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

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 McVeanSinéad 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. Taylor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

196 Scopus citations


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 among500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1andPIGQ. It alsouncovers unexpected geneticmechanisms and emphasizes the power ofWGSas a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders.

Original languageEnglish (US)
Pages (from-to)3200-3211
Number of pages12
JournalHuman molecular genetics
Issue number12
StatePublished - Jun 15 2014

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Molecular Biology


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