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De novo mutations in epileptic encephalopathies.

Publication ,  Journal Article
Epi4K Consortium, ; Epilepsy Phenome/Genome Project, ; Allen, AS; Berkovic, SF; Cossette, P; Delanty, N; Dlugos, D; Eichler, EE; Epstein, MP ...
Published in: Nature
September 12, 2013

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.

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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

September 12, 2013

Volume

501

Issue

7466

Start / End Page

217 / 221

Location

England

Related Subject Headings

  • Spasms, Infantile
  • Receptors, GABA-A
  • Probability
  • N-Acetylglucosaminyltransferases
  • Mutation Rate
  • Mutation
  • Male
  • Lennox Gastaut Syndrome
  • Intellectual Disability
  • Infant
 

Citation

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Epi4K Consortium, ., Epilepsy Phenome/Genome Project, ., Allen, A. S., Berkovic, S. F., Cossette, P., Delanty, N., … Winawer, M. R. (2013). De novo mutations in epileptic encephalopathies. Nature, 501(7466), 217–221. https://doi.org/10.1038/nature12439
Epi4K Consortium, Melodie R., Melodie R. Epilepsy Phenome/Genome Project, Andrew S. Allen, Samuel F. Berkovic, Patrick Cossette, Norman Delanty, Dennis Dlugos, et al. “De novo mutations in epileptic encephalopathies.Nature 501, no. 7466 (September 12, 2013): 217–21. https://doi.org/10.1038/nature12439.
Epi4K Consortium, Epilepsy Phenome/Genome Project, Allen AS, Berkovic SF, Cossette P, Delanty N, et al. De novo mutations in epileptic encephalopathies. Nature. 2013 Sep 12;501(7466):217–21.
Epi4K Consortium, Melodie R., et al. “De novo mutations in epileptic encephalopathies.Nature, vol. 501, no. 7466, Sept. 2013, pp. 217–21. Pubmed, doi:10.1038/nature12439.
Epi4K Consortium, Epilepsy Phenome/Genome Project, Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, Epstein MP, Glauser T, Goldstein DB, Han Y, Heinzen EL, Hitomi Y, Howell KB, Johnson MR, Kuzniecky R, Lowenstein DH, Lu Y-F, Madou MRZ, Marson AG, Mefford HC, Esmaeeli Nieh S, O’Brien TJ, Ottman R, Petrovski S, Poduri A, Ruzzo EK, Scheffer IE, Sherr EH, Yuskaitis CJ, Abou-Khalil B, Alldredge BK, Bautista JF, Boro A, Cascino GD, Consalvo D, Crumrine P, Devinsky O, Fiol M, Fountain NB, French J, Friedman D, Geller EB, Glynn S, Haut SR, Hayward J, Helmers SL, Joshi S, Kanner A, Kirsch HE, Knowlton RC, Kossoff EH, Kuperman R, McGuire SM, Motika PV, Novotny EJ, Paolicchi JM, Parent JM, Park K, Shellhaas RA, Shih JJ, Singh R, Sirven J, Smith MC, Sullivan J, Lin Thio L, Venkat A, Vining EPG, Von Allmen GK, Weisenberg JL, Widdess-Walsh P, Winawer MR. De novo mutations in epileptic encephalopathies. Nature. 2013 Sep 12;501(7466):217–221.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

September 12, 2013

Volume

501

Issue

7466

Start / End Page

217 / 221

Location

England

Related Subject Headings

  • Spasms, Infantile
  • Receptors, GABA-A
  • Probability
  • N-Acetylglucosaminyltransferases
  • Mutation Rate
  • Mutation
  • Male
  • Lennox Gastaut Syndrome
  • Intellectual Disability
  • Infant