Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy

Purpose We aimed to gain insight into frequencies of genetic variants in genes implicated in neurodevelopmental disorder with epilepsy (NDD+E) by investigating large cohorts of patients in a diagnostic setting. Methods We analyzed variants in NDD+E using epilepsy gene panel sequencing performed between 2013 and 2017 by two large diagnostic companies. We compared variant frequencies in 6,994 panels to other 8,588 recently published panels as well as exome-wide de novo variants in 1,942 individuals with NDD+E and 10,937 controls. Results Genes with highest frequencies of ultra-rare variants in NDD+E comprised SCN1A, KCNQ2, SCN2A, CDKL5, SCN8A and STXBP1 , concordant with the two other epilepsy cohorts we investigated. Only 46% of the analysed 262 dominant and X-linked panel genes contained ultra-rare variants in patients. Among genes with contradictory evidence of association with epilepsy CACNB4, CLCN2, EFHC1, GABRD, MAGI2 and SRPX2 showed equal frequencies in cases and controls. Conclusion We show that improvement of panel design increased diagnostic yield over time, but panels still display genes with low or no diagnostic yield. With our data, we hope to improve current diagnostic NDD+E panel design and provide a resource of ultra-rare variants in individuals with NDD+E to the community.