Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/12060
Title: Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.
Authors: Martin, Hilary C;Kim, Grace E;Pagnamenta, Alistair T;Murakami, Yoshiko;Carvill, Gemma L;Meyer, Esther;Copley, Richard R;Rimmer, Andrew;Barcia, Giulia;Fleming, Matthew R;Kronengold, Jack;Brown, Maile R;Hudspith, Karl A;Broxholme, John;Kanapin, Alexander;Cazier, Jean-Baptiste;Kinoshita, Taroh;Nabbout, Rima;Bentley, David;McVean, Gil;Heavin, Sinéad;Zaiwalla, Zenobia;McShane, Tony;Mefford, Heather C;Shears, Deborah;Stewart, Helen;Kurian, Manju A;Scheffer, Ingrid E;Blair, Edward;Donnelly, Peter;Kaczmarek, Leonard K;Taylor, Jenny C
Institutional Author: WGS500 Consortium
Affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Neurosciences Unit, UCL-Institute of Child Health, London, UK, Department of Neurology, Great Ormond Street Hospital, London, UK.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK.
Department of Paediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Paris, France.
Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
Illumina Inc., San Diego, CA, USA.
Department of Clinical Neurophysiology, John Radcliffe Hospital, Oxford, UK.
Department of Paediatrics, Children's Hospital Oxford, John Radcliffe Hospital, Oxford, UK.
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.
Neurosciences Unit, UCL-Institute of Child Health, London, UK.
Departments of Medicine and Paediatrics, Florey Institute, The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, VIC, Australia.
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK, jenny@well.ox.ac.uk.
Issue Date: 25-Jan-2014
Citation: Human Molecular Genetics 2014; 23(12): 3200-11
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.
Internal ID Number: 24463883
URI: http://ahro.austin.org.au/austinjspui/handle/1/12060
DOI: 10.1093/hmg/ddu030
URL: http://www.ncbi.nlm.nih.gov/pubmed/24463883
Type: Journal Article
Subjects: Child
Child, Preschool
Chromosomes, Human, Pair 9
Epilepsy.diagnosis.genetics.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
Appears in Collections:Journal articles

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