The role of rare genetic variants enrichment in epilepsies of presumed genetic etiology

March 10, 2023

Linnaeus Bundalian 1Yin-Yuan Su 2Siwei Chen 3 4Akhil Velluva 5 6Anna Sophia Kirstein 7Antje Garten 7Saskia Biskup 8 9Florian Battke 8Dennis Lal 3 10Henrike O Heyne 4 11 12 13Konrad Platzer 1Chen-Ching Lin 2Johannes R Lemke 1 14Diana Le Duc 1 6Epi25 Collaborative


Previous studies suggested that severe epilepsies e.g., developmental and epileptic encephalopathies (DEE) are mainly caused by ultra-rare de novo genetic variants. For milder phenotypes, rare genetic variants could contribute to the phenotype. To determine the importance of rare variants for different epilepsy types, we analyzed a whole-exome sequencing cohort of 9,170 epilepsy-affected individuals and 8,436 controls. Here, we separately analyzed three different groups of epilepsies : severe DEEs, genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We required qualifying rare variants (QRVs) to occur in controls at a minor allele frequency ≤ 1:1,000, to be predicted as deleterious (CADD≥20), and to have an odds ratio in epilepsy cases ≥2. We identified genes enriched with QRVs in DEE (n=21), NAFE (n=72), and GGE (n=32) – the number of enriched genes are found greatest in NAFE and least in DEE. This suggests that rare variants may play a more important role for causality of NAFE than in DEE. Moreover, we found that QRV-carrying genes e.g., HSGP2FLNA or TNC are involved in structuring the brain extracellular matrix. The present study confirms an involvement of rare variants for NAFE, while in DEE and GGE, the contribution of such variants appears more limited.