Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/12060
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dc.contributor.authorMartin, Hilary Cen
dc.contributor.authorKim, Grace Een
dc.contributor.authorPagnamenta, Alistair Ten
dc.contributor.authorMurakami, Yoshikoen
dc.contributor.authorCarvill, Gemma Len
dc.contributor.authorMeyer, Estheren
dc.contributor.authorCopley, Richard Ren
dc.contributor.authorRimmer, Andrewen
dc.contributor.authorBarcia, Giuliaen
dc.contributor.authorFleming, Matthew Ren
dc.contributor.authorKronengold, Jacken
dc.contributor.authorBrown, Maile Ren
dc.contributor.authorHudspith, Karl Aen
dc.contributor.authorBroxholme, Johnen
dc.contributor.authorKanapin, Alexanderen
dc.contributor.authorCazier, Jean-Baptisteen
dc.contributor.authorKinoshita, Tarohen
dc.contributor.authorNabbout, Rimaen
dc.contributor.authorBentley, Daviden
dc.contributor.authorMcVean, Gilen
dc.contributor.authorHeavin, Sinéaden
dc.contributor.authorZaiwalla, Zenobiaen
dc.contributor.authorMcShane, Tonyen
dc.contributor.authorMefford, Heather Cen
dc.contributor.authorShears, Deborahen
dc.contributor.authorStewart, Helenen
dc.contributor.authorKurian, Manju Aen
dc.contributor.authorScheffer, Ingrid Een
dc.contributor.authorBlair, Edwarden
dc.contributor.authorDonnelly, Peteren
dc.contributor.authorKaczmarek, Leonard Ken
dc.contributor.authorTaylor, Jenny Cen
dc.date.accessioned2015-05-16T01:42:21Z
dc.date.available2015-05-16T01:42:21Z
dc.date.issued2014-01-25en
dc.identifier.citationHuman Molecular Genetics 2014; 23(12): 3200-11en
dc.identifier.govdoc24463883en
dc.identifier.otherPUBMEDen
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/12060en
dc.description.abstractIn 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.en
dc.language.isoenen
dc.subject.otherChilden
dc.subject.otherChild, Preschoolen
dc.subject.otherChromosomes, Human, Pair 9en
dc.subject.otherEpilepsy.diagnosis.genetics.pathologyen
dc.subject.otherGenetic Predisposition to Diseaseen
dc.subject.otherGenome-Wide Association Studyen
dc.subject.otherHigh-Throughput Nucleotide Sequencingen
dc.subject.otherHumansen
dc.subject.otherKCNQ2 Potassium Channel.geneticsen
dc.subject.otherMaleen
dc.subject.otherMembrane Proteins.geneticsen
dc.subject.otherMutationen
dc.subject.otherNAV1.2 Voltage-Gated Sodium Channel.geneticsen
dc.subject.otherNerve Tissue Proteins.geneticsen
dc.subject.otherPathology, Molecularen
dc.subject.otherPotassium Channels.geneticsen
dc.subject.otherProto-Oncogene Proteins c-cbl.geneticsen
dc.subject.otherUniparental Disomyen
dc.subject.otherYoung Adulten
dc.titleClinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.en
dc.typeJournal Articleen
dc.identifier.journaltitleHuman molecular geneticsen
dc.identifier.affiliationDepartment of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UKen
dc.identifier.affiliationDepartment of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USAen
dc.identifier.affiliationDepartments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USAen
dc.identifier.affiliationDepartment of Clinical Neurophysiology, John Radcliffe Hospital, Oxford, UKen
dc.identifier.affiliationDepartment of Paediatrics, Children's Hospital Oxford, John Radcliffe Hospital, Oxford, UKen
dc.identifier.affiliationNeurosciences Unit, UCL-Institute of Child Health, London, UKen
dc.identifier.affiliationWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UKen
dc.identifier.affiliationNeurosciences Unit, UCL-Institute of Child Health, London, UK, Department of Neurology, Great Ormond Street Hospital, London, UKen
dc.identifier.affiliationWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UKen
dc.identifier.affiliationWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK, jenny@well.ox.ac.UKen
dc.identifier.affiliationIllumina Inc., San Diego, CA, USAen
dc.identifier.affiliationDepartments of Medicine and Paediatrics, Florey Institute, The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Victoria, Australiaen
dc.identifier.affiliationDepartment of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.en
dc.identifier.affiliationDepartment of Paediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Paris, France.en
dc.identifier.doi10.1093/hmg/ddu030en
dc.description.pages3200-11en
dc.relation.urlhttps://pubmed.ncbi.nlm.nih.gov/24463883en
dc.contributor.corpauthorWGS500 Consortiumen
dc.type.austinJournal Articleen
local.name.researcherScheffer, Ingrid E
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
item.fulltextNo Fulltext-
item.grantfulltextnone-
item.languageiso639-1en-
item.openairetypeJournal Article-
crisitem.author.deptEpilepsy Research Centre-
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