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

EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project, Epi4K Consortium

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)360-370
Number of pages11
JournalAmerican Journal of Human Genetics
Volume95
Issue number4
DOIs
StatePublished - 2014
Externally publishedYes

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Brain Diseases
Synaptic Transmission
Mutation
Genes
Exome
Infantile Spasms
Ion Channels
Cohort Studies

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Medicine(all)

Cite this

De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. / EuroEPINOMICS-RES Consortium; Epilepsy Phenome/Genome Project; Epi4K Consortium.

In: American Journal of Human Genetics, Vol. 95, No. 4, 2014, p. 360-370.

Research output: Contribution to journalArticle

EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project & Epi4K Consortium 2014, 'De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies', American Journal of Human Genetics, vol. 95, no. 4, pp. 360-370. https://doi.org/10.1016/j.ajhg.2014.08.013
EuroEPINOMICS-RES Consortium ; Epilepsy Phenome/Genome Project ; Epi4K Consortium. / De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. In: American Journal of Human Genetics. 2014 ; Vol. 95, No. 4. pp. 360-370.
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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.",
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T1 - De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies

AU - EuroEPINOMICS-RES Consortium

AU - Epilepsy Phenome/Genome Project

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AU - Appenzeller, Silke

AU - Balling, Rudi

AU - Barisic, Nina

AU - Baulac, Stéphanie

AU - Caglayan, Hande

AU - Craiu, Dana

AU - De Jonghe, Peter

AU - Depienne, Christel

AU - Dimova, Petia

AU - Djémié, Tania

AU - Gormley, Padhraig

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AU - Helbig, Ingo

AU - Hjalgrim, Helle

AU - Hoffman-Zacharska, Dorota

AU - Jähn, Johanna

AU - Klein, Karl Martin

AU - Koeleman, Bobby

AU - Komarek, Vladimir

AU - Krause, Roland

AU - Kuhlenbäumer, Gregor

AU - Leguern, Eric

AU - Lehesjoki, Anna Elina

AU - Lemke, Johannes R.

AU - Lerche, Holger

AU - Linnankivi, Tarja

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AU - May, Patrick

AU - Møller, Rikke S.

AU - Muhle, Hiltrud

AU - Pal, Deb

AU - Palotie, Aarno

AU - Pendziwiat, Manuela

AU - Robbiano, Angela

AU - Roelens, Filip

AU - Rosenow, Felix

AU - Selmer, Kaja

AU - Serratosa, Jose M.

AU - Sisodiya, Sanjay

AU - Stephani, Ulrich

AU - Sterbova, Katalin

AU - Striano, Pasquale

AU - Suls, Arvid

AU - Talvik, Tiina

AU - Von Spiczak, Sarah

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AU - Abou-Khalil, Bassel

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