link___k07oy">et al.</span><span> <!-- -->2018</span></div><span class="Paper__lineItem___FXrg7"><span class="Reference__reference___AIzFu"><span><a class="Link__link___plGt2 Link__underline___K1Y7j" tabindex="0" href="/journals/genes-brain-behavior-8GXV3"><em>Genes Brain and Behavior</em></a></span></span></span></div><div class="Paper__tallyLayout___k19c4"><a class="HorizontalTally__horizontalTally___gMrpx" href="/reports/de-novo-mutations-of-i-stxbp1-i-4LDD2JP"><div class="HorizontalTally__inner___AzKR8"><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--publications___MBaqU icon-publications"></i><span class="HorizontalTally__count___ZuxQA">28</span></div></div><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--supporting___ru3vm icon-supporting"></i><span class="HorizontalTally__count___ZuxQA">2</span></div></div><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--mentioning___zHr8j icon-mentioning"></i><span class="HorizontalTally__count___ZuxQA">23</span></div></div><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--contradicting___BpYwd icon-contradicting"></i><span class="HorizontalTally__count___ZuxQA">0</span></div></div></div></a></div><div class="Paper__linksLayout___Ql9Qd"><a class="Paper__link___YsYPi Link__link___plGt2 Link__blueLink___BhE5_ Link__underline___K1Y7j Paper__link___YsYPi" href="https://doi.org/10.1111/gbb.12492" tabindex="0" role="link" target="_blank" rel="noopener noreferrer nofollow">View full text</a><a class="Paper__link___YsYPi Link__link___plGt2 Link__blueLink___BhE5_ Link__underline___K1Y7j Paper__link___YsYPi" tabindex="0" role="button">Add to dashboard</a><a class="Paper__link___YsYPi Link__link___plGt2 Link__blueLink___BhE5_ Link__underline___K1Y7j Paper__link___YsYPi" tabindex="0" role="button">Cite</a></div></div><div aria-hidden="true" style="overflow:hidden;height:0;opacity:0"><div style="width:auto"><p class="Abstract__abstract___V8wNr PaperCard__abstract___lR5RS Paragraph__body____m5FY"><span><span>To detect syntaxin-binding protein 1 (STXBP1) mutations in Chinese patients with early onset epileptic encephalopathy (EOEE) of unknown etiology. Targeted next-generation sequencing was used to identify STXBP1 mutations in 143 Chinese patients with EOEE of unknown etiology. A filtering process was applied to prioritize rare variants of potential functional significance. Then Sanger sequencing was employed to validate the parental origin of the variants. Detailed clinical and genetic data were collected for 9 STXBP1-positive patients. Eight de novo heterozygous STXBP1 mutations were identified in 9 patients; 5 were novel mutations (c.1155delC, c.1030-1G>A, c.217G>C, c.268G>C, c.1480_1481 insT) and 3 were previously reported (c.1216C> T, c.1217G>A [2 cases], c.875G>A). Two patients had Ohtahara syndrome and 1 had West syndrome at onset, whereas the other 6 presented with EOEE that did not fit a specific recognized epilepsy syndrome. Six of these patients later evolved to West syndrome. All but 2 cases were prescribed more than 2 antiepileptic drugs (AEDs) plus other regimens. Four subjects showed good responses to levetiracetam (LEV) alone or in combination with other AEDs, and one case (1/3) achieved complete freedom from seizures with a ketogenic diet (KD). All patients exhibited severe to profound global developmental delay. Five novel heterozygous de novo STXBP1 mutations were discovered in patients with EOEE from China. STXBP1 mutational analysis should be performed in cases of EOEE of unknown etiology. LEV as monotherapy or adjunctive therapy with other regimens, as well as KD should be considered for management of this patient group.</span></span></p></div></div></div><div class="PaperCard__menu___wXkM0"><a class="PaperCard__textButton___ncs_Z" tabindex="0">show abstract</a><div class=""><i class="fa fa-2x fa-ellipsis-h DropdownMenu__dropdownMenuIcon___LGAcI"></i></div></div></div></div><div class="PaperCard__paperCard___Tkx_L PaperCard__card___rYfBl"><div><div><div class="Citation__citation___I7BGj Citation__citationGrid___yNzom"><div class="Citation__rightCol___rqdSW"><div class="Citation__snippetLayout___VCTXv"><div class="Snippet__snippetWrapper___pL8c1"><span><span><div>“…<cite data-doi="10.1016/j.eplepsyres.2017.08.010">28</cite> <cite class="target" data-doi="10.1016/j.ajhg.2017.09.008">29</cite> Taken together, these data suggest that NTRK2 could be specifically associated with drug-resistant forms of epilepsy, a phenotype that has not been systematically investigated. <cite data-doi="10.1016/j.eplepsyres.2017.08.010">28</cite> <cite data-doi="10.1016/j.ajhg.2017.09.008">29</cite> Taken together, these data suggest that NTRK2 could be specifically associated with drug-resistant forms of epilepsy, a phenotype that has not been systematically investigated.…”</div></span></span></div></div><div class="Citation__citeInfo___v24kU"><span class="Citation__section___YjAW3"><b>Section</b>: <!-- -->Discussion</span><span class="Citation__typeInfo___s7iNF"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--mentioning___zHr8j icon-mentioning"></i><span class="Citation__citationType___LuRbr">mentioning</span><div class="Tooltip__reference___hgPSY"><div class="Citation__classificationDetails___xRtK5"><span class="Citation__classificationDetail___vPtBx">confidence: <!-- -->94%</span></div></div></span></div></div><div class="Citation__actions___STMoF"><div class="Tooltip__reference___hgPSY"><i class="CopyButton__copyButton___I1ybw fa fa-copy" role="button" tabindex="0"></i></div><div class=""><i class="fa fa-2x fa-ellipsis-h DropdownMenu__dropdownMenuIcon___LGAcI"></i></div></div></div></div><div aria-hidden="true" class="PaperCard__expandingWrapper___JmHu_" style="overflow:hidden;height:0;opacity:0"><div style="width:fit-content"></div></div></div><div class="PaperCard__grid___NMQAD"><div class="PaperCard__abstractWrapper___Yq394"><div class="Paper__paper___CWi0y"><a class="Paper__title___WkJQP Link__link___plGt2 Link__bold___JGJNO Paper__title___WkJQP" href="https://scite.ai/reports/drug-resistant-epilepsy-classified-by-a-K6EMX11" tabindex="0" role="link" target="_blank" rel="noopener noreferrer"><h3 class="Paper__title___WkJQP">Drug‐resistant epilepsy classified by a phenotyping algorithm associates with <i>NTRK2</i></h3></a><div class="Paper__referenceLine___quVTP"><div class="Authors__authors___uWMEz Paper__lineItem___FXrg7"><div class="Authors__author___TTnHS"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/authors/berta-almoguera-pn6Xrz"><span>Almoguera</span></a><div class="Tooltip__reference___hgPSY"><sup class="Authors__affiliationSup___Vvflj"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/affiliations/children-s-hospital-of-philadelphia-N0lg">1</a></sup></div><span>, </span></div><div class="Authors__author___TTnHS"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/authors/emily-mcginnis-VKwXwE"><span>McGinnis</span></a><div class="Tooltip__reference___hgPSY"><sup class="Authors__affiliationSup___Vvflj"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/affiliations/children-s-hospital-of-philadelphia-N0lg">2</a></sup></div><span>, </span></div><div class="Authors__author___TTnHS"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/authors/debra-abrams-ORERv6"><span>Abrams</span></a><div class="Tooltip__reference___hgPSY"><sup class="Authors__affiliationSup___Vvflj"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/affiliations/children-s-hospital-of-philadelphia-N0lg">3</a></sup></div><span> </span></div><span class="Authors__link___k07oy">et al.</span><span> <!-- -->2019</span></div><span class="Paper__lineItem___FXrg7"><span class="Reference__reference___AIzFu"><span><a class="Link__link___plGt2 Link__underline___K1Y7j" tabindex="0" href="/journals/acta-neurologica-scandinavica-OVXMn"><em>Acta Neurol Scand</em></a></span></span></span></div><div class="Paper__tallyLayout___k19c4"><a class="HorizontalTally__horizontalTally___gMrpx" href="/reports/drug-resistant-epilepsy-classified-by-a-K6EMX11"><div class="HorizontalTally__inner___AzKR8"><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--publications___MBaqU icon-publications"></i><span class="HorizontalTally__count___ZuxQA">8</span></div></div><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--supporting___ru3vm icon-supporting"></i><span class="HorizontalTally__count___ZuxQA">0</span></div></div><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--mentioning___zHr8j icon-mentioning"></i><span class="HorizontalTally__count___ZuxQA">7</span></div></div><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--contradicting___BpYwd icon-contradicting"></i><span class="HorizontalTally__count___ZuxQA">1</span></div></div></div></a></div><div class="Paper__linksLayout___Ql9Qd"><a class="Paper__link___YsYPi Link__link___plGt2 Link__blueLink___BhE5_ Link__underline___K1Y7j Paper__link___YsYPi" href="https://doi.org/10.1111/ane.13115" tabindex="0" role="link" target="_blank" rel="noopener noreferrer nofollow">View full text</a><a class="Paper__link___YsYPi Link__link___plGt2 Link__blueLink___BhE5_ Link__underline___K1Y7j Paper__link___YsYPi" tabindex="0" role="button">Add to dashboard</a><a class="Paper__link___YsYPi Link__link___plGt2 Link__blueLink___BhE5_ Link__underline___K1Y7j Paper__link___YsYPi" tabindex="0" role="button">Cite</a></div></div><div aria-hidden="true" style="overflow:hidden;height:0;opacity:0"><div style="width:auto"><p class="Abstract__abstract___V8wNr PaperCard__abstract___lR5RS Paragraph__body____m5FY"><span><span>Objective: Up to 40% of patients with epilepsy become drug resistant (DRE). Genetic factors are likely to play a role. While efforts have focused on the transporter and target hypotheses, neither of them fully explains the pan-pharmacoresistance seen in DRE. Materials and methods:In this study, we developed and used a phenotyping algorithm for the identification of DRE, responders, and epilepsy-free controls that were sequenced using a gene panel developed by the Pharmacogenomics Research Network (PGRN), which includes 82 genes involved in drug response. We tested the transporter hypothesis of DRE, the association between drug resistance and variants in the ATP-binding cassette family of genes previously associated with DRE, and also investigated potential new genetic factors. Results:In the analysis of DRE vs controls, NTRK2 was significantly associated with DRE (rs76950094; P = 1.19 × 10 −7 and gene-based P-value = 1.67 × 10 −4 ). NTRK2encodes TrkB, which is involved in the development and maturation of the central nervous system, and increased activation of TrkB signaling is suggested to promote epilepsy. Conclusion:Although the role of NTRK2 in DRE needs to be elucidated, these results support alternative mechanisms underlying DRE, complementary to the existing hypotheses, that should be evaluated. K E Y W O R D Salgorithm, drug-resistant epilepsy, electronic health records, NTRK2</span></span></p></div></div></div><div class="PaperCard__menu___wXkM0"><a class="PaperCard__textButton___ncs_Z" tabindex="0">show abstract</a><div class=""><i class="fa fa-2x fa-ellipsis-h DropdownMenu__dropdownMenuIcon___LGAcI"></i></div></div></div></div><div class="PaperCard__paperCard___Tkx_L PaperCard__card___rYfBl"><div><div><div class="Citation__citation___I7BGj Citation__citationGrid___yNzom"><div class="Citation__rightCol___rqdSW"><div class="Citation__snippetLayout___VCTXv"><div class="Snippet__snippetWrapper___pL8c1"><span><span><div>“…Latest advances in genome analysis have significantly enabled the discovery of molecular defects underlying neurodevelopmental disorders (NDDs), a clinically heterogeneous group of rare diseases presenting with central nervous system (CNS) malformations often associated with developmental and epileptic encephalopathies (DEEs) <cite data-doi="10.1093/hmg/ddu030 10.1371/journal.pgen.1004772 10.1007/s11910-017-0720-7 10.1016/j.ajhg.2017.09.008 10.1111/epi.13709 10.1016/j.ajhg.2017.08.004"></cite>. Among the genes that have recently been implicated in DEEs, PACS1 (phosphofurin acid cluster sortin protein 1, OMIM 607492), encoding a trans ‐Golgi‐membrane traffic regulator highly expressed during human embryonic brain development, has been implicated in Schuurs‐Hoeijmakers syndrome (OMIM 615009), a dominantly inherited DEE with recognizable gestalt and brain structural abnormalities <cite data-doi="10.1016/j.ajhg.2012.10.013"></cite>.…”</div></span></span></div></div><div class="Citation__citeInfo___v24kU"><span class="Citation__section___YjAW3"><b>Section</b>: <!-- -->Introduction</span><span class="Citation__typeInfo___s7iNF"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--mentioning___zHr8j icon-mentioning"></i><span class="Citation__citationType___LuRbr">mentioning</span><div class="Tooltip__reference___hgPSY"><div class="Citation__classificationDetails___xRtK5"><span class="Citation__classificationDetail___vPtBx">confidence: <!-- -->99%</span></div></div></span></div></div><div class="Citation__actions___STMoF"><div class="Tooltip__reference___hgPSY"><i class="CopyButton__copyButton___I1ybw fa fa-copy" role="button" tabindex="0"></i></div><div class=""><i class="fa fa-2x fa-ellipsis-h DropdownMenu__dropdownMenuIcon___LGAcI"></i></div></div></div></div><div aria-hidden="true" class="PaperCard__expandingWrapper___JmHu_" style="overflow:hidden;height:0;opacity:0"><div style="width:fit-content"></div></div></div><div class="PaperCard__grid___NMQAD"><div class="PaperCard__abstractWrapper___Yq394"><div class="Paper__paper___CWi0y"><a class="Paper__title___WkJQP Link__link___plGt2 Link__bold___JGJNO Paper__title___WkJQP" href="https://scite.ai/reports/expanding-the-clinical-spectrum-associated-xXKpee3" tabindex="0" role="link" target="_blank" rel="noopener noreferrer"><h3 class="Paper__title___WkJQP">Expanding the clinical spectrum associated with <i>PACS2</i> mutations</h3></a><div class="Paper__referenceLine___quVTP"><div class="Authors__authors___uWMEz Paper__lineItem___FXrg7"><div class="Authors__author___TTnHS"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/authors/maria-lisa-dentici-r60MED"><span>Dentici</span></a><div class="Tooltip__reference___hgPSY"><sup class="Authors__affiliationSup___Vvflj"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/affiliations/bambino-gesu-children-s-hospital-YDy33">1</a></sup></div><span>, </span></div><div class="Authors__author___TTnHS"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/authors/sabina-barresi-EWyYNW"><span>Barresi</span></a><div class="Tooltip__reference___hgPSY"><sup class="Authors__affiliationSup___Vvflj"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/affiliations/bambino-gesu-children-s-hospital-YDy33">2</a></sup></div><span>, </span></div><div class="Authors__author___TTnHS"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/authors/marcello-niceta-V0mJAO"><span>Niceta</span></a><div class="Tooltip__reference___hgPSY"><sup class="Authors__affiliationSup___Vvflj"><a class="Link__link___plGt2 Link__blueLink___BhE5_" tabindex="0" href="/affiliations/bambino-gesu-children-s-hospital-YDy33">3</a></sup></div><span> </span></div><span class="Authors__link___k07oy">et al.</span><span> <!-- -->2019</span></div><span class="Paper__lineItem___FXrg7"><span class="Reference__reference___AIzFu"><span><a class="Link__link___plGt2 Link__underline___K1Y7j" tabindex="0" href="/journals/clinical-genetics-OV56O"><em>Clinical Genetics</em></a></span><span class="Badge__pill___QnwOm Reference__preprintBadge___m9cqn"><span><div class="Tooltip__reference___hgPSY">Self Cite</div></span></span></span></span></div><div class="Paper__tallyLayout___k19c4"><a class="HorizontalTally__horizontalTally___gMrpx" href="/reports/expanding-the-clinical-spectrum-associated-xXKpee3"><div class="HorizontalTally__inner___AzKR8"><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--publications___MBaqU icon-publications"></i><span class="HorizontalTally__count___ZuxQA">22</span></div></div><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--supporting___ru3vm icon-supporting"></i><span class="HorizontalTally__count___ZuxQA">3</span></div></div><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--mentioning___zHr8j icon-mentioning"></i><span class="HorizontalTally__count___ZuxQA">44</span></div></div><div class="HorizontalTally__column___d6ltY"><div class="Tooltip__reference___hgPSY"><i class="undefined TypeIcon__typeIcon___USGCh icon TypeIcon__typeIcon--contradicting___BpYwd icon-contradicting"></i><span class="HorizontalTally__count___ZuxQA">0</span></div></div></div></a></div><div class="Paper__linksLayout___Ql9Qd"><a class="Paper__link___YsYPi Link__link___plGt2 Link__blueLink___BhE5_ Link__underline___K1Y7j Paper__link___YsYPi" href="https://doi.org/10.1111/cge.13516" tabindex="0" role="link" target="_blank" rel="noopener noreferrer nofollow">View full text</a><a class="Paper__link___YsYPi Link__link___plGt2 Link__blueLink___BhE5_ Link__underline___K1Y7j Paper__link___YsYPi" tabindex="0" role="button">Add to dashboard</a><a class="Paper__link___YsYPi Link__link___plGt2 Link__blueLink___BhE5_ Link__underline___K1Y7j Paper__link___YsYPi" tabindex="0" role="button">Cite</a></div></div><div aria-hidden="true" style="overflow:hidden;height:0;opacity:0"><div style="width:auto"><p class="Abstract__abstract___V8wNr PaperCard__abstract___lR5RS Paragraph__body____m5FY"><span><span>Whole exome sequencing (WES) has led to the understanding of the molecular events affecting neurodevelopment in an extremely diverse clinical context, including diseases with intellectual disability (ID) associated with variable central nervous system (CNS) malformations, and developmental and epileptic encephalopathies (DEEs). Recently, PACS2 mutations have been causally linked to a DEE with cerebellar dysgenesis and facial dysmorphism. All known patients presented with a recurrent de novo missense mutation, c.625G>A (p.Glu209Lys). Here, we report on a 7‐year‐old boy with DEE, cerebellar dysgenesis, facial dysmorphism and postnatal growth delay, apparently not fitting with any recognized disorder. WES disclosed a de novo novel missense PACS2 variant, c.631G>A (p.Glu211Lys), as the molecular cause of this complex phenotype. We provide a detailed clinical characterization of this patient, and analyse the available clinical data of individuals with PACS2 mutations to delineate more accurately the clinical spectrum associated with this recently described syndrome. Our study expands the clinical and molecular spectrum of PACS2 mutations. Overview of the available clinical data allow to delineate the condition associated with PACS2 mutations as a variable trait, in which the key features are represented by moderate to severe ID, cerebellar dysgenesis and other CNS malformations, reduced growth, and facial dysmorphism.</span></span></p></div></div></div><div class="PaperCard__menu___wXkM0"><a class="PaperCard__textButton___ncs_Z" tabindex="0">show abstract</a><div class=""><i class="fa fa-2x fa-ellipsis-h DropdownMenu__dropdownMenuIcon___LGAcI"></i></div></div></div></div></div></div></div><div class="PapersList__loading___Yxc5F" style="opacity:0;pointer-events:none"><div data-testid="circle-spinner" class="CircleSpinner__sciteLoadingRing___nlTrH" style="width:80px;height:80px"><div class="CircleSpinner__ringComponent____iKPi" style="border-color:#0062ff transparent transparent transparent;width:64px;height:64px;margin:8px;border-width:8px"></div><div class="CircleSpinner__ringComponent____iKPi" style="border-color:#0062ff transparent transparent transparent;width:64px;height:64px;margin:8px;border-width:8px"></div><div class="CircleSpinner__ringComponent____iKPi" style="border-color:#0062ff transparent transparent transparent;width:64px;height:64px;margin:8px;border-width:8px"></div><div class="CircleSpinner__ringComponent____iKPi" style="border-color:#0062ff transparent transparent transparent;width:64px;height:64px;margin:8px;border-width:8px"></div></div></div></div></div></div></div></div></div></div></div><div class="Footer__layout___jrAhC"><div class="Footer__mainLayout___MVOfi"><div class="Footer__aboutContainer___TwE0S"><img width="128px" height="41px" alt="scite logo" src="https://cdn.scite.ai/assets/images/logo.svg"/><p class="Paragraph__body____m5FY">scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.</p><div class="Footer__contact___DGc_M"><h6 class="Header__h6___QzBvp">Contact Info</h6><div><p class="Footer__address___VMUTY Paragraph__body____m5FY">customersupport@researchsolutions.com</p><p class="Footer__address___VMUTY Paragraph__body____m5FY">10624 S. 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All rights reserved.</p><p class="Paragraph__small___OZxzF">Made with 💙 for researchers</p><div class="Footer__rsssFamily___jPDL1"><p class="Footer__rsssBlurb___XhmEW Paragraph__small___OZxzF">Part of the Research Solutions Family.</p><img src="https://cdn.scite.ai/assets/images/logo-rs-black-new.png" class="Footer__rsssLogo___bG803"/></div></div></div></div><div style="position:fixed;z-index:9999"></div><!--/$--></div><div id="scite-tooltips"></div><script type="application/javascript">window.__SCITE_STORE_STATE = {"addReportDashboardModal":{"selectedPapers":[]},"ui":{"referralPartner":null,"freeReports":0,"bannerContent":null,"bannerClosed":false,"navMenu":{},"createDashboardFromSearchResultsModalShow":false,"savedSearchModalShow":false,"searchFilterModalShow":false,"flagModalShow":false,"resetPasswordModalShow":false,"loginModalShow":false,"referenceCheckModalShow":false,"deleteDashboardModalShow":false,"addReportToDashboardModalShow":false,"shareDashboardModalShow":false,"editDashboardModalShow":false,"upgradeModalShow":false,"exportReportModalShow":false,"exportReferenceModalShow":false,"generateCitationModalShow":false,"exportDashboardModalShow":false,"exportStructuredOutputModalShow":false,"dashboardLimitErrorModalShow":false,"whatIsThisReportModalShow":false,"whatIsThisSearchModalShow":false,"whatIsAssistantModalShow":false,"trialOverModalShow":false,"activateTrialModalShow":false,"cancelTrialCheckoutModalShow":false,"cookieModalShow":false,"personaModalShow":false,"loggedOutModalShow":true,"modalFromContext":"","shownModals":[],"hasUser":false,"user":null,"ipLocationData":{"data":null,"error":false,"loading":false},"fetchingUser":false,"savingUser":false,"saveUserError":false,"onboardingLoadTracker":{"state":undefined},"userEntitlements":null,"entitlementsLoading":false,"referralsLoading":false,"pageError":null,"browser":null,"extensionLoaded":false,"organizationLicense":{"hasLicense":false},"linkResolver":null,"sickoMode":false,"authors":[],"navOpen":false,"showMobileSearch":false,"redeemCodeLoading":false,"redeemCodeError":null,"redeemCodeSuccess":false,"applyDiscountLoading":false,"applyDiscountError":null,"applyDiscountSuccess":false,"userDiscount":null,"search":{"term":"","focused":false,"autocompletesLoadTracker":{},"autocompletes":{}},"referencesToExport":[],"citeGeneratorPaperData":{},"dimensions":{},"cookiePreference":null,"userChurnKey":null,"churnKeyLoading":false,"fullTextLinkState":{},"agAvailabilityState":{},"agAvailabilityQueue":[]},"verifyEmail":{"loading":false,"verified":false,"expired":false},"dashboard":{"id":"","name":"","displayName":"","normalizedName":"","description":"","slug":"","dashboardType":"","accessType":"","isPublic":null,"componentLayout":[],"doiQuery":{},"journalMetadata":{},"affiliationMetadata":{},"institutionMetadata":{},"haveAccessToDashboard":null,"lastUpdated":null,"doisUpdatedTS":null,"doisRefreshedTS":null,"refreshStatus":"","loadState":{},"deleteDashboardError":false,"deletingDashboard":false,"totalDoiCount":0,"matchedDoiCount":0,"unmatchedDoiCount":0,"exportLoadTracker":{},"setDashboardUsersLoading":false,"setDashboardUsersError":false,"setDashboardUsersSuccess":false,"dashboardAccessList":null,"getDashboardAccessListLoading":false,"getDashboardAccessListSuccess":false,"getDashboardAccessListError":false},"notifications":{"notifications":[],"loading":false,"error":null,"notificationItems":[],"notificationItemsLoading":false,"notificationItemsError":null,"notificationItemsPage":1,"notificationItemsTotal":0,"newNotificationItems":0,"notificationItemsFilters":{},"dropDownNotificationItems":[],"dropDownNotificationItemsLoading":false,"dropDownNotificationItemsError":null,"notificationSetStatusLoading":false,"notificationSetStatusError":null},"report":{"paper":"10.1016\u002Fj.ajhg.2017.09.008","tally":"10.1016\u002Fj.ajhg.2017.09.008","citations":[{"id":1676993657,"source":"10.1111\u002Fgbb.12492","target":"10.1016\u002Fj.ajhg.2017.09.008","negative":0.0414278581738472,"positive":0.4556674659252167,"neutral":0.5607902467250825,"section":"discussion","type":"mentioning","typeConfidence":0.5607902467250825,"snippet":"Similarly, Romaniello et al\u003Ccite data-doi=\"10.1097\u002Fwnr.0000000000000337\"\u003E\u003C\u002Fcite\u003E reported the case of a 9‐year‐old girl with the STXBP1 mutation c.1217G>A who presented with Rett syndrome following the onset of epilepsy. All the clinical features of the patients included in this study justify the definition of developmental and EE, emphasizing a genetic component in the mechanisms of both the developmental delay and epilepsy \u003Ccite data-doi=\"10.1016\u002Fj.ajhg.2017.09.008\"\u003E\u003C\u002Fcite\u003E. Furthermore, Hamdan et al\u003Ccite data-doi=\"10.1002\u002Fana.21625\"\u003E\u003C\u002Fcite\u003E reported 2 cases with de novo mutations, p.R388X and c.169 + 1G>A presenting with mental retardation and nonsyndromic epilepsy.","lang":"en","langConfidence":"0.9100000262260437","refLocation":"gbb12492-bib-0012\u002F1","memberId":311,"selfCites":[],"snippetHidden":false},{"id":1632393906,"source":"10.1111\u002Fane.13115","target":"10.1016\u002Fj.ajhg.2017.09.008","negative":0.029033175855875015,"positive":0.11833633482456207,"neutral":0.9432162523269654,"section":"discussion","type":"mentioning","typeConfidence":0.9432162523269654,"snippet":"\u003Ccite data-doi=\"10.1016\u002Fj.eplepsyres.2017.08.010\"\u003E28\u003C\u002Fcite\u003E \u003Ccite data-doi=\"10.1016\u002Fj.ajhg.2017.09.008\"\u003E29\u003C\u002Fcite\u003E Taken together, these data suggest that NTRK2 could be specifically associated with drug-resistant forms of epilepsy, a phenotype that has not been systematically investigated. \u003Ccite data-doi=\"10.1016\u002Fj.eplepsyres.2017.08.010\"\u003E28\u003C\u002Fcite\u003E \u003Ccite data-doi=\"10.1016\u002Fj.ajhg.2017.09.008\"\u003E29\u003C\u002Fcite\u003E Taken together, these data suggest that NTRK2 could be specifically associated with drug-resistant forms of epilepsy, a phenotype that has not been systematically investigated.","lang":"en","langConfidence":"0.9599999785423279","refLocation":"b28\u002F1","memberId":311,"selfCites":[],"snippetHidden":false},{"id":1673122919,"source":"10.1111\u002Fcge.13516","target":"10.1016\u002Fj.ajhg.2017.09.008","negative":0.007890935987234116,"positive":0.008503733202815056,"neutral":1,"section":"introduction","type":"mentioning","typeConfidence":1,"snippet":"Latest advances in genome analysis have significantly enabled the discovery of molecular defects underlying neurodevelopmental disorders (NDDs), a clinically heterogeneous group of rare diseases presenting with central nervous system (CNS) malformations often associated with developmental and epileptic encephalopathies (DEEs) \u003Ccite data-doi=\"10.1093\u002Fhmg\u002Fddu030 10.1371\u002Fjournal.pgen.1004772 10.1007\u002Fs11910-017-0720-7 10.1016\u002Fj.ajhg.2017.09.008 10.1111\u002Fepi.13709 10.1016\u002Fj.ajhg.2017.08.004\"\u003E\u003C\u002Fcite\u003E. Among the genes that have recently been implicated in DEEs, PACS1 (phosphofurin acid cluster sortin protein 1, OMIM 607492), encoding a trans ‐Golgi‐membrane traffic regulator highly expressed during human embryonic brain development, has been implicated in Schuurs‐Hoeijmakers syndrome (OMIM 615009), a dominantly inherited DEE with recognizable gestalt and brain structural abnormalities \u003Ccite data-doi=\"10.1016\u002Fj.ajhg.2012.10.013\"\u003E\u003C\u002Fcite\u003E.","lang":"en","langConfidence":"0.8899999856948853","refLocation":"cge13516-bib-0004\u002F1","memberId":311,"selfCites":[{"type":"SHAREDAUTHOR","family":"Dallapiccola","given":"Bruno"},{"type":"SHAREDAUTHOR","family":"Tartaglia","given":"Marco"}],"snippetHidden":false},{"id":1071654279,"source":"10.1159\u002F000499710","target":"10.1016\u002Fj.ajhg.2017.09.008","negative":0.0004962034989148378,"positive":0.0008631358563434332,"neutral":1.0979733169078827,"section":"discussion","type":"mentioning","typeConfidence":1.0979733169078827,"snippet":"Among these chromosomal microarray analysis techniques, SNP arrays have the advantage of identifying copy number variants in addition to losses of heterozygosity. The technological advance in genetics has allowed us to identify new genes possibly involved in ID and distinguish diverse genetic factors of ID that include chromosomal aberrations, autosomal dominant\u002Frecessive, X-linked, and mitochondrial DNA mutations [\u003Ccite data-doi=\"10.1016\u002Fj.ajhg.2017.09.008\"\u003E36\u003C\u002Fcite\u003E]. Indeed, X-linked ID may account for 10–12% of all ID cases [\u003Ccite data-doi=\"10.1038\u002Fnrg1501\"\u003E4\u003C\u002Fcite\u003E].","lang":"en","langConfidence":"0.8600000143051147","refLocation":"ref36\u002F1","memberId":127,"selfCites":[],"snippetHidden":false},{"id":1671605973,"source":"10.1111\u002Fepi.14727","target":"10.1016\u002Fj.ajhg.2017.09.008","negative":0.013292638957500458,"positive":0.009124311618506908,"neutral":1,"section":"introduction","type":"mentioning","typeConfidence":1,"snippet":"Early epileptic and developmental encephalopathies are characterized by severe epilepsy, starting early in life and a neurodevelopmental disorder the severity of which is, at least in part, attributed to epilepsy \u003Ccite data-doi=\"10.1111\u002Fepi.13709\"\u003E\u003C\u002Fcite\u003E. It has a strong but heterogeneous genetic basis; in recent years, dozens of pathogenic variants have been described \u003Ccite data-doi=\"10.1016\u002Fj.ajhg.2017.09.008\"\u003E\u003C\u002Fcite\u003E. The use of next‐generation sequencing (NGS) techniques in the diagnostic workup of early onset epilepsy and epileptic encephalopathy (EOEE) has largely helped to overcome the issue of genetic heterogeneity.","lang":"en","langConfidence":"0.9399999976158142","refLocation":"epi14727-bib-0002\u002F1","memberId":311,"selfCites":[{"type":"SHAREDAUTHOR","family":"Mignot","given":"Cyril"}],"snippetHidden":false},{"source":"10.1002\u002F9780470015902.a0027866","target":"10.1016\u002Fj.ajhg.2017.09.008","selfCites":[],"dataSource":"CR"},{"source":"10.1002\u002Facn3.51483","target":"10.1016\u002Fj.ajhg.2017.09.008","selfCites":[],"dataSource":"CR"},{"source":"10.1002\u002Facn3.51598","target":"10.1016\u002Fj.ajhg.2017.09.008","selfCites":[{"type":"SHAREDAUTHOR","family":"Minassian","given":"Berge A."},{"type":"SHAREDAUTHOR","family":"Girard","given":"Simon L."},{"type":"SHAREDAUTHOR","family":"Michaud","given":"Jacques L."},{"type":"SHAREDAUTHOR","family":"Cossette","given":"Patrick"},{"type":"SHAREDAUTHOR","family":"Hamdan","given":"Fadi F."}],"dataSource":"KALA"},{"source":"10.1002\u002Facn3.52062","target":"10.1016\u002Fj.ajhg.2017.09.008","selfCites":[],"dataSource":"CR"},{"source":"10.1002\u002Facn3.52211","target":"10.1016\u002Fj.ajhg.2017.09.008","selfCites":[],"dataSource":"CR"}],"citationTallies":{"10.1159\u002F000499710":{"total":11,"supporting":0,"contradicting":0,"mentioning":11,"unclassified":0,"doi":"10.1159\u002F000499710","citingPublications":16},"10.1111\u002Fane.13115":{"total":8,"supporting":0,"contradicting":1,"mentioning":7,"unclassified":0,"doi":"10.1111\u002Fane.13115","citingPublications":8},"10.1111\u002Fepi.14727":{"total":26,"supporting":0,"contradicting":0,"mentioning":26,"unclassified":0,"doi":"10.1111\u002Fepi.14727","citingPublications":35},"10.1111\u002Fcge.13516":{"total":49,"supporting":3,"contradicting":0,"mentioning":44,"unclassified":2,"doi":"10.1111\u002Fcge.13516","citingPublications":22},"10.1111\u002Fgbb.12492":{"total":25,"supporting":2,"contradicting":0,"mentioning":23,"unclassified":0,"doi":"10.1111\u002Fgbb.12492","citingPublications":28},"10.1002\u002F9780470015902.a0027866":{"total":2,"supporting":0,"contradicting":0,"mentioning":2,"unclassified":0,"doi":"10.1002\u002F9780470015902.a0027866","citingPublications":2},"10.1002\u002Facn3.51483":{"total":12,"supporting":1,"contradicting":0,"mentioning":11,"unclassified":0,"doi":"10.1002\u002Facn3.51483","citingPublications":12},"10.1002\u002Facn3.51598":{"total":1,"supporting":0,"contradicting":0,"mentioning":1,"unclassified":0,"doi":"10.1002\u002Facn3.51598","citingPublications":2},"10.1002\u002Facn3.52062":{"total":0,"supporting":0,"contradicting":0,"mentioning":0,"unclassified":0,"doi":"10.1002\u002Facn3.52062","citingPublications":1},"10.1002\u002Facn3.52211":{"total":0,"supporting":0,"contradicting":0,"mentioning":0,"unclassified":0,"doi":"10.1002\u002Facn3.52211","citingPublications":2}},"metadata":{"totalCitationCount":410,"restrictedCitationCount":5,"distinctSourceCount":396},"papers":{"10.1159\u002F000499710":{"id":585660743,"doi":"10.1159\u002F000499710","slug":"chromosomal-abnormalities-in-patients-with-mePXxzg","type":"journal-article","title":"Chromosomal Abnormalities in Patients with Intellectual Disability: A 21-Year Retrospective Study","abstract":"<b><i>Background:<\u002Fi><\u002Fb> Intellectual disability (ID) has been defined as a considerably reduced ability to understand new or complex information and to learn new skills. It is associated with life-long intellectual and adaptive functioning impairments that have a profound impact on individuals, families, and society. It affects about 3% of the general population. ID often comes out with other mental conditions like attention deficit, hyperactivity, and autism spectrum disorders (ASD), and it can be part of a malformation syndrome that affects other organs. It may be syndromic (S-ID) or non-syndromic (NS-ID). <b><i>Objective:<\u002Fi><\u002Fb> The aims of this study were to identify the profile of intellectually disable patients being referred for cytogenetic analysis in Morocco, to determine the prevalence of chromosomal abnormalities in a Moroccan group, and to compare the results with those of analogous studies from other countries. <b><i>Participants:<\u002Fi><\u002Fb> We included data from Moroccan patients with NS-ID and others with S-ID (mostly Down syndrome cases) who have been referred between 1996 and 2016. 1,626 patients were involved in this study, 1,200 were referred with a clinical diagnosis of Down syndrome, 37 were clinically diagnosed for ASD with ID, and 389 were suspected of NS-ID. <b><i>Results:<\u002Fi><\u002Fb> We identified 1,200 cases of Down syndrome. In 1,096 analyses (91.3%), a cytogenetic variant of trisomy 21 was identified: standard trisomy 21 in 1,037 cases (94.6%), a translocation in 34 cases (3.10%), and mosaicism in 25 cases (2.3%). The cytogenetic analysis among ASD with ID cases did not reveal any specific chromosomal abnormalities. The present study also shows that chromosomal abnormalities were present in 6.43% of the patients with NS-ID (25 abnormal karyotypes out of 389 NS-ID cases). Autosomal structural abnormalities were the largest proportion of chromosomal aberrations. <b><i>Conclusion:<\u002Fi><\u002Fb> The high rate of chromosomal abnormalities found in the Moroccan patients studied demonstrates the capital importance of cytogenetic evaluation in patients who show ID or any clinical development abnormality.","authors":[{"family":"Belkady","given":"Boutaina","affiliation":"University of Hassan II Casablanca","authorSlug":"boutaina-belkady-OMpYMP","authorName":"Boutaina Belkady","authorID":"14456278","authorSequenceNumber":1,"affiliationSlug":"university-of-hassan-ii-casablanca-eNO6","affiliationID":"26711"},{"family":"Elkhattabi","given":"Lamiae","affiliation":"Institut Pasteur du Maroc","authorSlug":"lamiae-elkhattabi-NYW3XQ","authorName":"Lamiae Elkhattabi","authorID":"11822471","authorSequenceNumber":2,"affiliationSlug":"institut-pasteur-du-maroc-OjNd6","affiliationID":"186578"},{"family":"Elkarhat","given":"Zouhair","affiliation":"Institut Pasteur du Maroc","authorSlug":"zouhair-elkarhat-KlaW82","authorName":"Zouhair Elkarhat","authorID":"12016735","authorSequenceNumber":3,"affiliationSlug":"institut-pasteur-du-maroc-OjNd6","affiliationID":"186578"},{"family":"Zarouf","given":"Latifa","affiliation":"Institut Pasteur du Maroc","authorSlug":"latifa-zarouf-vxmbGO","authorName":"Latifa Zarouf","authorID":"14882853","authorSequenceNumber":4,"affiliationSlug":"institut-pasteur-du-maroc-OjNd6","affiliationID":"186578"},{"family":"Razoki","given":"Lunda","affiliation":"Institut Pasteur du Maroc","authorSlug":"lunda-razoki-DZN1ad","authorName":"Lunda Razoki","authorID":"13887319","authorSequenceNumber":5,"affiliationSlug":"institut-pasteur-du-maroc-OjNd6","affiliationID":"186578"},{"family":"Aboulfaraj","given":"Jamila","affiliation":"Institut Pasteur du Maroc","authorSlug":"jamila-aboulfaraj-0XKDw0","authorName":"Jamila Aboulfaraj","authorID":"14875456","authorSequenceNumber":6,"affiliationSlug":"institut-pasteur-du-maroc-OjNd6","affiliationID":"186578"},{"family":"Nassereddine","given":"Sanaa","affiliation":"Institut Pasteur du Maroc","authorSlug":"sanaa-nassereddine-PvxJnm","authorName":"Sanaa Nassereddine","authorID":"15620345","authorSequenceNumber":7,"affiliationSlug":"institut-pasteur-du-maroc-OjNd6","affiliationID":"186578"},{"family":"Cadi","given":"Rachida","affiliation":"University of Hassan II Casablanca","authorSlug":"rachida-cadi-YgRwkG","authorName":"Rachida Cadi","authorID":"10782351","authorSequenceNumber":8,"affiliationSlug":"university-of-hassan-ii-casablanca-eNO6","affiliationID":"26711"},{"family":"Rouba","given":"Hassan","affiliation":"Institut Pasteur du Maroc","authorSlug":"hassan-rouba-81pjXQ","authorName":"Hassan Rouba","authorID":"135947165","authorSequenceNumber":9,"affiliationSlug":"institut-pasteur-du-maroc-OjNd6","affiliationID":"186578"},{"family":"Barakat","given":"Abdelhamid","affiliation":"Institut Pasteur du Maroc","authorSlug":"abdelhamid-barakat-K6nOa5","authorName":"Abdelhamid Barakat","authorID":"5130835","authorSequenceNumber":10,"affiliationSlug":"institut-pasteur-du-maroc-OjNd6","affiliationID":"186578"}],"year":2018,"shortJournal":"Hum Hered","publisher":"S. Karger AG","issue":"5","volume":"83","page":"274-282","retracted":false,"memberId":127,"issns":["0001-5652","1423-0062"],"editorialNotices":[],"journalSlug":"human-heredity-ejMDr","journal":"Human Heredity","preprintLinks":[],"publicationLinks":[],"normalizedTypes":["article"]},"10.1111\u002Fane.13115":{"id":250411379,"doi":"10.1111\u002Fane.13115","slug":"drug-resistant-epilepsy-classified-by-a-K6EMX11","type":"journal-article","title":"Drug‐resistant epilepsy classified by a phenotyping algorithm associates with\n \u003Ci\u003ENTRK2\u003C\u002Fi\u003E","abstract":"Objective: Up to 40% of patients with epilepsy become drug resistant (DRE). Genetic factors are likely to play a role. While efforts have focused on the transporter and target hypotheses, neither of them fully explains the pan-pharmacoresistance seen in DRE.\nMaterials and methods:In this study, we developed and used a phenotyping algorithm for the identification of DRE, responders, and epilepsy-free controls that were sequenced using a gene panel developed by the Pharmacogenomics Research Network (PGRN), which includes 82 genes involved in drug response. We tested the transporter hypothesis of DRE, the association between drug resistance and variants in the ATP-binding cassette family of genes previously associated with DRE, and also investigated potential new genetic factors.\nResults:In the analysis of DRE vs controls, NTRK2 was significantly associated with DRE (rs76950094; P = 1.19 × 10 −7 and gene-based P-value = 1.67 × 10 −4 ). NTRK2encodes TrkB, which is involved in the development and maturation of the central nervous system, and increased activation of TrkB signaling is suggested to promote epilepsy.\nConclusion:Although the role of NTRK2 in DRE needs to be elucidated, these results support alternative mechanisms underlying DRE, complementary to the existing hypotheses, that should be evaluated.\nK E Y W O R D Salgorithm, drug-resistant epilepsy, electronic health records, NTRK2","authors":[{"family":"Almoguera","given":"Berta","affiliation":"Children's Hospital of Philadelphia","authorSlug":"berta-almoguera-pn6Xrz","authorName":"Berta Almoguera","authorID":"6740474","authorSequenceNumber":1,"affiliationSlug":"children-s-hospital-of-philadelphia-N0lg","affiliationID":"25227"},{"family":"McGinnis","given":"Emily","affiliation":"Children's Hospital of Philadelphia","authorSlug":"emily-mcginnis-VKwXwE","authorName":"Emily McGinnis","authorID":"9671438","authorSequenceNumber":2,"affiliationSlug":"children-s-hospital-of-philadelphia-N0lg","affiliationID":"25227"},{"family":"Abrams","given":"Debra","affiliation":"Children's Hospital of Philadelphia","authorSlug":"debra-abrams-ORERv6","authorName":"Debra Abrams","authorID":"136960578","authorSequenceNumber":3,"affiliationSlug":"children-s-hospital-of-philadelphia-N0lg","affiliationID":"25227"},{"family":"Vazquez","given":"Lyam","affiliation":"Children's Hospital of Philadelphia","authorSlug":"lyam-vazquez-ANK9M2","authorName":"Lyam Vazquez","authorID":"8763193","authorSequenceNumber":4,"affiliationSlug":"children-s-hospital-of-philadelphia-N0lg","affiliationID":"25227"},{"family":"Cederquist","given":"Anna","affiliation":"Children's Hospital of Philadelphia","authorSlug":"anna-cederquist-2A6mX1","authorName":"Anna Cederquist","authorID":"27391176","authorSequenceNumber":5,"affiliationSlug":"children-s-hospital-of-philadelphia-N0lg","affiliationID":"25227"},{"family":"Sleiman","given":"Patrick","affiliation":"Children's Hospital of Philadelphia","authorSlug":"patrick-sleiman-gZmvbA","authorName":"Patrick Sleiman","authorID":"5821558","authorSequenceNumber":6,"affiliationSlug":"children-s-hospital-of-philadelphia-N0lg","affiliationID":"25227"},{"family":"Dlugos","given":"Dennis","affiliation":"Children's Hospital of Philadelphia","authorSlug":"dennis-dlugos-Xxwe8Y","authorName":"Dennis Dlugos","authorID":"5883141","authorSequenceNumber":7,"affiliationSlug":"children-s-hospital-of-philadelphia-N0lg","affiliationID":"25227"},{"family":"Hákonarson","given":"Hákon","affiliation":"Children's Hospital of Philadelphia","authorSlug":"hakon-hakonarson-2NJr8G","authorName":"Hákon Hákonarson","authorID":"4788932","authorSequenceNumber":8,"affiliationSlug":"children-s-hospital-of-philadelphia-N0lg","affiliationID":"25227"},{"family":"Cagan","given":"Andrew","authorSlug":"andrew-cagan-zRyYzb","authorName":"Andrew Cagan","authorID":"6787794","authorSequenceNumber":9},{"family":"Connolly","given":"John J.","authorSlug":"john-j-connolly-3nd32g","authorName":"John J. Connolly","authorID":"5488400","authorSequenceNumber":10},{"family":"Gainer","given":"Vivian S.","authorSlug":"vivian-s-gainer-PQ3mzQ","authorName":"Vivian S. Gainer","authorID":"6034601","authorSequenceNumber":11},{"family":"Garifallou","given":"James","authorSlug":"james-garifallou-ngxAr6","authorName":"James Garifallou","authorID":"8432733","authorSequenceNumber":12},{"family":"Kaminski","given":"Courtney","authorSlug":"courtney-kaminski-r8gXbO","authorName":"Courtney Kaminski","authorID":"41517373","authorSequenceNumber":13},{"family":"Lee","given":"Yvonne","authorSlug":"yvonne-lee-OV49RQ","authorName":"Yvonne Lee","authorID":"6326534","authorSequenceNumber":14},{"family":"Mafra","given":"Fernanda","authorSlug":"fernanda-mafra-M2Q0RY","authorName":"Fernanda Mafra","authorID":"8278952","authorSequenceNumber":15},{"family":"Mentch","given":"Frank","authorSlug":"frank-mentch-b2JQnk","authorName":"Frank Mentch","authorID":"5131015","authorSequenceNumber":16},{"family":"Pellegrino","given":"Renata","authorSlug":"renata-pellegrino-MV8MXp","authorName":"Renata Pellegrino","authorID":"7276752","authorSequenceNumber":17},{"family":"Qiu","given":"Haijun","authorSlug":"haijun-qiu-pnNmgK","authorName":"Haijun Qiu","authorID":"6363830","authorSequenceNumber":18},{"family":"Snyder","given":"James","authorSlug":"james-snyder-393ZJK","authorName":"James Snyder","authorID":"140229588","authorSequenceNumber":19},{"family":"Tian","given":"Lifeng","authorSlug":"lifeng-tian-W8Rn6g","authorName":"Lifeng Tian","authorID":"5630392","authorSequenceNumber":20},{"family":"Wang","given":"Fengxiang","authorSlug":"fengxiang-wang-PNO62V","authorName":"Fengxiang Wang","authorID":"136125489","authorSequenceNumber":21},{"family":"Manolio","given":"Teri A.","authorSlug":"teri-a-manolio-Ow8exQ","authorName":"Teri A. Manolio","authorID":"103113334","authorSequenceNumber":22},{"family":"Manzi","given":"Shanon","authorSlug":"shanon-manzi-9n3pO9","authorName":"Shanon Manzi","authorID":"31624646","authorSequenceNumber":23},{"family":"Holm","given":"Ingrid A.","authorSlug":"ingrid-a-holm-YZ23gD","authorName":"Ingrid A. Holm","authorID":"5101451","authorSequenceNumber":24},{"family":"Karlson","given":"Elizabeth W.","authorSlug":"elizabeth-w-karlson-6Pvlyg","authorName":"Elizabeth W. Karlson","authorID":"135652754","authorSequenceNumber":25}],"keywords":[],"year":2019,"shortJournal":"Acta Neurol Scand","publisher":"Wiley","issue":"3","volume":"140","page":"169-176","retracted":false,"memberId":311,"issns":["0001-6314","1600-0404"],"editorialNotices":[],"journalSlug":"acta-neurologica-scandinavica-OVXMn","journal":"Acta Neurologica Scandinavica","preprintLinks":[],"publicationLinks":[],"normalizedTypes":["article"]},"10.1111\u002Fepi.14727":{"id":249528009,"doi":"10.1111\u002Fepi.14727","slug":"clinical-study-of-19-patients-vJKvjnZ","type":"journal-article","title":"Clinical study of 19 patients with \u003Ci\u003E\u003Cscp\u003ESCN\u003C\u002Fscp\u003E8A\u003C\u002Fi\u003E‐related epilepsy: Two modes of onset regarding \u003Cscp\u003EEEG\u003C\u002Fscp\u003E and seizures","abstract":"Summary\nObjective\nTo describe the mode of onset of SCN8A‐related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers.\nMethods\nWe reviewed the phenotype of patients carrying a mutation in the SCN8A gene, among a multicentric cohort of 638 patients prospectively followed by several pediatric neurologists. We focused on the way clinicians made the diagnosis of epileptic encephalopathy, the very first symptoms, electroencephalography (EEG) findings, and seizure types. We made genotypic\u002Fphenotypic correlation based on epilepsy‐associated missense variant localization over the protein.\nResults\nWe found 19 patients carrying a de novo mutation of SCN8A, representing 3% of our cohort, with 9 mutations being novel. Age at onset of epilepsy was 1 day to 16 months. We found two modes of onset: 12 patients had slowly emerging onset with rare and\u002For subtle seizures and normal interictal EEG (group 1). The first event was either acute generalized tonic–clonic seizure (GTCS; Group 1a, n = 6) or episodes of myoclonic jerks that were often mistaken for sleep‐related movements or other movement disorders (Group 1b, n = 6). Seven patients had a sudden onset of frequent tonic seizures or epileptic spasms with abnormal interictal EEG leading to rapid diagnosis of epileptic encephalopathy. Sodium channel blockers were effective or nonaggravating in most cases.\nSignificance\nSCN8A is the third most prevalent early onset epileptic encephalopathy gene and is associated with two modes of onset of epilepsy.","authors":[{"family":"Denis","given":"Julien","affiliation":"Hôpital de la Timone","authorSlug":"julien-denis-9geAgr","authorName":"Julien Denis","authorID":"15011946","authorSequenceNumber":1,"affiliationSlug":"hopital-de-la-timone-j6KJM","affiliationID":"214237"},{"family":"Villeneuve","given":"Nathalie","affiliation":"Hôpital de la Timone","authorSlug":"nathalie-villeneuve-PQMM1Q","authorName":"Nathalie Villeneuve","authorID":"6449301","authorSequenceNumber":2,"affiliationSlug":"hopital-de-la-timone-j6KJM","affiliationID":"214237"},{"family":"Cacciagli","given":"Pierre","authorSlug":"pierre-cacciagli-RVxQ2G","authorName":"Pierre Cacciagli","authorID":"5803926","authorSequenceNumber":3},{"family":"Mignon‐Ravix","given":"Cécile","affiliation":"Aix-Marseille Université","authorSlug":"cecile-mignon-ravix-D1rvkZ","authorName":"Cécile Mignon‐Ravix","authorID":"6041819","authorSequenceNumber":4,"affiliationSlug":"aix-marseille-universite-6OGr","affiliationID":"22698"},{"family":"Lacoste","given":"Caroline","authorSlug":"caroline-lacoste-ej45zY","authorName":"Caroline Lacoste","authorID":"7287955","authorSequenceNumber":5},{"family":"Lefranc","given":"Jérémie","authorSlug":"jeremie-lefranc-bONynv","authorName":"Jérémie Lefranc","authorID":"8158915","authorSequenceNumber":6},{"family":"Napuri","given":"Sylvia","affiliation":"Centre Hospitalier Universitaire de Rennes","authorSlug":"sylvia-napuri-kGMG3","authorName":"Sylvia Napuri","authorID":"1355868","authorSequenceNumber":7,"affiliationSlug":"centre-hospitalier-universitaire-de-rennes-zbgdb","affiliationID":"217406"},{"family":"Damaj","given":"Léna","affiliation":"Centre Hospitalier Universitaire de Rennes","authorSlug":"lena-damaj-WGG8O5","authorName":"Léna Damaj","authorID":"7670104","authorSequenceNumber":8,"affiliationSlug":"centre-hospitalier-universitaire-de-rennes-zbgdb","affiliationID":"217406"},{"family":"Villega","given":"Frédéric","authorSlug":"frederic-villega-zRnkK8","authorName":"Frédéric Villega","authorID":"7115806","authorSequenceNumber":9},{"family":"Pedespan","given":"Jean‐Michel","authorSlug":"jean-michel-pedespan-eaQkp2","authorName":"Jean‐Michel Pedespan","authorID":"137519855","authorSequenceNumber":10},{"family":"Moutton","given":"Sébastien","authorSlug":"sebastien-moutton-NlevlN","authorName":"Sébastien Moutton","authorID":"6764471","authorSequenceNumber":11},{"family":"Mignot","given":"Cyril","affiliation":"Assistance Publique – Hôpitaux de Paris","authorSlug":"cyril-mignot-vJvKN4","authorName":"Cyril Mignot","authorID":"5921253","authorSequenceNumber":12,"affiliationSlug":"assistance-publique-hopitaux-de-JWV5k","affiliationID":"195267"},{"family":"Doummar","given":"Diane","affiliation":"Assistance Publique – Hôpitaux de Paris","authorSlug":"diane-doummar-pnpPYz","authorName":"Diane Doummar","authorID":"5599730","authorSequenceNumber":13,"affiliationSlug":"assistance-publique-hopitaux-de-JWV5k","affiliationID":"195267"},{"family":"Lion‐François","given":"Laurence","authorSlug":"laurence-lion-francois-K6yYal","authorName":"Laurence Lion‐François","authorID":"7366879","authorSequenceNumber":14},{"family":"Gataullina","given":"Svetlana","affiliation":"Bicêtre Hospital","authorSlug":"svetlana-gataullina-5YKvv2","authorName":"Svetlana Gataullina","authorID":"7904269","authorSequenceNumber":15,"affiliationSlug":"bicetre-hospital-Qe1lM","affiliationID":"152216"},{"family":"Dulac","given":"Olivier","affiliation":"Inserm","authorSlug":"olivier-dulac-PQyDn0","authorName":"Olivier Dulac","authorID":"5799001","authorSequenceNumber":16,"affiliationSlug":"inserm-MaEp","affiliationID":"6896"},{"family":"Martin","given":"Mélanie","affiliation":"Université de Limoges","authorSlug":"melanie-martin-wmvlvM","authorName":"Mélanie Martin","authorID":"6064772","authorSequenceNumber":17,"affiliationSlug":"universite-de-limoges-MQrW","affiliationID":"18896"},{"family":"Guéden","given":"Sophie","affiliation":"Université d'Angers","authorSlug":"sophie-gueden-QyYVRx","authorName":"Sophie Guéden","authorID":"8040160","authorSequenceNumber":18,"affiliationSlug":"universite-d-angers-049b","affiliationID":"11812"},{"family":"Lesca","given":"Gaëtan","affiliation":"Hospices Civils de Lyon","authorSlug":"gaetan-lesca-EWL5dy","authorName":"Gaëtan Lesca","authorID":"5944261","authorSequenceNumber":19,"affiliationSlug":"hospices-civils-de-lyon-Rj8Yp","affiliationID":"273526"},{"family":"Julia","given":"Sophie","affiliation":"Université de Toulouse","authorSlug":"sophie-julia-J1bMLD","authorName":"Sophie Julia","authorID":"7181767","authorSequenceNumber":20,"affiliationSlug":"universite-de-toulouse-aylx","affiliationID":"4839"},{"family":"Cancès","given":"Claude","affiliation":"Université de Toulouse","authorSlug":"claude-cances-zR2zb9","authorName":"Claude Cancès","authorID":"4778150","authorSequenceNumber":21,"affiliationSlug":"universite-de-toulouse-aylx","affiliationID":"4839"},{"family":"Journel","given":"Hubert","affiliation":"Centre hospitalier Bretagne Atlantique","authorSlug":"hubert-journel-b2pjxW","authorName":"Hubert Journel","authorID":"5715615","authorSequenceNumber":22,"affiliationSlug":"centre-hospitalier-bretagne-atlantique-YZaD3","affiliationID":"155051"},{"family":"Altuzarra","given":"Cécilia","affiliation":"Hôpital Saint-Jacques","authorSlug":"cecilia-altuzarra-zbR248","authorName":"Cécilia Altuzarra","authorID":"7606450","authorSequenceNumber":23,"affiliationSlug":"hopital-saint-jacques-9baek","affiliationID":"203302"},{"family":"Zeev","given":"Bruria Ben","affiliation":"Edmond and Lily Safra Children's Hospital","authorSlug":"bruria-ben-zeev-zRn0PK","authorName":"Bruria Ben Zeev","authorID":"7123050","authorSequenceNumber":24,"affiliationSlug":"edmond-and-lily-safra-children-s-PzrJL","affiliationID":"213689"},{"family":"Afenjar","given":"Alexandra","affiliation":"Sorbonne Université","authorSlug":"alexandra-afenjar-2nAWKJ","authorName":"Alexandra Afenjar","authorID":"135533432","authorSequenceNumber":25,"affiliationSlug":"sorbonne-universite-g0bQ","affiliationID":"21314"},{"family":"Barth","given":"Magalie","affiliation":"Université d'Angers","authorSlug":"magalie-barth-naEEJd","authorName":"Magalie Barth","authorID":"136674177","authorSequenceNumber":26,"affiliationSlug":"universite-d-angers-049b","affiliationID":"11812"},{"family":"Villard","given":"Laurent","affiliation":"Aix-Marseille Université","authorSlug":"laurent-villard-W8NYm5","authorName":"Laurent Villard","authorID":"4481248","authorSequenceNumber":27,"affiliationSlug":"aix-marseille-universite-6OGr","affiliationID":"22698"},{"family":"Milh","given":"Mathieu","affiliation":"Hôpital de la Timone","authorSlug":"mathieu-milh-D1eyWz","authorName":"Mathieu Milh","authorID":"5431163","authorSequenceNumber":28,"affiliationSlug":"hopital-de-la-timone-j6KJM","affiliationID":"214237"}],"keywords":["epileptic encephalopathy","genetics","pediatrics","sodium channel blocker"],"year":2019,"shortJournal":"Epilepsia","publisher":"Wiley","issue":"5","volume":"60","page":"845-856","retracted":false,"memberId":311,"issns":["0013-9580","1528-1167"],"editorialNotices":[],"journalSlug":"epilepsia-V0rVR","journal":"Epilepsia","preprintLinks":[],"publicationLinks":[],"normalizedTypes":["article"]},"10.1111\u002Fcge.13516":{"id":248105322,"doi":"10.1111\u002Fcge.13516","slug":"expanding-the-clinical-spectrum-associated-xXKpee3","type":"journal-article","title":"Expanding the clinical spectrum associated with \u003Ci\u003EPACS2\u003C\u002Fi\u003E mutations","abstract":"Whole exome sequencing (WES) has led to the understanding of the molecular events affecting neurodevelopment in an extremely diverse clinical context, including diseases with intellectual disability (ID) associated with variable central nervous system (CNS) malformations, and developmental and epileptic encephalopathies (DEEs). Recently, PACS2 mutations have been causally linked to a DEE with cerebellar dysgenesis and facial dysmorphism. All known patients presented with a recurrent de novo missense mutation, c.625G\u003EA (p.Glu209Lys). Here, we report on a 7‐year‐old boy with DEE, cerebellar dysgenesis, facial dysmorphism and postnatal growth delay, apparently not fitting with any recognized disorder. WES disclosed a de novo novel missense PACS2 variant, c.631G\u003EA (p.Glu211Lys), as the molecular cause of this complex phenotype. We provide a detailed clinical characterization of this patient, and analyse the available clinical data of individuals with PACS2 mutations to delineate more accurately the clinical spectrum associated with this recently described syndrome. Our study expands the clinical and molecular spectrum of PACS2 mutations. Overview of the available clinical data allow to delineate the condition associated with PACS2 mutations as a variable trait, in which the key features are represented by moderate to severe ID, cerebellar dysgenesis and other CNS malformations, reduced growth, and facial dysmorphism.","authors":[{"family":"Dentici","given":"Maria Lisa","affiliation":"Bambino Gesù Children's Hospital","authorSlug":"maria-lisa-dentici-r60MED","authorName":"Maria Lisa Dentici","authorID":"6781729","authorSequenceNumber":1,"affiliationSlug":"bambino-gesu-children-s-hospital-YDy33","affiliationID":"257307"},{"family":"Barresi","given":"Sabina","affiliation":"Bambino Gesù Children's Hospital","authorSlug":"sabina-barresi-EWyYNW","authorName":"Sabina Barresi","authorID":"6944917","authorSequenceNumber":2,"affiliationSlug":"bambino-gesu-children-s-hospital-YDy33","affiliationID":"257307"},{"family":"Niceta","given":"Marcello","affiliation":"Bambino Gesù Children's Hospital","authorSlug":"marcello-niceta-V0mJAO","authorName":"Marcello Niceta","authorID":"6974938","authorSequenceNumber":3,"affiliationSlug":"bambino-gesu-children-s-hospital-YDy33","affiliationID":"257307"},{"family":"Ciolfi","given":"Andrea","affiliation":"Bambino Gesù Children's Hospital","authorSlug":"andrea-ciolfi-xX01rQ","authorName":"Andrea Ciolfi","authorID":"5824722","authorSequenceNumber":4,"affiliationSlug":"bambino-gesu-children-s-hospital-YDy33","affiliationID":"257307"},{"family":"Trivisano","given":"Marina","affiliation":"Bambino Gesù Children's Hospital","authorSlug":"marina-trivisano-4LyYR3","authorName":"Marina Trivisano","authorID":"6734386","authorSequenceNumber":5,"affiliationSlug":"bambino-gesu-children-s-hospital-YDy33","affiliationID":"257307"},{"family":"Bartuli","given":"Andrea","affiliation":"Bambino Gesù Children's Hospital","authorSlug":"andrea-bartuli-r6aKWO","authorName":"Andrea Bartuli","authorID":"6858529","authorSequenceNumber":6,"affiliationSlug":"bambino-gesu-children-s-hospital-YDy33","affiliationID":"257307"},{"family":"Digilio","given":"M. Cristina","affiliation":"Bambino Gesù Children's Hospital","authorSlug":"m-cristina-digilio-j9lby","authorName":"M. Cristina Digilio","authorID":"552281","authorSequenceNumber":7,"affiliationSlug":"bambino-gesu-children-s-hospital-YDy33","affiliationID":"257307"},{"family":"Specchio","given":"Nicola","affiliation":"Bambino Gesù Children's Hospital","authorSlug":"nicola-specchio-OVKVAn","authorName":"Nicola Specchio","authorID":"5198434","authorSequenceNumber":8,"affiliationSlug":"bambino-gesu-children-s-hospital-YDy33","affiliationID":"257307"},{"family":"Dallapiccola","given":"Bruno","affiliation":"Bambino Gesù Children's Hospital","authorSlug":"bruno-dallapiccola-A315A2","authorName":"Bruno Dallapiccola","authorID":"5723893","authorSequenceNumber":9,"affiliationSlug":"bambino-gesu-children-s-hospital-YDy33","affiliationID":"257307"},{"family":"Tartaglia","given":"Marco","affiliation":"Bambino Gesù Children's Hospital","authorSlug":"marco-tartaglia-PQdpvm","authorName":"Marco Tartaglia","authorID":"5783045","authorSequenceNumber":10,"affiliationSlug":"bambino-gesu-children-s-hospital-YDy33","affiliationID":"257307"}],"keywords":["cerebellar dysgenesis","developmental and epileptic encephalopathy","facial dysmorphism","growth deficiency","PACS2"],"year":2019,"shortJournal":"Clinical Genetics","publisher":"Wiley","issue":"4","volume":"95","page":"525-531","retracted":false,"memberId":311,"issns":["0009-9163","1399-0004"],"editorialNotices":[],"journalSlug":"clinical-genetics-OV56O","journal":"Clinical Genetics","preprintLinks":[],"publicationLinks":[],"normalizedTypes":["article"]},"10.1111\u002Fgbb.12492":{"id":241623686,"doi":"10.1111\u002Fgbb.12492","slug":"de-novo-mutations-of-i-stxbp1-i-4LDD2JP","type":"journal-article","title":"De novo mutations of \u003Ci\u003ESTXBP1\u003C\u002Fi\u003E in Chinese children with early onset epileptic encephalopathy","abstract":"To detect syntaxin-binding protein 1 (STXBP1) mutations in Chinese patients with early onset epileptic encephalopathy (EOEE) of unknown etiology. Targeted next-generation sequencing was used to identify STXBP1 mutations in 143 Chinese patients with EOEE of unknown etiology. A filtering process was applied to prioritize rare variants of potential functional significance. Then Sanger sequencing was employed to validate the parental origin of the variants. Detailed clinical and genetic data were collected for 9 STXBP1-positive patients. Eight de novo heterozygous STXBP1 mutations were identified in 9 patients; 5 were novel mutations (c.1155delC, c.1030-1G\u003EA, c.217G\u003EC, c.268G\u003EC, c.1480_1481 insT) and 3 were previously reported (c.1216C\u003E T, c.1217G\u003EA [2 cases], c.875G\u003EA). Two patients had Ohtahara syndrome and 1 had West syndrome at onset, whereas the other 6 presented with EOEE that did not fit a specific recognized epilepsy syndrome. Six of these patients later evolved to West syndrome. All but 2 cases were prescribed more than 2 antiepileptic drugs (AEDs) plus other regimens. Four subjects showed good responses to levetiracetam (LEV) alone or in combination with other AEDs, and one case (1\u002F3) achieved complete freedom from seizures with a ketogenic diet (KD). All patients exhibited severe to profound global developmental delay. Five novel heterozygous de novo STXBP1 mutations were discovered in patients with EOEE from China. STXBP1 mutational analysis should be performed in cases of EOEE of unknown etiology. LEV as monotherapy or adjunctive therapy with other regimens, as well as KD should be considered for management of this patient group.","authors":[{"family":"Li","given":"Tingsong","affiliation":"China International Science and Technology Cooperation","authorSlug":"tingsong-li-6My56r","authorName":"Tingsong Li","authorID":"9679598","authorSequenceNumber":1,"affiliationSlug":"china-international-science-and-technology-lXdYk","affiliationID":"197236"},{"family":"Cheng","given":"M.-L.","affiliation":"Children's Hospital of Chongqing Medical University","authorSlug":"m-l-cheng-9MOPA2","authorName":"M.-L. Cheng","authorID":"138844590","authorSequenceNumber":2,"affiliationSlug":"children-s-hospital-of-chongqing-medical-K62kp","affiliationID":"138079"},{"family":"Wang","given":"J.","affiliation":"Chongqing Medical University","authorSlug":"j-wang-5MvR22","authorName":"J. Wang","authorID":"14151169","authorSequenceNumber":3,"affiliationSlug":"chongqing-medical-university-w2Vz","affiliationID":"23428"},{"family":"Hong","given":"Shiyuan","affiliation":"Children's Hospital of Chongqing Medical University","authorSlug":"shiyuan-hong-68b8wp","authorName":"Shiyuan Hong","authorID":"5709510","authorSequenceNumber":4,"affiliationSlug":"children-s-hospital-of-chongqing-medical-K62kp","affiliationID":"138079"},{"family":"Li","given":"M.","affiliation":"Chongqing Medical University","authorSlug":"m-li-WnxGp1","authorName":"M. Li","authorID":"15252848","authorSequenceNumber":5,"affiliationSlug":"chongqing-medical-university-w2Vz","affiliationID":"23428"},{"family":"Liao","given":"Shuang","affiliation":"Children's Hospital of Chongqing Medical University","authorSlug":"shuang-liao-VaybVZ","authorName":"Shuang Liao","authorID":"11610938","authorSequenceNumber":6,"affiliationSlug":"children-s-hospital-of-chongqing-medical-K62kp","affiliationID":"138079"},{"family":"Xie","given":"Lingling","affiliation":"Children's Hospital of Chongqing Medical University","authorSlug":"lingling-xie-QyExQM","authorName":"Lingling Xie","authorID":"8340660","authorSequenceNumber":7,"affiliationSlug":"children-s-hospital-of-chongqing-medical-K62kp","affiliationID":"138079"},{"family":"Jiang","given":"Li","affiliation":"Children's Hospital of Chongqing Medical University","authorSlug":"li-jiang-ZWn8G9","authorName":"Li Jiang","authorID":"139285575","authorSequenceNumber":8,"affiliationSlug":"children-s-hospital-of-chongqing-medical-K62kp","affiliationID":"138079"}],"keywords":["early onset epileptic encephalopathy","mutation","syntaxin‐binding protein 1","treatment"],"year":2018,"shortJournal":"Genes Brain and Behavior","publisher":"Wiley","issue":"8","volume":"17","retracted":false,"memberId":311,"issns":["1601-1848","1601-183X"],"editorialNotices":[],"journalSlug":"genes-brain-behavior-8GXV3","journal":"Genes, Brain and Behavior","preprintLinks":[],"publicationLinks":[],"normalizedTypes":["article"]},"10.1002\u002F9780470015902.a0027866":{"id":242510389,"doi":"10.1002\u002F9780470015902.a0027866","slug":"i-de-novo-i-mutations-in-human-PQY4pw2","type":"other","title":"\u003Ci\u003EDe Novo\u003C\u002Fi\u003E\n Mutations in Human Inherited Disease","authors":[{"family":"Oliveira","given":"Sofia","affiliation":"Universidade do Porto","authorSlug":"sofia-oliveira-rxKDPO","authorName":"Sofia Oliveira","authorID":"9388573","authorSequenceNumber":1,"affiliationSlug":"universidade-do-porto-MZRW","affiliationID":"19996"},{"family":"Cooper","given":"D.N.","affiliation":"Cardiff University","authorSlug":"d-n-cooper-gZL8yn","authorName":"D.N. Cooper","authorID":"4796758","authorSequenceNumber":2,"affiliationSlug":"cardiff-university-eKQ0","affiliationID":"14911"},{"family":"Azevedo","given":"Luı́sa","affiliation":"Universidade do Porto","authorSlug":"luisa-azevedo-A3PKde","authorName":"Luı́sa Azevedo","authorID":"7439549","authorSequenceNumber":3,"affiliationSlug":"universidade-do-porto-MZRW","affiliationID":"19996"}],"year":2018,"publisher":"Wiley","page":"1-7","retracted":false,"memberId":311,"issns":[],"editorialNotices":[],"journal":"Encyclopedia of Life Sciences","preprintLinks":[],"publicationLinks":[],"normalizedTypes":["other"]},"10.1002\u002Facn3.51483":{"id":11206297008,"doi":"10.1002\u002Facn3.51483","slug":"adult-onset-rapidly-worsening-progressive-myoclonic-MVb8gYEm","type":"journal-article","title":"Adult‐onset rapidly worsening progressive myoclonic epilepsy caused by a novel variant in DHDDS","abstract":"Progressive myoclonic epilepsy (PME) is a heterogeneous neurogenetic disorder manifesting as progressive myoclonus, seizure, and ataxia. We report a case of PME caused by a novel DHDDS variant. Additionally, by reviewing the literature on DHDDS mutations, we compared the phenotype of our patient with previously reported phenotypes. We identified DHDDS (c.638G\u003EA, p. Ser213-Asn) as a likely pathogenic variant. The literature review revealed 15 PME patients with DHDDS mutations from 13 unrelated families. According to previous studies, late-onset patients tend to have a slow-progressive disease course. Although his myoclonus and ataxia were adult onset, our patient experienced rapid disease aggravation.","authors":[{"family":"Kim","given":"Seondeuk","affiliation":"Seoul National University Hospital","authorSlug":"seondeuk-kim-2D5QVn","authorName":"Seondeuk Kim","authorID":"18279132","authorSequenceNumber":1,"affiliationSlug":"seoul-national-university-hospital-X3n2","affiliationID":"23185"},{"family":"Kim","given":"Man Jin","affiliation":"Seoul National University Hospital","authorSlug":"man-jin-kim-WG6ar1","authorName":"Man Jin Kim","authorID":"8446048","authorSequenceNumber":2,"affiliationSlug":"seoul-national-university-hospital-X3n2","affiliationID":"23185"},{"family":"Son","given":"Hyoshin","affiliation":"Seoul National University Hospital","authorSlug":"hyoshin-son-e6LWx0","authorName":"Hyoshin Son","authorID":"12349255","authorSequenceNumber":3,"affiliationSlug":"seoul-national-university-hospital-X3n2","affiliationID":"23185"},{"family":"Hwang","given":"Sungeun","affiliation":"Seoul National University Hospital","authorSlug":"sungeun-hwang-XenzQ2","authorName":"Sungeun Hwang","authorID":"11094685","authorSequenceNumber":4,"affiliationSlug":"seoul-national-university-hospital-X3n2","affiliationID":"23185"},{"family":"Kang","given":"Mi‐Kyoung","affiliation":"Seoul National University Hospital","authorSlug":"mi-kyoung-kang-rE2E0w","authorName":"Mi‐Kyoung Kang","authorID":"158525129","authorSequenceNumber":5,"affiliationSlug":"seoul-national-university-hospital-X3n2","affiliationID":"23185"},{"family":"Chu","given":"Kon","affiliation":"Seoul National University Hospital","authorSlug":"kon-chu-b2J0j6","authorName":"Kon Chu","authorID":"5182859","authorSequenceNumber":6,"affiliationSlug":"seoul-national-university-hospital-X3n2","affiliationID":"23185"},{"family":"Lee","given":"Sang Kun","affiliation":"Seoul National University Hospital","authorSlug":"sang-kun-lee-gajE0z","authorName":"Sang Kun Lee","authorID":"136366558","authorSequenceNumber":7,"affiliationSlug":"seoul-national-university-hospital-X3n2","affiliationID":"23185"},{"family":"Moon","given":"Jangsup","affiliation":"Seoul National University Hospital","authorSlug":"jangsup-moon-YZEOy3","authorName":"Jangsup Moon","authorID":"6470151","authorSequenceNumber":8,"affiliationSlug":"seoul-national-university-hospital-X3n2","affiliationID":"23185"}],"keywords":[],"year":2021,"shortJournal":"Ann Clin Transl Neurol","publisher":"Wiley","issue":"12","volume":"8","page":"2319-2326","memberId":311,"issns":["2328-9503","2328-9503"],"editorialNotices":[],"journalSlug":"annals-of-clinical-and-translational-gZDd1","journal":"Annals of Clinical and Translational Neurology","preprintLinks":[],"publicationLinks":[],"normalizedTypes":["article"]},"10.1002\u002Facn3.51598":{"id":11575524894,"doi":"10.1002\u002Facn3.51598","slug":"assessment-of-burden-and-segregation-zRQpANj3","type":"journal-article","title":"Assessment of burden and segregation profiles of \u003Cscp\u003ECNVs\u003C\u002Fscp\u003E in patients with epilepsy","abstract":"Objective\n \n\n Microdeletions are associated with different forms of epilepsy but show incomplete penetrance, which is not well understood. We aimed to assess whether unmasked variants or double CNVs could explain incomplete penetrance.\n \n\n\n\n Methods\n \n\n We analyzed copy number variants (CNVs) in 603 patients with four different subgroups of epilepsy and 945 controls. CNVs were called from genotypes and validated on whole‐genome (WGS) or whole‐exome sequences (WES). CNV burden difference between patients and controls was obtained by fitting a logistic regression. CNV burden was assessed for small and large (\u003E1 Mb) deletions and duplications and for deletions overlapping different gene sets.\n \n\n\n\n Results\n \n\n Large deletions were enriched in genetic generalized epilepsies (GGE) compared to controls. We also found enrichment of deletions in epilepsy genes and hotspots for GGE. We did not find truncating or functional variants that could have been unmasked by the deletions. We observed a double CNV hit in two patients. One patient also carried a de novo deletion in the 22q11.2 hotspot.\n \n\n\n\n Interpretation\n \n\n We could corroborate previous findings of an enrichment of large microdeletions and deletions in epilepsy genes in GGE. We could also replicate that microdeletions show incomplete penetrance. However, we could not validate the hypothesis of unmasked variants nor the hypothesis of double CNVs to explain the incomplete penetrance. We found a de novo CNV on 22q11.2 that could be of interest. We also observed GGE families carrying a deletion on 15q13.3 hotspot that could be investigated in the Quebec founder population.","authors":[{"family":"Moreau","given":"Claudia","affiliation":"Université du Québec à Chicoutimi","authorSlug":"claudia-moreau-aXJMGb","authorName":"Claudia Moreau","authorID":"5187783","authorSequenceNumber":1,"affiliationSlug":"universite-du-quebec-a-chicoutimi-Mml","affiliationID":"708"},{"family":"Tremblay","given":"Frédérique","affiliation":"Université du Québec à Chicoutimi","authorSlug":"frederique-tremblay-8mJbaG","authorName":"Frédérique Tremblay","authorID":"19993821","authorSequenceNumber":2,"affiliationSlug":"universite-du-quebec-a-chicoutimi-Mml","affiliationID":"708"},{"family":"Wolking","given":"Stefan","affiliation":"RWTH Aachen University","authorSlug":"stefan-wolking-J1mLJD","authorName":"Stefan Wolking","authorID":"7374267","authorSequenceNumber":3,"affiliationSlug":"rwth-aachen-university-eKr0","affiliationID":"14955"},{"family":"Girard","given":"Alexandre","affiliation":"Université du Québec à Chicoutimi","authorSlug":"alexandre-girard-E6mKPL","authorName":"Alexandre Girard","authorID":"152002117","authorSequenceNumber":4,"affiliationSlug":"universite-du-quebec-a-chicoutimi-Mml","affiliationID":"708"},{"family":"Laprise","given":"Catherine","affiliation":"Université du Québec à Chicoutimi","authorSlug":"catherine-laprise-xXgJMM","authorName":"Catherine Laprise","authorID":"6045722","authorSequenceNumber":5,"affiliationSlug":"universite-du-quebec-a-chicoutimi-Mml","affiliationID":"708"},{"family":"Hamdan","given":"Fadi F.","affiliation":"Centre Hospitalier Universitaire Sainte-Justine","authorSlug":"fadi-f-hamdan-6PRNN9","authorName":"Fadi F. Hamdan","authorID":"137348298","authorSequenceNumber":6,"affiliationSlug":"centre-hospitalier-universitaire-sainte-justine-KWA1","affiliationID":"4079"},{"family":"Michaud","given":"Jacques L.","affiliation":"Centre Hospitalier Universitaire Sainte-Justine","authorSlug":"jacques-l-michaud-zR9QV5","authorName":"Jacques L. Michaud","authorID":"4991050","authorSequenceNumber":7,"affiliationSlug":"centre-hospitalier-universitaire-sainte-justine-KWA1","affiliationID":"4079"},{"family":"Minassian","given":"Berge A.","affiliation":"University of Toronto","authorSlug":"berge-a-minassian-Vn60WW","authorName":"Berge A. Minassian","authorID":"136552338","authorSequenceNumber":8,"affiliationSlug":"university-of-toronto-xWjA","affiliationID":"12922"},{"family":"Cossette","given":"Patrick","affiliation":"Centre Hospitalier de l’Université de Montréal","authorSlug":"patrick-cossette-0Gwz60","authorName":"Patrick Cossette","authorID":"5984156","authorSequenceNumber":9,"affiliationSlug":"centre-hospitalier-de-l-universite-de-Wx80g","affiliationID":"257904"},{"family":"Girard","given":"Simon","affiliation":"Université du Québec à Chicoutimi","authorSlug":"simon-girard-2NgwkE","authorName":"Simon Girard","authorID":"7462332","authorSequenceNumber":10,"affiliationSlug":"universite-du-quebec-a-chicoutimi-Mml","affiliationID":"708"}],"keywords":["\n Research Article\n "],"year":2022,"shortJournal":"Ann Clin Transl Neurol","publisher":"Wiley","issue":"7","volume":"9","page":"1050-1058","memberId":311,"issns":["2328-9503","2328-9503"],"editorialNotices":[],"journalSlug":"annals-of-clinical-and-translational-gZDd1","journal":"Annals of Clinical and Translational Neurology","preprintLinks":[{"preprintDoi":"10.1101\u002F2022.02.17.22271082"}],"publicationLinks":[],"normalizedTypes":["article"]},"10.1002\u002Facn3.52062":{"id":12226709976,"doi":"10.1002\u002Facn3.52062","slug":"primary-mitochondrial-disorders-and-mimics-2NVRDKGY","type":"journal-article","title":"Primary mitochondrial disorders and mimics: Insights from a large French cohort","abstract":"ObjectiveThe objective of this study was to evaluate the implementation of NGS within the French mitochondrial network, MitoDiag, from targeted gene panels to whole exome sequencing (WES) or whole genome sequencing (WGS) focusing on mitochondrial nuclear‐encoded genes.MethodsOver 2000 patients suspected of Primary Mitochondrial Diseases (PMD) were sequenced by either targeted gene panels, WES or WGS within MitoDiag. We described the clinical, biochemical, and molecular data of 397 genetically confirmed patients, comprising 294 children and 103 adults, carrying pathogenic or likely pathogenic variants in nuclear‐encoded genes.ResultsThe cohort exhibited a large genetic heterogeneity, with the identification of 172 distinct genes and 253 novel variants. Among children, a notable prevalence of pathogenic variants in genes associated with oxidative phosphorylation (OXPHOS) functions and mitochondrial translation was observed. In adults, pathogenic variants were primarily identified in genes linked to mtDNA maintenance. Additionally, a substantial proportion of patients (54% (42\u002F78) and 48% (13\u002F27) in children and adults, respectively), undergoing WES or WGS testing displayed PMD mimics, representing pathologies that clinically resemble mitochondrial diseases.InterpretationWe reported the largest French cohort of patients suspected of PMD with pathogenic variants in nuclear genes. We have emphasized the clinical complexity of PMD and the challenges associated with recognizing and distinguishing them from other pathologies, particularly neuromuscular disorders. We confirmed that WES\u002FWGS, instead of panel approach, was more valuable to identify the genetic basis in patients with “possible” PMD and we provided a genetic testing flowchart to guide physicians in their diagnostic strategy.","authors":[{"family":"Rouzier","given":"Cécile","affiliation":"Inserm","authorSlug":"cecile-rouzier-8GZvj2","authorName":"Cécile Rouzier","authorID":"7048821","authorSequenceNumber":1,"affiliationSlug":"inserm-MaEp","affiliationID":"6896"},{"family":"Pion","given":"Emmanuelle","affiliation":"Institut de Génétique Moléculaire de Montpellier","authorSlug":"emmanuelle-pion-lOezKm","authorName":"Emmanuelle Pion","authorID":"29883136","authorSequenceNumber":2,"affiliationSlug":"institut-de-genetique-moleculaire-de-jXR5J","affiliationID":"284137"},{"family":"Chaussenot","given":"Annabelle","affiliation":"Inserm","authorSlug":"annabelle-chaussenot-K6e9Jd","authorName":"Annabelle Chaussenot","authorID":"5065079","authorSequenceNumber":3,"affiliationSlug":"inserm-MaEp","affiliationID":"6896"},{"family":"Bris","given":"Céline","affiliation":"Inserm","authorSlug":"celine-bris-wblg69","authorName":"Céline Bris","authorID":"8213628","authorSequenceNumber":4,"affiliationSlug":"inserm-MaEp","affiliationID":"6896"},{"family":"Saadi","given":"Samira Ait‐El‐Mkadem","affiliation":"Inserm","authorSlug":"samira-ait-el-mkadem-saadi-RKO5p","authorName":"Samira Ait‐El‐Mkadem Saadi","authorID":"3690126","authorSequenceNumber":5,"affiliationSlug":"inserm-MaEp","affiliationID":"6896"},{"family":"Desquiret‐Dumas","given":"Valérie","affiliation":"Inserm","authorSlug":"valerie-desquiret-dumas-V0mKeM","authorName":"Valérie Desquiret‐Dumas","authorID":"6904338","authorSequenceNumber":6,"affiliationSlug":"inserm-MaEp","affiliationID":"6896"},{"family":"Guéguen","given":"Naïg","affiliation":"Inserm","authorSlug":"naig-gueguen-V0Aa6z","authorName":"Naïg Guéguen","authorID":"6565838","authorSequenceNumber":7,"affiliationSlug":"inserm-MaEp","affiliationID":"6896"},{"family":"Fragaki","given":"Konstantina","affiliation":"Inserm","authorSlug":"konstantina-fragaki-wmMa8l","authorName":"Konstantina Fragaki","authorID":"6544172","authorSequenceNumber":8,"affiliationSlug":"inserm-MaEp","affiliationID":"6896"},{"family":"Amati‐Bonneau","given":"Patrizia","affiliation":"Inserm","authorSlug":"patrizia-amati-bonneau-y8ebDG","authorName":"Patrizia Amati‐Bonneau","authorID":"6099964","authorSequenceNumber":9,"affiliationSlug":"inserm-MaEp","affiliationID":"6896"},{"family":"Barcia","given":"Giulia","affiliation":"Université Paris Cité","authorSlug":"giulia-barcia-NlZ82Q","authorName":"Giulia Barcia","authorID":"6484127","authorSequenceNumber":10,"affiliationSlug":"universite-paris-cite-9OMr","affiliationID":"3590"},{"family":"Gaignard","given":"Pauline","affiliation":"Bicêtre Hospital","authorSlug":"pauline-gaignard-2Wl2DL","authorName":"Pauline Gaignard","authorID":"7792576","authorSequenceNumber":11,"affiliationSlug":"bicetre-hospital-Qe1lM","affiliationID":"152216"},{"family":"Steffann","given":"Julie","affiliation":"Université Paris Cité","authorSlug":"julie-steffann-Nl525m","authorName":"Julie Steffann","authorID":"6835671","authorSequenceNumber":12,"affiliationSlug":"universite-paris-cite-9OMr","affiliationID":"3590"},{"family":"Pennisi","given":"Alessandra","affiliation":"Université Paris Cité","authorSlug":"alessandra-pennisi-Xgg1Kx","authorName":"Alessandra Pennisi","authorID":"15392785","authorSequenceNumber":13,"affiliationSlug":"universite-paris-cite-9OMr","affiliationID":"3590"},{"family":"Bonnefont","given":"Jean‐Paul","affiliation":"Université Paris Cité","authorSlug":"jean-paul-bonnefont-YZwamr","authorName":"Jean‐Paul Bonnefont","authorID":"5948695","authorSequenceNumber":14,"affiliationSlug":"universite-paris-cite-9OMr","affiliationID":"3590"},{"family":"Lebigot","given":"Élise","affiliation":"Bicêtre Hospital","authorSlug":"elise-lebigot-Ead3YP","authorName":"Élise Lebigot","authorID":"8895017","authorSequenceNumber":15,"affiliationSlug":"bicetre-hospital-Qe1lM","affiliationID":"152216"},{"family":"Bannwarth","given":"Sylvie","affiliation":"Inserm","authorSlug":"sylvie-bannwarth-jMkvGj","authorName":"Sylvie Bannwarth","authorID":"4682137","authorSequenceNumber":16,"affiliationSlug":"inserm-MaEp","affiliationID":"6896"},{"family":"Francou","given":"Bruno","affiliation":"Inserm","authorSlug":"bruno-francou-PQkJem","authorName":"Bruno Francou","authorID":"7272445","authorSequenceNumber":17,"affiliationSlug":"inserm-MaEp","affiliationID":"6896"},{"family":"Rucheton","given":"Benoît","authorSlug":"benoit-rucheton-9DVyjN","authorName":"Benoît Rucheton","authorID":"14683290","authorSequenceNumber":18},{"family":"Sternberg","given":"Damien","affiliation":"Sorbonne Université","authorSlug":"damien-sternberg-OVD5k4","authorName":"Damien Sternberg","authorID":"5850534","authorSequenceNumber":19,"affiliationSlug":"sorbonne-universite-g0bQ","affiliationID":"21314"},{"family":"Martin‐Négrier","given":"Marie‐Laure","affiliation":"Hôpital Pellegrin","authorSlug":"marie-laure-martin-negrier-Y1ZwW3","authorName":"Marie‐Laure Martin‐Négrier","authorID":"138814495","authorSequenceNumber":20,"affiliationSlug":"hopital-pellegrin-ajvvb","affiliationID":"277339"},{"family":"Trimouille","given":"Aurélien","affiliation":"Hôpital Pellegrin","authorSlug":"aurelien-trimouille-AwY2d3","authorName":"Aurélien Trimouille","authorID":"103114705","authorSequenceNumber":21,"affiliationSlug":"hopital-pellegrin-ajvvb","affiliationID":"277339"},{"family":"Hardy","given":"G.","affiliation":"Laboratoire de Microbiologie et Génétique Moléculaires","authorSlug":"g-hardy-G5aQV1","authorName":"G. Hardy","authorID":"8089157","authorSequenceNumber":22,"affiliationSlug":"laboratoire-de-microbiologie-et-genetique-5MGQZ","affiliationID":"258069"},{"family":"Allouche","given":"Stéphane","affiliation":"Université de Caen Normandie","authorSlug":"stephane-allouche-4Lj3yY","authorName":"Stéphane Allouche","authorID":"7261542","authorSequenceNumber":23,"affiliationSlug":"universite-de-caen-normandie-5eO2","affiliationID":"17269"},{"family":"Acquaviva","given":"Cécile","affiliation":"Hospices Civils de Lyon","authorSlug":"cecile-acquaviva-2N8dPm","authorName":"Cécile Acquaviva","authorID":"6117476","authorSequenceNumber":24,"affiliationSlug":"hospices-civils-de-lyon-Rj8Yp","affiliationID":"273526"},{"family":"Pagan","given":"Cécile","affiliation":"Hospices Civils de Lyon","authorSlug":"cecile-pagan-rwyKx4","authorName":"Cécile Pagan","authorID":"138722273","authorSequenceNumber":25,"affiliationSlug":"hospices-civils-de-lyon-Rj8Yp","affiliationID":"273526"},{"family":"Lebre","given":"Anne‐Sophie","affiliation":"Université de Reims Champagne-Ardenne","authorSlug":"anne-sophie-lebre-zPe918","authorName":"Anne‐Sophie Lebre","authorID":"43982306","authorSequenceNumber":26,"affiliationSlug":"universite-de-reims-champagne-ardenne-plAz","affiliationID":"13930"},{"family":"Reynier","given":"Pascal","affiliation":"Inserm","authorSlug":"pascal-reynier-YZ51YP","authorName":"Pascal Reynier","authorID":"5864595","authorSequenceNumber":27,"affiliationSlug":"inserm-MaEp","affiliationID":"6896"},{"family":"Cossée","given":"Mireille","affiliation":"Inserm","authorSlug":"mireille-cossee-W6mLQ","authorName":"Mireille Cossée","authorID":"996204","authorSequenceNumber":28,"affiliationSlug":"inserm-MaEp","affiliationID":"6896"},{"family":"Attarian","given":"Shahram","affiliation":"Aix-Marseille Université","authorSlug":"shahram-attarian-MVKZ4l","authorName":"Shahram Attarian","authorID":"5216908","authorSequenceNumber":29,"affiliationSlug":"aix-marseille-universite-6OGr","affiliationID":"22698"},{"family":"Paquis‐Flucklinger","given":"Véronique","affiliation":"Inserm","authorSlug":"veronique-paquis-flucklinger-Nl64Og","authorName":"Véronique Paquis‐Flucklinger","authorID":"5595671","authorSequenceNumber":30,"affiliationSlug":"inserm-MaEp","affiliationID":"6896"},{"family":"Procaccio","given":"Vincent","affiliation":"Inserm","authorSlug":"vincent-procaccio-mOPaMj","authorName":"Vincent Procaccio","authorID":"5863887","authorSequenceNumber":31,"affiliationSlug":"inserm-MaEp","affiliationID":"6896"}],"keywords":[],"year":2024,"shortJournal":"Ann Clin Transl Neurol","publisher":"Wiley","issue":"6","volume":"11","page":"1478-1491","memberId":311,"issns":["2328-9503","2328-9503"],"editorialNotices":[],"journalSlug":"annals-of-clinical-and-translational-gZDd1","journal":"Annals of Clinical and Translational Neurology","preprintLinks":[],"publicationLinks":[],"normalizedTypes":["article"]},"10.1002\u002Facn3.52211":{"id":12417392134,"doi":"10.1002\u002Facn3.52211","slug":"clinical-trials-for-lennox-gastaut-syndrome-OVYWr6ga","type":"journal-article","title":"Clinical trials for Lennox–Gastaut syndrome: Challenges and priorities","abstract":"Objective: Lennox‐Gastaut syndrome (LGS) is a severe, childhood‐onset epilepsy that is typically refractory to treatment. We surveyed the current landscape of LGS treatment, aiming to identify challenges to the development of efficacious therapies, and to articulate corresponding priorities toward clinical trials that improve outcomes. Methods: The LGS Special Interest Group of the Pediatric Epilepsy Research Consortium integrated evidence from the literature and expert opinion, into a narrative review. Results: We provide an overview of approved and emerging medical, dietary, surgical and neuromodulation approaches for LGS. We note that quality of care could be improved by standardizing LGS treatment based on expert consensus and empirical data. Whereas LGS natural history is incompletely understood, prospective studies and use of large retrospective datasets to understand LGS across the lifespan would enable clinical trials that address these dynamics. Recent discoveries related to LGS pathophysiology should enable development of disease‐modifying therapies, which are currently lacking. Finally, clinical trials have focused chiefly on seizures involving “drops,” but should incorporate additional patient‐centered outcomes, using emerging measures adapted to people with LGS. Interpretation: Clinicians and researchers should enact these priorities, with the goal of patient‐centered clinical trials that are tailored to LGS pathophysiology and natural history.","authors":[{"family":"Knowles","given":"Juliet K.","affiliation":"Stanford University","authorSlug":"juliet-k-knowles-bOM24N","authorName":"Juliet K. Knowles","authorID":"7925859","authorSequenceNumber":1,"affiliationSlug":"stanford-university-EVVW","affiliationID":"23761"},{"family":"Warren","given":"Aaron E. L.","affiliation":"Brigham and Women's Hospital","authorSlug":"aaron-e-l-warren-38kAdb","authorName":"Aaron E. L. Warren","authorID":"9371144","authorSequenceNumber":2,"affiliationSlug":"brigham-and-women-s-hospital-6JX1","affiliationID":"9610"},{"family":"Mohamed","given":"Ismail","affiliation":"University of Alabama at Birmingham","authorSlug":"ismail-mohamed-W89Gy1","authorName":"Ismail Mohamed","authorID":"7416448","authorSequenceNumber":3,"affiliationSlug":"university-of-alabama-at-birmingham-eNxm","affiliationID":"26599"},{"family":"Stafstrom","given":"Carl E.","affiliation":"Johns Hopkins Medicine","authorSlug":"carl-e-stafstrom-0O5w9","authorName":"Carl E. 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Patel","authorID":"5841952","authorSequenceNumber":13,"affiliationSlug":"the-ohio-state-university-eGb2","affiliationID":"20999"},{"family":"Grinspan","given":"Zachary M.","affiliation":"Cornell University","authorSlug":"zachary-m-grinspan-gZ5j6A","authorName":"Zachary M. Grinspan","authorID":"6676214","authorSequenceNumber":14,"affiliationSlug":"cornell-university-5MP2","affiliationID":"6269"}],"keywords":[],"year":2024,"shortJournal":"Ann Clin Transl Neurol","publisher":"Wiley","issue":"11","volume":"11","page":"2818-2835","memberId":311,"issns":["2328-9503","2328-9503"],"editorialNotices":[],"journalSlug":"annals-of-clinical-and-translational-gZDd1","journal":"Annals of Clinical and Translational Neurology","preprintLinks":[],"publicationLinks":[],"normalizedTypes":["article"]},"10.1016\u002Fj.ajhg.2017.09.008":{"id":242511967,"doi":"10.1016\u002Fj.ajhg.2017.09.008","slug":"high-rate-of-recurrent-de-J1P4bEw","type":"journal-article","title":"High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies","abstract":"Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63\u002F197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53\u002F63 solved cases), followed by inherited mutations (6\u002F63 solved cases) and de novo CNVs (4\u002F63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.","authors":[{"family":"Hamdan","given":"Fadi F.","affiliation":"Centre Hospitalier Universitaire Sainte-Justine","authorSlug":"fadi-f-hamdan-ka0km5","authorName":"Fadi F. 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