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Cited by 1,514Epilepsy research and treatmentGenomics and Rare DiseasesGenetics and Neurodevelopmental Disorders

De novo mutations in epileptic encephalopathies

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Epi4K Consortium, Epilepsy Phenome/Genome Project·2013·Nature
DOI 10.1038/nature12439PMC PMC3773011
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Abstract

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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  • LGS may occur with GOF and LOF CACNA1A variants.

    “LGS may occur with GOF and LOF CACNA1A variants 64,65 .”

    From Developmental and epileptic encephalopathies (2024) · cites this paper as [64]

    The paper’s Abstract (page unavailable) reports a de novo CACNA1A mutation in a cohort comprising patients with infantile spasms and LGS. It does not identify which diagnosis the CACNA1A carrier had or establish that both gain-of-function and loss-of-function CACNA1A variants may occur with LGS; its loss-of-function result concerns mutations across the cohort, not CACNA1A specifically. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • LOF variants in GABRA1, GABRA2, GABRB2 and GABRB3, which encode GABAA subunits, lead to decreased neuronal inhibition resulting in many DEE phenotypes.

    “LOF variants in GABRA1, GABRA2, GABRB2 and GABRB3, which encode GABAA subunits, lead to decreased neuronal inhibition resulting in many DEE phenotypes 64,[69][70][71][72] .”

    From Developmental and epileptic encephalopathies (2024) · cites this paper as [64]

    The section labeled “De novo mutations in the classic epileptic encephalopathies > Abstract” (page unavailable) reports GABA-receptor-subunit mutations in patients with epileptic encephalopathies, including GABRA1 and GABRB3, and implicates GABRB3 as a cause. It identifies GABRB1—not GABRA2 or GABRB2—as the third subunit gene observed. It does not establish that the cited variants are loss-of-function or demonstrate decreased neuronal inhibition as the mechanism. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • IQSEC2 is associated with DEEs; males are more severely affected than females with de novo pathogenic variants.

    “IQSEC2 is associated with DEEs; males are more severely affected than females with de novo pathogenic variants 64,111,112 .”

    From Developmental and epileptic encephalopathies (2024) · cites this paper as [64]

    The Abstract lists IQSEC2 among genes with de novo mutations in patients with epileptic encephalopathies, supporting its connection to DEEs. Our copy does not report that males with de novo pathogenic IQSEC2 variants are more severely affected than females. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • De novo heterozygous missense variants in GRIN1 cause a neonatal DEE with a hyperkinetic movement disorder, stereotypies and oculogyric crises.

    “De novo heterozygous missense variants cause a neonatal DEE with a hyperkinetic movement disorder, stereotypies and oculogyric crises 64,81 ; whereas, truncating heterozygous variants do not cause disease.”

    From Developmental and epileptic encephalopathies (2024) · cites this paper as [64]

    The paper’s Abstract (page not provided) lists GRIN1 among genes with de novo mutations in patients with infantile spasms or Lennox–Gastaut syndrome. It does not establish that GRIN1 missense variants cause the specified neonatal phenotype or report hyperkinetic movements, stereotypies, or oculogyric crises; the Additional Methods, ‘Study subjects’ (page not provided), say patients with neonatal seizures were excluded. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Whole-exome sequencing studies have found enrichment of FMRP targets among rare mutations in schizophrenia, intellectual disability, and epilepsy.

    “Additionally, whole-exome sequencing studies of other neurodevelopmental disorders have found enrichment for FMRP targets in rare mutations in schizophrenia81, intellectual disability68 and epilepsy78.”

    From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [78]

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Cites

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Research works printed but not linked: 30

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Authors
Epi4K Consortium, & Epilepsy Phenome/Genome Project
Affiliations
Duke University (US)
Corresponding author
Epilepsy Phenome/Genome Project
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2013-08-11
Volume
501
Issue
7466
Pages
217-221
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature12439
PMC
PMC3773011
OpenAlex
W1749057191
Cited by
1,514
References
35
Citations by year
2026: 45 · 2025: 64 · 2024: 89 · 2023: 73 · 2022: 98 · 2021: 113 · 2020: 157 · 2019: 111 · 2018: 134 · 2017: 171 · 2016: 153 · 2015: 150 · 2014: 138 · 2013: 14 · 2012: 1
FWCI
107.47
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion)
Funders
  • Citizens United for Research in Epilepsy
  • Finding A Cure for Epilepsy and Seizures
  • Dravet Syndrome Foundation
  • Epilepsy Society
  • National Institutes of Health (UL1TR000005, 5rc2ns070342-02)
  • University of California, San Francisco
  • National Institute of Allergy and Infectious Diseases (R56AI098588, U01AI067854)
  • National Institute of Neurological Disorders and Stroke (U01NS077303, NS077364, 1RC2NS070342, U01NS077364, NS077303, NS077276, NS053998, NS077274, U01NS077276, U01NS053998, U01NS077274)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
de novo mutations, epileptic encephalopathy, infantile spasms, Lennox-Gastaut syndrome, GABRB3, ALG13, exome sequencing, pediatric epilepsy, autism spectrum disorder, CACNA1A, CHD2, GRIN1, NR2B subunit, mTOR, NEDD4L
MeSH terms
Child Development Disorders, Pervasive, Female, Humans, Infant, Male, Intellectual Disability, Mutation, Probability, Receptors, GABA-A, Spasms, Infantile, Cohort Studies, N-Acetylglucosaminyltransferases, Genetic Predisposition to Disease, Fragile X Messenger Ribonucleoprotein 1, Exome, Mutation Rate, Lennox Gastaut Syndrome

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