De Novo Variants in Neurodevelopmental Disorders With Epilepsy
Abstract number :
1.393
Submission category :
12. Genetics / 12A. Human Studies
Year :
2018
Submission ID :
501472
Source :
www.aesnet.org
Presentation date :
12/1/2018 6:00:00 PM
Published date :
Nov 5, 2018, 18:00 PM
Authors :
Henrike Heyne, Massachusetts General Hospital; Tarjinder Singh, Massachusetts General Hospital; Hannah Stamberger, Epilepsy Research Centre, University of Melbourne, Austin Health; Annapurna Poduri, Boston Children's Hospital, Harvard Medical School; Yvon
Rationale: De novo variants (DNV) are genetic variants newly occurring in children and not present in either parent. It has been shown that DNV in specific genes contribute substantially to severe neurodevelopmental disorders (NDD), often comorbid with epilepsy. In this study, we systematically searched for genes associated with NDD with epilepsy in a cohort of 1942 individuals. Methods: We analyzed 6753 parent-offspring trios with severe NDD (88% of children had intellectual disability), focusing on 1942 individuals with epilepsy. We compared DNV in NDD with and without epilepsy to identify genetic differences between these phenotypic groups. We further investigated the potential impact of our findings on the design of genetic testing approaches and assessed the extent of therapeutically relevant diagnoses. Results: In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with significantly more DNV than expected by chance (p-value < 5x10-7). The genes SNAP25, GABRB2 and CACNA1E had previously only limited evidence for disease association. Comparing NDD with and without epilepsy, we found missense DNV, DNV in specific genes, age of recruitment and severity of intellectual disability to be significantly associated with epilepsy. 24 routinely used diagnostic epilepsy panels would only have detected on average 59% of DNV in the 33 genes with significant excess of DNV. We further found low evidence for disease association for 25 genes frequently used on diagnostic epilepsy panels. 5.3% of DNV in our study were in eight genes for which we could confirm therapeutic consequences. Conclusions: We generate hitherto sparse statistical evidence for implication of the genes SNAP25, GABRB2 and CACNA1E among others, in NDD with epilepsy. We demonstrate, that our results should greatly benefit currently available epilepsy diagnostics. Treatment consequence of genes with DNV in our study emphasize the importance of accurate genetic diagnosis in NDD with epilepsy. Funding: This work has been supported by the Eurocores program EuroEPINOMICS and grants from the German Research Foundation (DFG) and Institute for Science and Technology (IWT)-Flanders.