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De novo variants in neurodevelopmental disorders with epilepsy.

Henrike O HeyneTarjinder SinghHannah StambergerRami Abou JamraHande CaglayanDana CraiuPeter De JongheRenzo GuerriniKatherine L HelbigBobby P C KoelemanJack A KosmickiTarja LinnankiviPatrick MayHiltrud MuhleRikke S MøllerBernd A NeubauerAarno PalotieManuela PendziwiatPasquale StrianoSha TangSitao Wunull nullAnnapurna PoduriYvonne G WeberSarah WeckhuysenSanjay M SisodiyaMark J DalyIngo HelbigDennis LalJohannes R Lemke
Published in: Nature genetics (2018)
Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent-offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.
Keyphrases
  • intellectual disability
  • genome wide
  • copy number
  • metabolic syndrome
  • type diabetes
  • genome wide identification
  • high fat diet
  • high resolution
  • neural network