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Am J Hum Genet. 2014 Oct 2;95(4):360-70. doi: 10.1016/j.ajhg.2014.08.013. Epub 2014 Sep 25.

De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies.

Collaborators (131)

Appenzeller S, Balling R, Barisic N, Baulac S, Caglayan H, Craiu D, De Jonghe P, Depienne C, Dimova P, Djémié T, Gormley P, Guerrini R, Helbig I, Hjalgrim H, Hoffman-Zacharska D, Jähn J, Klein KM, Koeleman B, Komarek V, Krause R, Kuhlenbäumer G, Leguern E, Lehesjoki AE, Lemke JR, Lerche H, Linnankivi T, Marini C, May P, Møller RS, Muhle H, Pal D, Palotie A, Pendziwiat M, Robbiano A, Roelens F, Rosenow F, Selmer K, Serratosa JM, Sisodiya S, Stephani U, Sterbova K, Striano P, Suls A, Talvik T, von Spiczak S, Weber Y, Weckhuysen S, Zara F, Abou-Khalil B, Alldredge BK, Andermann E, Andermann F, Amrom D, Bautista JF, Berkovic SF, Bluvstein J, Boro A, Cascino G, Consalvo D, Crumrine P, Devinsky O, Dlugos D, Epstein MP, Fiol M, Fountain NB, French J, Friedman D, Geller EB, Glauser T, Glynn S, Haas K, Haut SR, Hayward J, Helmers SL, Joshi S, Kanner A, Kirsch HE, Knowlton RC, Kossoff EH, Kuperman R, Kuzniecky R, Lowenstein DH, McGuire SM, Motika PV, Novotny EJ, Ottman R, Paolicchi JM, Parent J, Park K, Poduri A, Sadleir L, Scheffer IE, Shellhaas RA, Sherr E, Shih JJ, Singh R, Sirven J, Smith MC, Sullivan J, Thio LL, Venkat A, Vining EP, Von Allmen GK, Weisenberg JL, Widdess-Walsh P, Winawer MR, Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, Epstein MP, Glauser T, Goldstein DB, Han Y, Heinzen EL, Johnson MR, Kuzniecky R, Lowenstein DH, Marson AG, Mefford HC, Nieh SE, O'Brien TJ, Ottman R, Petrou S, Petrovski S, Poduri A, Ruzzo EK, Scheffer IE, Sherr E.

Abstract

Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10(-4)), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.

PMID:
25262651
PMCID:
PMC4185114
DOI:
10.1016/j.ajhg.2014.08.013
[Indexed for MEDLINE]
Free PMC Article

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