De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies
PBN-AR
Instytucja
Instytut Matki i Dziecka
Źródłowe zdarzenia ewaluacyjne
Informacje podstawowe
Główny język publikacji
en
Czasopismo
AMERICAN JOURNAL OF HUMAN GENETICS
ISSN
0002-9297
EISSN
1537-6605
Wydawca
CELL PRESS
DOI
URL
Rok publikacji
2014
Numer zeszytu
4
Strony od-do
360-370
Numer tomu
95
Identyfikator DOI
Liczba arkuszy
Autorzy
(liczba autorów: 131)
Pozostali autorzy
+ 130
Słowa kluczowe
en
epileptic encephalopathies
infantile spasms
Lennox Gastaut syndrome
Streszczenia
Język
en
Treść
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.
Cechy publikacji
ORIGINAL_ARTICLE
Inne
System-identifier
586496
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