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Hum Mol Genet. 2014 Jun 15;23(12):3200-11. doi: 10.1093/hmg/ddu030. Epub 2014 Jan 25.

Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.

Author information

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK.
Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.
Neurosciences Unit, UCL-Institute of Child Health, London, UK, Department of Neurology, Great Ormond Street Hospital, London, UK.
Department of Paediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Paris, France.
Illumina Inc., San Diego, CA, USA.
Departments of Medicine and Paediatrics, Florey Institute, The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, VIC, Australia.
Department of Clinical Neurophysiology, John Radcliffe Hospital, Oxford, UK.
Department of Paediatrics, Children's Hospital Oxford, John Radcliffe Hospital, Oxford, UK.
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
Neurosciences Unit, UCL-Institute of Child Health, London, UK.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK,


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.

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