Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.
Identifieur interne : 003715 ( PubMed/Corpus ); précédent : 003714; suivant : 003716Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.
Auteurs : Hilary C. Martin ; Grace E. Kim ; Alistair T. Pagnamenta ; Yoshiko Murakami ; Gemma L. Carvill ; Esther Meyer ; Richard R. Copley ; Andrew Rimmer ; Giulia Barcia ; Matthew R. Fleming ; Jack Kronengold ; Maile R. Brown ; Karl A. Hudspith ; John Broxholme ; Alexander Kanapin ; Jean-Baptiste Cazier ; Taroh Kinoshita ; Rima Nabbout ; David Bentley ; Gil Mcvean ; Sinéad Heavin ; Zenobia Zaiwalla ; Tony Mcshane ; Heather C. Mefford ; Deborah Shears ; Helen Stewart ; Manju A. Kurian ; Ingrid E. Scheffer ; Edward Blair ; Peter Donnelly ; Leonard K. Kaczmarek ; Jenny C. TaylorSource :
- Human molecular genetics [ 1460-2083 ] ; 2014.
English descriptors
- KwdEn :
- Child, Child, Preschool, Chromosomes, Human, Pair 9, Epilepsy (diagnosis), Epilepsy (genetics), Epilepsy (pathology), Genetic Predisposition to Disease, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Humans, KCNQ2 Potassium Channel (genetics), Male, Membrane Proteins (genetics), Mutation, NAV1.2 Voltage-Gated Sodium Channel (genetics), Nerve Tissue Proteins (genetics), Pathology, Molecular, Potassium Channels (genetics), Proto-Oncogene Proteins c-cbl (genetics), Uniparental Disomy, Young Adult.
- MESH :
- chemical , genetics : KCNQ2 Potassium Channel, Membrane Proteins, NAV1.2 Voltage-Gated Sodium Channel, Nerve Tissue Proteins, Potassium Channels, Proto-Oncogene Proteins c-cbl.
- diagnosis : Epilepsy.
- genetics : Epilepsy.
- pathology : Epilepsy.
- Child, Child, Preschool, Chromosomes, Human, Pair 9, Genetic Predisposition to Disease, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Humans, Male, Mutation, Pathology, Molecular, Uniparental Disomy, Young Adult.
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 de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. 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.
DOI: 10.1093/hmg/ddu030
PubMed: 24463883
Links to Exploration step
pubmed:24463883Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.</title><author><name sortKey="Martin, Hilary C" sort="Martin, Hilary C" uniqKey="Martin H" first="Hilary C" last="Martin">Hilary C. Martin</name><affiliation><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</nlm:affiliation></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><nlm:affiliation>Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.</nlm:affiliation></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><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Murakami, Yoshiko" sort="Murakami, Yoshiko" uniqKey="Murakami Y" first="Yoshiko" last="Murakami">Yoshiko Murakami</name><affiliation><nlm:affiliation>Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.</nlm:affiliation></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><nlm:affiliation>Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Meyer, Esther" sort="Meyer, Esther" uniqKey="Meyer E" first="Esther" last="Meyer">Esther Meyer</name><affiliation><nlm:affiliation>Neurosciences Unit, UCL-Institute of Child Health, London, UK, Department of Neurology, Great Ormond Street Hospital, London, UK.</nlm:affiliation></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><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Rimmer, Andrew" sort="Rimmer, Andrew" uniqKey="Rimmer A" first="Andrew" last="Rimmer">Andrew Rimmer</name><affiliation><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Barcia, Giulia" sort="Barcia, Giulia" uniqKey="Barcia G" first="Giulia" last="Barcia">Giulia Barcia</name><affiliation><nlm:affiliation>Department of Paediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Paris, France.</nlm:affiliation></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><nlm:affiliation>Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Kronengold, Jack" sort="Kronengold, Jack" uniqKey="Kronengold J" first="Jack" last="Kronengold">Jack Kronengold</name><affiliation><nlm:affiliation>Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.</nlm:affiliation></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><nlm:affiliation>Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.</nlm:affiliation></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><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Broxholme, John" sort="Broxholme, John" uniqKey="Broxholme J" first="John" last="Broxholme">John Broxholme</name><affiliation><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Kanapin, Alexander" sort="Kanapin, Alexander" uniqKey="Kanapin A" first="Alexander" last="Kanapin">Alexander Kanapin</name><affiliation><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</nlm:affiliation></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><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Kinoshita, Taroh" sort="Kinoshita, Taroh" uniqKey="Kinoshita T" first="Taroh" last="Kinoshita">Taroh Kinoshita</name><affiliation><nlm:affiliation>Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Nabbout, Rima" sort="Nabbout, Rima" uniqKey="Nabbout R" first="Rima" last="Nabbout">Rima Nabbout</name><affiliation><nlm:affiliation>Department of Paediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Bentley, David" sort="Bentley, David" uniqKey="Bentley D" first="David" last="Bentley">David Bentley</name><affiliation><nlm:affiliation>Illumina Inc., San Diego, CA, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mcvean, Gil" sort="Mcvean, Gil" uniqKey="Mcvean G" first="Gil" last="Mcvean">Gil Mcvean</name><affiliation><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Heavin, Sinead" sort="Heavin, Sinead" uniqKey="Heavin S" first="Sinéad" last="Heavin">Sinéad Heavin</name><affiliation><nlm:affiliation>Departments of Medicine and Paediatrics, Florey Institute, The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, VIC, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Zaiwalla, Zenobia" sort="Zaiwalla, Zenobia" uniqKey="Zaiwalla Z" first="Zenobia" last="Zaiwalla">Zenobia Zaiwalla</name><affiliation><nlm:affiliation>Department of Clinical Neurophysiology, John Radcliffe Hospital, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Mcshane, Tony" sort="Mcshane, Tony" uniqKey="Mcshane T" first="Tony" last="Mcshane">Tony Mcshane</name><affiliation><nlm:affiliation>Department of Paediatrics, Children's Hospital Oxford, John Radcliffe Hospital, Oxford, UK.</nlm:affiliation></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><nlm:affiliation>Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Shears, Deborah" sort="Shears, Deborah" uniqKey="Shears D" first="Deborah" last="Shears">Deborah Shears</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Stewart, Helen" sort="Stewart, Helen" uniqKey="Stewart H" first="Helen" last="Stewart">Helen Stewart</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.</nlm:affiliation></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><nlm:affiliation>Neurosciences Unit, UCL-Institute of Child Health, London, UK.</nlm:affiliation></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><nlm:affiliation>Departments of Medicine and Paediatrics, Florey Institute, The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, VIC, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Blair, Edward" sort="Blair, Edward" uniqKey="Blair E" first="Edward" last="Blair">Edward Blair</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Donnelly, Peter" sort="Donnelly, Peter" uniqKey="Donnelly P" first="Peter" last="Donnelly">Peter Donnelly</name><affiliation><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</nlm:affiliation></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><nlm:affiliation>Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.</nlm:affiliation></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><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK, jenny@well.ox.ac.uk.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2014">2014</date><idno type="RBID">pubmed:24463883</idno><idno type="pmid">24463883</idno><idno type="doi">10.1093/hmg/ddu030</idno><idno type="wicri:Area/PubMed/Corpus">003715</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">003715</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.</title><author><name sortKey="Martin, Hilary C" sort="Martin, Hilary C" uniqKey="Martin H" first="Hilary C" last="Martin">Hilary C. Martin</name><affiliation><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</nlm:affiliation></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><nlm:affiliation>Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.</nlm:affiliation></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><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Murakami, Yoshiko" sort="Murakami, Yoshiko" uniqKey="Murakami Y" first="Yoshiko" last="Murakami">Yoshiko Murakami</name><affiliation><nlm:affiliation>Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.</nlm:affiliation></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><nlm:affiliation>Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Meyer, Esther" sort="Meyer, Esther" uniqKey="Meyer E" first="Esther" last="Meyer">Esther Meyer</name><affiliation><nlm:affiliation>Neurosciences Unit, UCL-Institute of Child Health, London, UK, Department of Neurology, Great Ormond Street Hospital, London, UK.</nlm:affiliation></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><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Rimmer, Andrew" sort="Rimmer, Andrew" uniqKey="Rimmer A" first="Andrew" last="Rimmer">Andrew Rimmer</name><affiliation><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Barcia, Giulia" sort="Barcia, Giulia" uniqKey="Barcia G" first="Giulia" last="Barcia">Giulia Barcia</name><affiliation><nlm:affiliation>Department of Paediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Paris, France.</nlm:affiliation></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><nlm:affiliation>Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Kronengold, Jack" sort="Kronengold, Jack" uniqKey="Kronengold J" first="Jack" last="Kronengold">Jack Kronengold</name><affiliation><nlm:affiliation>Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.</nlm:affiliation></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><nlm:affiliation>Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.</nlm:affiliation></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><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Broxholme, John" sort="Broxholme, John" uniqKey="Broxholme J" first="John" last="Broxholme">John Broxholme</name><affiliation><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Kanapin, Alexander" sort="Kanapin, Alexander" uniqKey="Kanapin A" first="Alexander" last="Kanapin">Alexander Kanapin</name><affiliation><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</nlm:affiliation></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><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Kinoshita, Taroh" sort="Kinoshita, Taroh" uniqKey="Kinoshita T" first="Taroh" last="Kinoshita">Taroh Kinoshita</name><affiliation><nlm:affiliation>Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Nabbout, Rima" sort="Nabbout, Rima" uniqKey="Nabbout R" first="Rima" last="Nabbout">Rima Nabbout</name><affiliation><nlm:affiliation>Department of Paediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Bentley, David" sort="Bentley, David" uniqKey="Bentley D" first="David" last="Bentley">David Bentley</name><affiliation><nlm:affiliation>Illumina Inc., San Diego, CA, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Mcvean, Gil" sort="Mcvean, Gil" uniqKey="Mcvean G" first="Gil" last="Mcvean">Gil Mcvean</name><affiliation><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Heavin, Sinead" sort="Heavin, Sinead" uniqKey="Heavin S" first="Sinéad" last="Heavin">Sinéad Heavin</name><affiliation><nlm:affiliation>Departments of Medicine and Paediatrics, Florey Institute, The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, VIC, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Zaiwalla, Zenobia" sort="Zaiwalla, Zenobia" uniqKey="Zaiwalla Z" first="Zenobia" last="Zaiwalla">Zenobia Zaiwalla</name><affiliation><nlm:affiliation>Department of Clinical Neurophysiology, John Radcliffe Hospital, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Mcshane, Tony" sort="Mcshane, Tony" uniqKey="Mcshane T" first="Tony" last="Mcshane">Tony Mcshane</name><affiliation><nlm:affiliation>Department of Paediatrics, Children's Hospital Oxford, John Radcliffe Hospital, Oxford, UK.</nlm:affiliation></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><nlm:affiliation>Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Shears, Deborah" sort="Shears, Deborah" uniqKey="Shears D" first="Deborah" last="Shears">Deborah Shears</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Stewart, Helen" sort="Stewart, Helen" uniqKey="Stewart H" first="Helen" last="Stewart">Helen Stewart</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.</nlm:affiliation></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><nlm:affiliation>Neurosciences Unit, UCL-Institute of Child Health, London, UK.</nlm:affiliation></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><nlm:affiliation>Departments of Medicine and Paediatrics, Florey Institute, The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, VIC, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Blair, Edward" sort="Blair, Edward" uniqKey="Blair E" first="Edward" last="Blair">Edward Blair</name><affiliation><nlm:affiliation>Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Donnelly, Peter" sort="Donnelly, Peter" uniqKey="Donnelly P" first="Peter" last="Donnelly">Peter Donnelly</name><affiliation><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</nlm:affiliation></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><nlm:affiliation>Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.</nlm:affiliation></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><nlm:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK, jenny@well.ox.ac.uk.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Human molecular genetics</title><idno type="eISSN">1460-2083</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Child</term><term>Child, Preschool</term><term>Chromosomes, Human, Pair 9</term><term>Epilepsy (diagnosis)</term><term>Epilepsy (genetics)</term><term>Epilepsy (pathology)</term><term>Genetic Predisposition to Disease</term><term>Genome-Wide Association Study</term><term>High-Throughput Nucleotide Sequencing</term><term>Humans</term><term>KCNQ2 Potassium Channel (genetics)</term><term>Male</term><term>Membrane Proteins (genetics)</term><term>Mutation</term><term>NAV1.2 Voltage-Gated Sodium Channel (genetics)</term><term>Nerve Tissue Proteins (genetics)</term><term>Pathology, Molecular</term><term>Potassium Channels (genetics)</term><term>Proto-Oncogene Proteins c-cbl (genetics)</term><term>Uniparental Disomy</term><term>Young Adult</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>KCNQ2 Potassium Channel</term><term>Membrane Proteins</term><term>NAV1.2 Voltage-Gated Sodium Channel</term><term>Nerve Tissue Proteins</term><term>Potassium Channels</term><term>Proto-Oncogene Proteins c-cbl</term></keywords><keywords scheme="MESH" qualifier="diagnosis" xml:lang="en"><term>Epilepsy</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Epilepsy</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Epilepsy</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Child</term><term>Child, Preschool</term><term>Chromosomes, Human, Pair 9</term><term>Genetic Predisposition to Disease</term><term>Genome-Wide Association Study</term><term>High-Throughput Nucleotide Sequencing</term><term>Humans</term><term>Male</term><term>Mutation</term><term>Pathology, Molecular</term><term>Uniparental Disomy</term><term>Young Adult</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. 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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">24463883</PMID><DateCreated><Year>2014</Year><Month>05</Month><Day>23</Day></DateCreated><DateCompleted><Year>2015</Year><Month>01</Month><Day>12</Day></DateCompleted><DateRevised><Year>2017</Year><Month>09</Month><Day>22</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1460-2083</ISSN><JournalIssue CitedMedium="Internet"><Volume>23</Volume><Issue>12</Issue><PubDate><Year>2014</Year><Month>Jun</Month><Day>15</Day></PubDate></JournalIssue><Title>Human molecular genetics</Title><ISOAbbreviation>Hum. Mol. Genet.</ISOAbbreviation></Journal><ArticleTitle>Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.</ArticleTitle><Pagination><MedlinePgn>3200-11</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1093/hmg/ddu030</ELocationID><Abstract><AbstractText>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 de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. 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.</AbstractText><CopyrightInformation>© The Author 2014. Published by Oxford University Press.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Martin</LastName><ForeName>Hilary C</ForeName><Initials>HC</Initials><AffiliationInfo><Affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kim</LastName><ForeName>Grace E</ForeName><Initials>GE</Initials><AffiliationInfo><Affiliation>Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pagnamenta</LastName><ForeName>Alistair T</ForeName><Initials>AT</Initials><AffiliationInfo><Affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Murakami</LastName><ForeName>Yoshiko</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Carvill</LastName><ForeName>Gemma L</ForeName><Initials>GL</Initials><AffiliationInfo><Affiliation>Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Meyer</LastName><ForeName>Esther</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Neurosciences Unit, UCL-Institute of Child Health, London, UK, Department of Neurology, Great Ormond Street Hospital, London, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Copley</LastName><ForeName>Richard R</ForeName><Initials>RR</Initials><AffiliationInfo><Affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rimmer</LastName><ForeName>Andrew</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Barcia</LastName><ForeName>Giulia</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Department of Paediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fleming</LastName><ForeName>Matthew R</ForeName><Initials>MR</Initials><AffiliationInfo><Affiliation>Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kronengold</LastName><ForeName>Jack</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Brown</LastName><ForeName>Maile R</ForeName><Initials>MR</Initials><AffiliationInfo><Affiliation>Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hudspith</LastName><ForeName>Karl A</ForeName><Initials>KA</Initials><AffiliationInfo><Affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Broxholme</LastName><ForeName>John</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kanapin</LastName><ForeName>Alexander</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cazier</LastName><ForeName>Jean-Baptiste</ForeName><Initials>JB</Initials><AffiliationInfo><Affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kinoshita</LastName><ForeName>Taroh</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nabbout</LastName><ForeName>Rima</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Department of Paediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><CollectiveName>WGS500 Consortium</CollectiveName></Author><Author ValidYN="Y"><LastName>Bentley</LastName><ForeName>David</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Illumina Inc., San Diego, CA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>McVean</LastName><ForeName>Gil</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Heavin</LastName><ForeName>Sinéad</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Departments of Medicine and Paediatrics, Florey Institute, The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, VIC, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zaiwalla</LastName><ForeName>Zenobia</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>Department of Clinical Neurophysiology, John Radcliffe Hospital, Oxford, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>McShane</LastName><ForeName>Tony</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Department of Paediatrics, Children's Hospital Oxford, John Radcliffe Hospital, Oxford, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mefford</LastName><ForeName>Heather C</ForeName><Initials>HC</Initials><AffiliationInfo><Affiliation>Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shears</LastName><ForeName>Deborah</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stewart</LastName><ForeName>Helen</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kurian</LastName><ForeName>Manju A</ForeName><Initials>MA</Initials><AffiliationInfo><Affiliation>Neurosciences Unit, UCL-Institute of Child Health, London, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Scheffer</LastName><ForeName>Ingrid E</ForeName><Initials>IE</Initials><AffiliationInfo><Affiliation>Departments of Medicine and Paediatrics, Florey Institute, The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, VIC, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Blair</LastName><ForeName>Edward</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Donnelly</LastName><ForeName>Peter</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kaczmarek</LastName><ForeName>Leonard K</ForeName><Initials>LK</Initials><AffiliationInfo><Affiliation>Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Taylor</LastName><ForeName>Jenny C</ForeName><Initials>JC</Initials><AffiliationInfo><Affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK, jenny@well.ox.ac.uk.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>090532/Z/09/Z</GrantID><Agency>Wellcome Trust</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>095552</GrantID><Agency>Wellcome Trust</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>R01 HD067517</GrantID><Acronym>HD</Acronym><Agency>NICHD NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>095552/2/11/2</GrantID><Agency>Wellcome Trust</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>090532</GrantID><Agency>Wellcome Trust</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>HD067517</GrantID><Acronym>HD</Acronym><Agency>NICHD NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>MR/L016265/1</GrantID><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2014</Year><Month>01</Month><Day>25</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Hum Mol Genet</MedlineTA><NlmUniqueID>9208958</NlmUniqueID><ISSNLinking>0964-6906</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D051658">KCNQ2 Potassium Channel</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C496914">KCNQ2 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C585122">KCNT1 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008565">Membrane Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D062551">NAV1.2 Voltage-Gated Sodium Channel</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D009419">Nerve Tissue Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C484451">PIGQ protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D015221">Potassium Channels</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C568251">SCN2A protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.3.2.27</RegistryNumber><NameOfSubstance UI="D050721">Proto-Oncogene Proteins c-cbl</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 6.3.2.-</RegistryNumber><NameOfSubstance 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RefType="Cites"><RefSource>Neurology. 2010 Sep 28;75(13):1159-65</RefSource><PMID Version="1">20876469</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D002648" MajorTopicYN="N">Child</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002675" MajorTopicYN="N">Child, Preschool</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002899" MajorTopicYN="N">Chromosomes, Human, Pair 9</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004827" MajorTopicYN="N">Epilepsy</DescriptorName><QualifierName UI="Q000175" MajorTopicYN="N">diagnosis</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000473" MajorTopicYN="Y">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020022" MajorTopicYN="N">Genetic Predisposition to Disease</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D055106" MajorTopicYN="N">Genome-Wide 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