TY - JOUR T1 - The Spectrum of <em>de novo</em> Variants in Neurodevelopmental Disorders with Epilepsy JF - bioRxiv DO - 10.1101/123323 SP - 123323 AU - Henrike O. Heyne AU - EuroEPINOMICS RES Consortium AU - Rami Abou Jamra AU - Hande Caglayan AU - Dana Craiu AU - Peter De Jonghe AU - Renzo Guerrini AU - Katherine L. Helbig AU - Bobby P. C. Koeleman AU - Jack A. Kosmicki AU - Tarja Linnankivi AU - Patrick May AU - Hiltrud Muhle AU - Rikke S. Møller AU - Bernd A. Neubauer AU - Aarno Palotie AU - Manuela Pendziwiat AU - Hannah Stamberger AU - Pasquale Striano AU - Sha Tang AU - Sitao Wu AU - Mark Daly AU - Annapurna Poduri AU - Yvonne G. Weber AU - Sarah Weckhuysen AU - Sanjay M. Sisodiya AU - Ingo Helbig AU - Dennis Lal AU - Johannes R. Lemke Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/04/03/123323.abstract N2 - Neurodevelopmental disorders (NDD) with epilepsy constitute a complex and heterogeneous phenotypic spectrum of largely unclear genetic architecture. We conducted exome-wide enrichment analyses for protein-altering de novo variants (DNV) in 7088 parent-offspring trios with NDD of which 2151 were comorbid with epilepsy. In this cohort, the genetic spectrum of epileptic encephalopathy (EE) and nonspecific NDD with epilepsy were markedly similar. We identified 33 genes significantly enriched for DNV in NDD with epilepsy, of which 27.3% were associated with therapeutic consequences. These 33 DNV-enriched genes were more often associated with synaptic transmission but less with chromatin modification when compared to NDD without epilepsy. On average, only 53% of the DNV-enriched genes were represented on available diagnostic sequencing panels, so our findings should drive significant improvements of genetic testing approaches. ER -