Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy.

1. November 2019

Heyne HO1,2,3,4, ,Artomov M5,6,7, Battke F8, Bianchini C9, Smith DR10, Liebmann N11, Tadigotla V10, Stanley CM10, Lal D5,6,7,12, Rehm H13, Lerche H14, Daly MJ5,6,7, Helbig I15, Biskup S8, Weber YG1, Lemke JR16


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.

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 6994 panels with another 8588 recently published panels as well as exome-wide de novo variants in 1942 individuals with NDD+E and 10,937 controls.

Genes with highest frequencies of ultrarare variants in NDD+E comprised SCN1A, KCNQ2, SCN2A, CDKL5, SCN8A, and STXBP1, concordant with the two other epilepsy cohorts we investigated. In only 46% of the analyzed 262 dominant and X-linked panel genes ultrarare variants in patients were reported. Among genes with contradictory evidence of association with epilepsy, CACNB4, CLCN2, EFHC1, GABRD, MAGI2, and SRPX2 showed equal frequencies in cases and controls.

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 ultrarare variants in individuals with NDD+E to the community.

Mendelian genetics; clinical genetics, neurodevelopmental disorder; epilepsy; gene panel design