Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis
Identifieur interne : 001705 ( Pmc/Checkpoint ); précédent : 001704; suivant : 001706Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis
Auteurs : Hilary C. Martin [Royaume-Uni] ; Grace E. Kim [États-Unis] ; Alistair T. Pagnamenta [Royaume-Uni] ; Yoshiko Murakami [Japon] ; Gemma L. Carvill [États-Unis] ; Esther Meyer [Royaume-Uni] ; Richard R. Copley [Royaume-Uni] ; Andrew Rimmer [Royaume-Uni] ; Giulia Barcia [France] ; Matthew R. Fleming [États-Unis] ; Jack Kronengold [États-Unis] ; Maile R. Brown [États-Unis] ; Karl A. Hudspith [Royaume-Uni] ; John Broxholme [Royaume-Uni] ; Alexander Kanapin [Royaume-Uni] ; Jean-Baptiste Cazier [Royaume-Uni] ; Taroh Kinoshita [Japon] ; Rima Nabbout [France] ; David Bentley [États-Unis] ; Gil Mcvean [Royaume-Uni] ; Sinéad Heavin [Australie] ; Zenobia Zaiwalla [Royaume-Uni] ; Tony Mcshane [Royaume-Uni] ; Heather C. Mefford [États-Unis] ; Deborah Shears [Royaume-Uni] ; Helen Stewart [Royaume-Uni] ; Manju A. Kurian [Royaume-Uni] ; Ingrid E. Scheffer [Australie] ; Edward Blair [Royaume-Uni] ; Peter Donnelly [Royaume-Uni] ; Leonard K. Kaczmarek [États-Unis] ; Jenny C. Taylor [Royaume-Uni]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2014.
Abstract
In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found
Url:
DOI: 10.1093/hmg/ddu030
PubMed: 24463883
PubMed Central: 4030775
Affiliations:
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<author><name sortKey="Kim, Grace E" sort="Kim, Grace E" uniqKey="Kim G" first="Grace E." last="Kim">Grace E. Kim</name>
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<author><name sortKey="Pagnamenta, Alistair T" sort="Pagnamenta, Alistair T" uniqKey="Pagnamenta A" first="Alistair T." last="Pagnamenta">Alistair T. Pagnamenta</name>
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<author><name sortKey="Murakami, Yoshiko" sort="Murakami, Yoshiko" uniqKey="Murakami Y" first="Yoshiko" last="Murakami">Yoshiko Murakami</name>
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<author><name sortKey="Carvill, Gemma L" sort="Carvill, Gemma L" uniqKey="Carvill G" first="Gemma L." last="Carvill">Gemma L. Carvill</name>
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<author><name sortKey="Meyer, Esther" sort="Meyer, Esther" uniqKey="Meyer E" first="Esther" last="Meyer">Esther Meyer</name>
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<affiliation wicri:level="1"><nlm:aff id="af7"><addr-line>Department of Neurology</addr-line>
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<author><name sortKey="Copley, Richard R" sort="Copley, Richard R" uniqKey="Copley R" first="Richard R." last="Copley">Richard R. Copley</name>
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<author><name sortKey="Rimmer, Andrew" sort="Rimmer, Andrew" uniqKey="Rimmer A" first="Andrew" last="Rimmer">Andrew Rimmer</name>
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<author><name sortKey="Barcia, Giulia" sort="Barcia, Giulia" uniqKey="Barcia G" first="Giulia" last="Barcia">Giulia Barcia</name>
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<author><name sortKey="Fleming, Matthew R" sort="Fleming, Matthew R" uniqKey="Fleming M" first="Matthew R." last="Fleming">Matthew R. Fleming</name>
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<author><name sortKey="Kronengold, Jack" sort="Kronengold, Jack" uniqKey="Kronengold J" first="Jack" last="Kronengold">Jack Kronengold</name>
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<author><name sortKey="Brown, Maile R" sort="Brown, Maile R" uniqKey="Brown M" first="Maile R." last="Brown">Maile R. Brown</name>
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<author><name sortKey="Hudspith, Karl A" sort="Hudspith, Karl A" uniqKey="Hudspith K" first="Karl A." last="Hudspith">Karl A. Hudspith</name>
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<author><name sortKey="Broxholme, John" sort="Broxholme, John" uniqKey="Broxholme J" first="John" last="Broxholme">John Broxholme</name>
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<author><name sortKey="Kanapin, Alexander" sort="Kanapin, Alexander" uniqKey="Kanapin A" first="Alexander" last="Kanapin">Alexander Kanapin</name>
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<author><name sortKey="Cazier, Jean Baptiste" sort="Cazier, Jean Baptiste" uniqKey="Cazier J" first="Jean-Baptiste" last="Cazier">Jean-Baptiste Cazier</name>
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<author><name sortKey="Kinoshita, Taroh" sort="Kinoshita, Taroh" uniqKey="Kinoshita T" first="Taroh" last="Kinoshita">Taroh Kinoshita</name>
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<author><name sortKey="Nabbout, Rima" sort="Nabbout, Rima" uniqKey="Nabbout R" first="Rima" last="Nabbout">Rima Nabbout</name>
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<author><name sortKey="Bentley, David" sort="Bentley, David" uniqKey="Bentley D" first="David" last="Bentley">David Bentley</name>
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<author><name sortKey="Mcvean, Gil" sort="Mcvean, Gil" uniqKey="Mcvean G" first="Gil" last="Mcvean">Gil Mcvean</name>
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,<addr-line>Oxford</addr-line>
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<country xml:lang="fr">Royaume-Uni</country>
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<author><name sortKey="Heavin, Sinead" sort="Heavin, Sinead" uniqKey="Heavin S" first="Sinéad" last="Heavin">Sinéad Heavin</name>
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,<addr-line>Melbourne, VIC</addr-line>
,<country>Australia</country>
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<country xml:lang="fr">Australie</country>
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<author><name sortKey="Zaiwalla, Zenobia" sort="Zaiwalla, Zenobia" uniqKey="Zaiwalla Z" first="Zenobia" last="Zaiwalla">Zenobia Zaiwalla</name>
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,<institution>John Radcliffe Hospital</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
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<country xml:lang="fr">Royaume-Uni</country>
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<author><name sortKey="Mcshane, Tony" sort="Mcshane, Tony" uniqKey="Mcshane T" first="Tony" last="Mcshane">Tony Mcshane</name>
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,<addr-line>Oxford</addr-line>
,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
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<author><name sortKey="Mefford, Heather C" sort="Mefford, Heather C" uniqKey="Mefford H" first="Heather C." last="Mefford">Heather C. Mefford</name>
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,<institution>University of Washington</institution>
,<addr-line>Seattle, WA</addr-line>
,<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Shears, Deborah" sort="Shears, Deborah" uniqKey="Shears D" first="Deborah" last="Shears">Deborah Shears</name>
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<author><name sortKey="Stewart, Helen" sort="Stewart, Helen" uniqKey="Stewart H" first="Helen" last="Stewart">Helen Stewart</name>
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</nlm:aff>
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<author><name sortKey="Kurian, Manju A" sort="Kurian, Manju A" uniqKey="Kurian M" first="Manju A." last="Kurian">Manju A. Kurian</name>
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<author><name sortKey="Scheffer, Ingrid E" sort="Scheffer, Ingrid E" uniqKey="Scheffer I" first="Ingrid E." last="Scheffer">Ingrid E. Scheffer</name>
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,<addr-line>Melbourne, VIC</addr-line>
,<country>Australia</country>
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<author><name sortKey="Blair, Edward" sort="Blair, Edward" uniqKey="Blair E" first="Edward" last="Blair">Edward Blair</name>
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,<institution>Oxford University Hospitals NHS Trust</institution>
,<addr-line>Oxford</addr-line>
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</nlm:aff>
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<author><name sortKey="Donnelly, Peter" sort="Donnelly, Peter" uniqKey="Donnelly P" first="Peter" last="Donnelly">Peter Donnelly</name>
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,<institution>University of Oxford</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
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<country xml:lang="fr">Royaume-Uni</country>
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<author><name sortKey="Kaczmarek, Leonard K" sort="Kaczmarek, Leonard K" uniqKey="Kaczmarek L" first="Leonard K." last="Kaczmarek">Leonard K. Kaczmarek</name>
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,<institution>Yale University School of Medicine</institution>
,<addr-line>New Haven, CT</addr-line>
,<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Taylor, Jenny C" sort="Taylor, Jenny C" uniqKey="Taylor J" first="Jenny C." last="Taylor">Jenny C. Taylor</name>
<affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Wellcome Trust Centre for Human Genetics</addr-line>
,<institution>University of Oxford</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af3"><institution>NIHR Biomedical Research Centre</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis</title>
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</affiliation>
</author>
<author><name sortKey="Kim, Grace E" sort="Kim, Grace E" uniqKey="Kim G" first="Grace E." last="Kim">Grace E. Kim</name>
<affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Departments of Cellular and Molecular Physiology and Pharmacology</addr-line>
,<institution>Yale University School of Medicine</institution>
,<addr-line>New Haven, CT</addr-line>
,<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Pagnamenta, Alistair T" sort="Pagnamenta, Alistair T" uniqKey="Pagnamenta A" first="Alistair T." last="Pagnamenta">Alistair T. Pagnamenta</name>
<affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Wellcome Trust Centre for Human Genetics</addr-line>
,<institution>University of Oxford</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af3"><institution>NIHR Biomedical Research Centre</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Murakami, Yoshiko" sort="Murakami, Yoshiko" uniqKey="Murakami Y" first="Yoshiko" last="Murakami">Yoshiko Murakami</name>
<affiliation wicri:level="1"><nlm:aff id="af4"><addr-line>Department of Immunoregulation</addr-line>
,<institution>Research Institute for Microbial Diseases, Osaka University</institution>
,<addr-line>Osaka</addr-line>
,<country>Japan</country>
,</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Carvill, Gemma L" sort="Carvill, Gemma L" uniqKey="Carvill G" first="Gemma L." last="Carvill">Gemma L. Carvill</name>
<affiliation wicri:level="1"><nlm:aff id="af5"><addr-line>Department of Pediatrics, Division of Genetic Medicine</addr-line>
,<institution>University of Washington</institution>
,<addr-line>Seattle, WA</addr-line>
,<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Meyer, Esther" sort="Meyer, Esther" uniqKey="Meyer E" first="Esther" last="Meyer">Esther Meyer</name>
<affiliation wicri:level="1"><nlm:aff id="af6"><addr-line>Neurosciences Unit</addr-line>
,<institution>UCL-Institute of Child Health</institution>
,<addr-line>London</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af7"><addr-line>Department of Neurology</addr-line>
,<institution>Great Ormond Street Hospital</institution>
,<addr-line>London</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Copley, Richard R" sort="Copley, Richard R" uniqKey="Copley R" first="Richard R." last="Copley">Richard R. Copley</name>
<affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Wellcome Trust Centre for Human Genetics</addr-line>
,<institution>University of Oxford</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af3"><institution>NIHR Biomedical Research Centre</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rimmer, Andrew" sort="Rimmer, Andrew" uniqKey="Rimmer A" first="Andrew" last="Rimmer">Andrew Rimmer</name>
<affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Wellcome Trust Centre for Human Genetics</addr-line>
,<institution>University of Oxford</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Barcia, Giulia" sort="Barcia, Giulia" uniqKey="Barcia G" first="Giulia" last="Barcia">Giulia Barcia</name>
<affiliation wicri:level="1"><nlm:aff id="af8"><addr-line>Department of Paediatric Neurology, Centre de Reference Epilepsies Rares</addr-line>
,<institution>Hôpital Necker-Enfants Malades</institution>
,<addr-line>Paris</addr-line>
,<country>France</country>
,</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Fleming, Matthew R" sort="Fleming, Matthew R" uniqKey="Fleming M" first="Matthew R." last="Fleming">Matthew R. Fleming</name>
<affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Departments of Cellular and Molecular Physiology and Pharmacology</addr-line>
,<institution>Yale University School of Medicine</institution>
,<addr-line>New Haven, CT</addr-line>
,<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kronengold, Jack" sort="Kronengold, Jack" uniqKey="Kronengold J" first="Jack" last="Kronengold">Jack Kronengold</name>
<affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Departments of Cellular and Molecular Physiology and Pharmacology</addr-line>
,<institution>Yale University School of Medicine</institution>
,<addr-line>New Haven, CT</addr-line>
,<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Brown, Maile R" sort="Brown, Maile R" uniqKey="Brown M" first="Maile R." last="Brown">Maile R. Brown</name>
<affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Departments of Cellular and Molecular Physiology and Pharmacology</addr-line>
,<institution>Yale University School of Medicine</institution>
,<addr-line>New Haven, CT</addr-line>
,<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hudspith, Karl A" sort="Hudspith, Karl A" uniqKey="Hudspith K" first="Karl A." last="Hudspith">Karl A. Hudspith</name>
<affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Wellcome Trust Centre for Human Genetics</addr-line>
,<institution>University of Oxford</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af3"><institution>NIHR Biomedical Research Centre</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Broxholme, John" sort="Broxholme, John" uniqKey="Broxholme J" first="John" last="Broxholme">John Broxholme</name>
<affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Wellcome Trust Centre for Human Genetics</addr-line>
,<institution>University of Oxford</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kanapin, Alexander" sort="Kanapin, Alexander" uniqKey="Kanapin A" first="Alexander" last="Kanapin">Alexander Kanapin</name>
<affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Wellcome Trust Centre for Human Genetics</addr-line>
,<institution>University of Oxford</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Cazier, Jean Baptiste" sort="Cazier, Jean Baptiste" uniqKey="Cazier J" first="Jean-Baptiste" last="Cazier">Jean-Baptiste Cazier</name>
<affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Wellcome Trust Centre for Human Genetics</addr-line>
,<institution>University of Oxford</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kinoshita, Taroh" sort="Kinoshita, Taroh" uniqKey="Kinoshita T" first="Taroh" last="Kinoshita">Taroh Kinoshita</name>
<affiliation wicri:level="1"><nlm:aff id="af4"><addr-line>Department of Immunoregulation</addr-line>
,<institution>Research Institute for Microbial Diseases, Osaka University</institution>
,<addr-line>Osaka</addr-line>
,<country>Japan</country>
,</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nabbout, Rima" sort="Nabbout, Rima" uniqKey="Nabbout R" first="Rima" last="Nabbout">Rima Nabbout</name>
<affiliation wicri:level="1"><nlm:aff id="af8"><addr-line>Department of Paediatric Neurology, Centre de Reference Epilepsies Rares</addr-line>
,<institution>Hôpital Necker-Enfants Malades</institution>
,<addr-line>Paris</addr-line>
,<country>France</country>
,</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bentley, David" sort="Bentley, David" uniqKey="Bentley D" first="David" last="Bentley">David Bentley</name>
<affiliation wicri:level="1"><nlm:aff id="af9"><institution>Illumina Inc.</institution>
,<addr-line>San Diego, CA</addr-line>
,<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mcvean, Gil" sort="Mcvean, Gil" uniqKey="Mcvean G" first="Gil" last="Mcvean">Gil Mcvean</name>
<affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Wellcome Trust Centre for Human Genetics</addr-line>
,<institution>University of Oxford</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Heavin, Sinead" sort="Heavin, Sinead" uniqKey="Heavin S" first="Sinéad" last="Heavin">Sinéad Heavin</name>
<affiliation wicri:level="1"><nlm:aff id="af10"><addr-line>Departments of Medicine and Paediatrics</addr-line>
,<institution>Florey Institute, The University of Melbourne, Austin Health and Royal Children's Hospital</institution>
,<addr-line>Melbourne, VIC</addr-line>
,<country>Australia</country>
,</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Zaiwalla, Zenobia" sort="Zaiwalla, Zenobia" uniqKey="Zaiwalla Z" first="Zenobia" last="Zaiwalla">Zenobia Zaiwalla</name>
<affiliation wicri:level="1"><nlm:aff id="af11"><addr-line>Department of Clinical Neurophysiology</addr-line>
,<institution>John Radcliffe Hospital</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mcshane, Tony" sort="Mcshane, Tony" uniqKey="Mcshane T" first="Tony" last="Mcshane">Tony Mcshane</name>
<affiliation wicri:level="1"><nlm:aff id="af12"><addr-line>Department of Paediatrics</addr-line>
,<institution>Children's Hospital Oxford, John Radcliffe Hospital</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mefford, Heather C" sort="Mefford, Heather C" uniqKey="Mefford H" first="Heather C." last="Mefford">Heather C. Mefford</name>
<affiliation wicri:level="1"><nlm:aff id="af5"><addr-line>Department of Pediatrics, Division of Genetic Medicine</addr-line>
,<institution>University of Washington</institution>
,<addr-line>Seattle, WA</addr-line>
,<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Shears, Deborah" sort="Shears, Deborah" uniqKey="Shears D" first="Deborah" last="Shears">Deborah Shears</name>
<affiliation wicri:level="1"><nlm:aff id="af13"><addr-line>Department of Clinical Genetics</addr-line>
,<institution>Oxford University Hospitals NHS Trust</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Stewart, Helen" sort="Stewart, Helen" uniqKey="Stewart H" first="Helen" last="Stewart">Helen Stewart</name>
<affiliation wicri:level="1"><nlm:aff id="af13"><addr-line>Department of Clinical Genetics</addr-line>
,<institution>Oxford University Hospitals NHS Trust</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kurian, Manju A" sort="Kurian, Manju A" uniqKey="Kurian M" first="Manju A." last="Kurian">Manju A. Kurian</name>
<affiliation wicri:level="1"><nlm:aff id="af6"><addr-line>Neurosciences Unit</addr-line>
,<institution>UCL-Institute of Child Health</institution>
,<addr-line>London</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Scheffer, Ingrid E" sort="Scheffer, Ingrid E" uniqKey="Scheffer I" first="Ingrid E." last="Scheffer">Ingrid E. Scheffer</name>
<affiliation wicri:level="1"><nlm:aff id="af10"><addr-line>Departments of Medicine and Paediatrics</addr-line>
,<institution>Florey Institute, The University of Melbourne, Austin Health and Royal Children's Hospital</institution>
,<addr-line>Melbourne, VIC</addr-line>
,<country>Australia</country>
,</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Blair, Edward" sort="Blair, Edward" uniqKey="Blair E" first="Edward" last="Blair">Edward Blair</name>
<affiliation wicri:level="1"><nlm:aff id="af13"><addr-line>Department of Clinical Genetics</addr-line>
,<institution>Oxford University Hospitals NHS Trust</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Donnelly, Peter" sort="Donnelly, Peter" uniqKey="Donnelly P" first="Peter" last="Donnelly">Peter Donnelly</name>
<affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Wellcome Trust Centre for Human Genetics</addr-line>
,<institution>University of Oxford</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kaczmarek, Leonard K" sort="Kaczmarek, Leonard K" uniqKey="Kaczmarek L" first="Leonard K." last="Kaczmarek">Leonard K. Kaczmarek</name>
<affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Departments of Cellular and Molecular Physiology and Pharmacology</addr-line>
,<institution>Yale University School of Medicine</institution>
,<addr-line>New Haven, CT</addr-line>
,<country>USA</country>
,</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Taylor, Jenny C" sort="Taylor, Jenny C" uniqKey="Taylor J" first="Jenny C." last="Taylor">Jenny C. Taylor</name>
<affiliation wicri:level="1"><nlm:aff id="af1"><addr-line>Wellcome Trust Centre for Human Genetics</addr-line>
,<institution>University of Oxford</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="af3"><institution>NIHR Biomedical Research Centre</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Human Molecular Genetics</title>
<idno type="ISSN">0964-6906</idno>
<idno type="eISSN">1460-2083</idno>
<imprint><date when="2014">2014</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found <italic>de novo</italic>
non-synonymous mutations in the genes <italic>KCNQ2</italic>
and <italic>SCN2A.</italic>
In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in <italic>KCNT1</italic>
, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in <italic>PIGQ</italic>
that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic <italic>de novo</italic>
mutations in <italic>CBL</italic>
and <italic>CSNK1G1</italic>
, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, <italic>KCNT1</italic>
and <italic>PIGQ</italic>
. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders.</p>
</div>
</front>
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<issn pub-type="ppub">0964-6906</issn>
<issn pub-type="epub">1460-2083</issn>
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<article-id pub-id-type="pmc">4030775</article-id>
<article-id pub-id-type="doi">10.1093/hmg/ddu030</article-id>
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</name>
<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af3">3</xref>
<xref ref-type="author-notes" rid="AN3">¶</xref>
<xref ref-type="corresp" rid="cor1">*</xref>
</contrib>
<aff id="af1"><label>1</label>
<addr-line>Wellcome Trust Centre for Human Genetics</addr-line>
,<institution>University of Oxford</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</aff>
<aff id="af2"><label>2</label>
<addr-line>Departments of Cellular and Molecular Physiology and Pharmacology</addr-line>
,<institution>Yale University School of Medicine</institution>
,<addr-line>New Haven, CT</addr-line>
,<country>USA</country>
,</aff>
<aff id="af3"><label>3</label>
<institution>NIHR Biomedical Research Centre</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</aff>
<aff id="af4"><label>4</label>
<addr-line>Department of Immunoregulation</addr-line>
,<institution>Research Institute for Microbial Diseases, Osaka University</institution>
,<addr-line>Osaka</addr-line>
,<country>Japan</country>
,</aff>
<aff id="af5"><label>5</label>
<addr-line>Department of Pediatrics, Division of Genetic Medicine</addr-line>
,<institution>University of Washington</institution>
,<addr-line>Seattle, WA</addr-line>
,<country>USA</country>
,</aff>
<aff id="af6"><label>6</label>
<addr-line>Neurosciences Unit</addr-line>
,<institution>UCL-Institute of Child Health</institution>
,<addr-line>London</addr-line>
,<country>UK</country>
,</aff>
<aff id="af7"><label>7</label>
<addr-line>Department of Neurology</addr-line>
,<institution>Great Ormond Street Hospital</institution>
,<addr-line>London</addr-line>
,<country>UK</country>
,</aff>
<aff id="af8"><label>8</label>
<addr-line>Department of Paediatric Neurology, Centre de Reference Epilepsies Rares</addr-line>
,<institution>Hôpital Necker-Enfants Malades</institution>
,<addr-line>Paris</addr-line>
,<country>France</country>
,</aff>
<aff id="af9"><label>9</label>
<institution>Illumina Inc.</institution>
,<addr-line>San Diego, CA</addr-line>
,<country>USA</country>
,</aff>
<aff id="af10"><label>10</label>
<addr-line>Departments of Medicine and Paediatrics</addr-line>
,<institution>Florey Institute, The University of Melbourne, Austin Health and Royal Children's Hospital</institution>
,<addr-line>Melbourne, VIC</addr-line>
,<country>Australia</country>
,</aff>
<aff id="af11"><label>11</label>
<addr-line>Department of Clinical Neurophysiology</addr-line>
,<institution>John Radcliffe Hospital</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
,</aff>
<aff id="af12"><label>12</label>
<addr-line>Department of Paediatrics</addr-line>
,<institution>Children's Hospital Oxford, John Radcliffe Hospital</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
</aff>
<aff id="af13"><label>13</label>
<addr-line>Department of Clinical Genetics</addr-line>
,<institution>Oxford University Hospitals NHS Trust</institution>
,<addr-line>Oxford</addr-line>
,<country>UK</country>
</aff>
</contrib-group>
<author-notes><corresp id="cor1"><label>*</label>
To whom correspondence should be addressed at: Genomic Medicine Theme, Oxford Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK. Tel: +44 1865287633; Fax: +44 1865287770; Email: <email>jenny@well.ox.ac.uk</email>
</corresp>
<fn id="AN1"><label>†</label>
<p>These authors contributed equally to this work.</p>
</fn>
<fn id="AN2"><label>‡</label>
<p>A full list of members is provided in the <ext-link ext-link-type="uri" xlink:href="http://hmg.oxfordjournals.org/lookup/suppl/doi:10.1093/hmg/ddu030/-/DC1">Supplementary Material.</ext-link>
</p>
</fn>
<fn id="AN3"><label>¶</label>
<p>These authors jointly directed this work.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><day>15</day>
<month>6</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epub"><day>25</day>
<month>1</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>25</day>
<month>1</month>
<year>2014</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
. </pmc-comment>
<volume>23</volume>
<issue>12</issue>
<fpage>3200</fpage>
<lpage>3211</lpage>
<history><date date-type="received"><day>20</day>
<month>9</month>
<year>2013</year>
</date>
<date date-type="accepted"><day>20</day>
<month>1</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>© The Author 2014. Published by Oxford University Press.</copyright-statement>
<copyright-year>2014</copyright-year>
<license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by/3.0/"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/3.0/">http://creativecommons.org/licenses/by/3.0/</ext-link>
), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:type="simple" xlink:href="ddu030.pdf"></self-uri>
<abstract><p>In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found <italic>de novo</italic>
non-synonymous mutations in the genes <italic>KCNQ2</italic>
and <italic>SCN2A.</italic>
In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in <italic>KCNT1</italic>
, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in <italic>PIGQ</italic>
that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic <italic>de novo</italic>
mutations in <italic>CBL</italic>
and <italic>CSNK1G1</italic>
, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, <italic>KCNT1</italic>
and <italic>PIGQ</italic>
. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders.</p>
</abstract>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Australie</li>
<li>France</li>
<li>Japon</li>
<li>Royaume-Uni</li>
<li>États-Unis</li>
</country>
</list>
<tree><country name="Royaume-Uni"><noRegion><name sortKey="Martin, Hilary C" sort="Martin, Hilary C" uniqKey="Martin H" first="Hilary C." last="Martin">Hilary C. Martin</name>
</noRegion>
<name sortKey="Blair, Edward" sort="Blair, Edward" uniqKey="Blair E" first="Edward" last="Blair">Edward Blair</name>
<name sortKey="Broxholme, John" sort="Broxholme, John" uniqKey="Broxholme J" first="John" last="Broxholme">John Broxholme</name>
<name sortKey="Cazier, Jean Baptiste" sort="Cazier, Jean Baptiste" uniqKey="Cazier J" first="Jean-Baptiste" last="Cazier">Jean-Baptiste Cazier</name>
<name sortKey="Copley, Richard R" sort="Copley, Richard R" uniqKey="Copley R" first="Richard R." last="Copley">Richard R. Copley</name>
<name sortKey="Copley, Richard R" sort="Copley, Richard R" uniqKey="Copley R" first="Richard R." last="Copley">Richard R. Copley</name>
<name sortKey="Donnelly, Peter" sort="Donnelly, Peter" uniqKey="Donnelly P" first="Peter" last="Donnelly">Peter Donnelly</name>
<name sortKey="Hudspith, Karl A" sort="Hudspith, Karl A" uniqKey="Hudspith K" first="Karl A." last="Hudspith">Karl A. Hudspith</name>
<name sortKey="Hudspith, Karl A" sort="Hudspith, Karl A" uniqKey="Hudspith K" first="Karl A." last="Hudspith">Karl A. Hudspith</name>
<name sortKey="Kanapin, Alexander" sort="Kanapin, Alexander" uniqKey="Kanapin A" first="Alexander" last="Kanapin">Alexander Kanapin</name>
<name sortKey="Kurian, Manju A" sort="Kurian, Manju A" uniqKey="Kurian M" first="Manju A." last="Kurian">Manju A. Kurian</name>
<name sortKey="Mcshane, Tony" sort="Mcshane, Tony" uniqKey="Mcshane T" first="Tony" last="Mcshane">Tony Mcshane</name>
<name sortKey="Mcvean, Gil" sort="Mcvean, Gil" uniqKey="Mcvean G" first="Gil" last="Mcvean">Gil Mcvean</name>
<name sortKey="Meyer, Esther" sort="Meyer, Esther" uniqKey="Meyer E" first="Esther" last="Meyer">Esther Meyer</name>
<name sortKey="Meyer, Esther" sort="Meyer, Esther" uniqKey="Meyer E" first="Esther" last="Meyer">Esther Meyer</name>
<name sortKey="Pagnamenta, Alistair T" sort="Pagnamenta, Alistair T" uniqKey="Pagnamenta A" first="Alistair T." last="Pagnamenta">Alistair T. Pagnamenta</name>
<name sortKey="Pagnamenta, Alistair T" sort="Pagnamenta, Alistair T" uniqKey="Pagnamenta A" first="Alistair T." last="Pagnamenta">Alistair T. Pagnamenta</name>
<name sortKey="Rimmer, Andrew" sort="Rimmer, Andrew" uniqKey="Rimmer A" first="Andrew" last="Rimmer">Andrew Rimmer</name>
<name sortKey="Shears, Deborah" sort="Shears, Deborah" uniqKey="Shears D" first="Deborah" last="Shears">Deborah Shears</name>
<name sortKey="Stewart, Helen" sort="Stewart, Helen" uniqKey="Stewart H" first="Helen" last="Stewart">Helen Stewart</name>
<name sortKey="Taylor, Jenny C" sort="Taylor, Jenny C" uniqKey="Taylor J" first="Jenny C." last="Taylor">Jenny C. Taylor</name>
<name sortKey="Taylor, Jenny C" sort="Taylor, Jenny C" uniqKey="Taylor J" first="Jenny C." last="Taylor">Jenny C. Taylor</name>
<name sortKey="Zaiwalla, Zenobia" sort="Zaiwalla, Zenobia" uniqKey="Zaiwalla Z" first="Zenobia" last="Zaiwalla">Zenobia Zaiwalla</name>
</country>
<country name="États-Unis"><noRegion><name sortKey="Kim, Grace E" sort="Kim, Grace E" uniqKey="Kim G" first="Grace E." last="Kim">Grace E. Kim</name>
</noRegion>
<name sortKey="Bentley, David" sort="Bentley, David" uniqKey="Bentley D" first="David" last="Bentley">David Bentley</name>
<name sortKey="Brown, Maile R" sort="Brown, Maile R" uniqKey="Brown M" first="Maile R." last="Brown">Maile R. Brown</name>
<name sortKey="Carvill, Gemma L" sort="Carvill, Gemma L" uniqKey="Carvill G" first="Gemma L." last="Carvill">Gemma L. Carvill</name>
<name sortKey="Fleming, Matthew R" sort="Fleming, Matthew R" uniqKey="Fleming M" first="Matthew R." last="Fleming">Matthew R. Fleming</name>
<name sortKey="Kaczmarek, Leonard K" sort="Kaczmarek, Leonard K" uniqKey="Kaczmarek L" first="Leonard K." last="Kaczmarek">Leonard K. Kaczmarek</name>
<name sortKey="Kronengold, Jack" sort="Kronengold, Jack" uniqKey="Kronengold J" first="Jack" last="Kronengold">Jack Kronengold</name>
<name sortKey="Mefford, Heather C" sort="Mefford, Heather C" uniqKey="Mefford H" first="Heather C." last="Mefford">Heather C. Mefford</name>
</country>
<country name="Japon"><noRegion><name sortKey="Murakami, Yoshiko" sort="Murakami, Yoshiko" uniqKey="Murakami Y" first="Yoshiko" last="Murakami">Yoshiko Murakami</name>
</noRegion>
<name sortKey="Kinoshita, Taroh" sort="Kinoshita, Taroh" uniqKey="Kinoshita T" first="Taroh" last="Kinoshita">Taroh Kinoshita</name>
</country>
<country name="France"><noRegion><name sortKey="Barcia, Giulia" sort="Barcia, Giulia" uniqKey="Barcia G" first="Giulia" last="Barcia">Giulia Barcia</name>
</noRegion>
<name sortKey="Nabbout, Rima" sort="Nabbout, Rima" uniqKey="Nabbout R" first="Rima" last="Nabbout">Rima Nabbout</name>
</country>
<country name="Australie"><noRegion><name sortKey="Heavin, Sinead" sort="Heavin, Sinead" uniqKey="Heavin S" first="Sinéad" last="Heavin">Sinéad Heavin</name>
</noRegion>
<name sortKey="Scheffer, Ingrid E" sort="Scheffer, Ingrid E" uniqKey="Scheffer I" first="Ingrid E." last="Scheffer">Ingrid E. Scheffer</name>
</country>
</tree>
</affiliations>
</record>
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