De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies

Candace T. Myers, Jacinta M. McMahon, Amy L. Schneider, Slavé Petrovski, Andrew S. Allen, Gemma L. Carvill, Matthew Zemel, Julia E. Saykally, Amy J. LaCroix, Erin L. Heinzen, Georgina Hollingsworth, Marina Nikanorova, Mark Corbett, Jozef Gecz, David Coman, Jeremy Freeman, Sophie Calvert, Deepak Gill, Patrick Carney, Tally Lerman-SagieHugo Sampaio, Patrick Cossette, Norman Delanty, Dennis Dlugos, Evan E. Eichler, Michael P. Epstein, Tracy Glauser, Michael R. Johnson, Ruben Kuzniecky, Anthony G. Marson, Terence J. O'Brien, Ruth Ottman, Stephen Petrou, Annapurna Poduri, William O. Pickrell, Seo Kyung Chung, Mark I. Rees, Elliott Sherr, Lynette G. Sadleir, David B. Goldstein, Daniel H. Lowenstein, Rikke S. Møller, Samuel F. Berkovic, Ingrid E. Scheffer, Heather C. Mefford

Research output: Contribution to journalArticlepeer-review

190 Scopus citations


Epileptic encephalopathies (EEs) are the most clinically important group of severe early-onset epilepsies. Next-generation sequencing has highlighted the crucial contribution of de novo mutations to the genetic architecture of EEs as well as to their underlying genetic heterogeneity. Our previous whole-exome sequencing study of 264 parent-child trios revealed more than 290 candidate genes in which only a single individual had a de novo variant. We sought to identify additional pathogenic variants in a subset (n = 27) of these genes via targeted sequencing in an unsolved cohort of 531 individuals with a diverse range of EEs. We report 17 individuals with pathogenic variants in seven of the 27 genes, defining a genetic etiology in 3.2% of this unsolved cohort. Our results provide definitive evidence that de novo mutations in SLC1A2 and CACNA1A cause specific EEs and expand the compendium of clinically relevant genotypes for GABRB3. We also identified EEs caused by genetic variants in ALG13, DNM1, and GNAO1 and report a mutation in IQSEC2. Notably, recurrent mutations accounted for 7/17 of the pathogenic variants identified. As a result of high-depth coverage, parental mosaicism was identified in two out of 14 cases tested with mutant allelic fractions of 5%–6% in the unaffected parents, carrying significant reproductive counseling implications. These results confirm that dysregulation in diverse cellular neuronal pathways causes EEs, and they will inform the diagnosis and management of individuals with these devastating disorders.

Original languageEnglish (US)
Pages (from-to)287-298
Number of pages12
JournalAmerican journal of human genetics
Issue number2
StatePublished - Aug 4 2016

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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