Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.
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.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Hilary C
HC
Martin
Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
Grace E
GE
Kim
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK.
Alistair T
AT
Pagnamenta
Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Yoshiko
Y
Murakami
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.
Gemma L
GL
Carvill
Neurosciences Unit, UCL-Institute of Child Health, London, UK, Department of Neurology, Great Ormond Street Hospital, London, UK.
Esther
E
Meyer
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK.
Richard R
RR
Copley
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Andrew
A
Rimmer
Department of Paediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Paris, France.
Giulia
G
Barcia
Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
Matthew R
MR
Fleming
Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
Jack
J
Kronengold
Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
Maile R
MR
Brown
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK.
Karl A
KA
Hudspith
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
John
J
Broxholme
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Alexander
A
Kanapin
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Jean-Baptiste
JB
Cazier
Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Taroh
T
Kinoshita
Department of Paediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Paris, France.
Rima
R
Nabbout
Illumina Inc., San Diego, CA, USA.
David
D
Bentley
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Gil
G
McVean
Departments of Medicine and Paediatrics, Florey Institute, The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, VIC, Australia.
Sinéad
S
Heavin
Department of Clinical Neurophysiology, John Radcliffe Hospital, Oxford, UK.
Zenobia
Z
Zaiwalla
Department of Paediatrics, Children's Hospital Oxford, John Radcliffe Hospital, Oxford, UK.
Tony
T
McShane
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.
Heather C
HC
Mefford
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
Deborah
D
Shears
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
Helen
H
Stewart
Neurosciences Unit, UCL-Institute of Child Health, London, UK.
Manju A
MA
Kurian
Departments of Medicine and Paediatrics, Florey Institute, The University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, VIC, Australia.
Ingrid E
IE
Scheffer
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
Edward
E
Blair
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Peter
P
Donnelly
Departments of Cellular and Molecular Physiology and Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
Leonard K
LK
Kaczmarek
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK, NIHR Biomedical Research Centre, Oxford, UK, jenny@well.ox.ac.uk.
Jenny C
JC
Taylor
D002648:Child; D002675:Child, Preschool; D002899:Chromosomes, Human, Pair 9; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D057089:Pathology, Molecular; D015221:Potassium Channels / Q000235:genetics*; D000081033:Potassium Channels, Sodium-Activated; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics; D024182:Uniparental Disomy; D055815:Young Adult
D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; C585122:KCNT1 protein, human; D008565:Membrane Proteins; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C484451:PIGQ protein, human; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated; C568251:SCN2A protein, human; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human