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

• DOI: 10.1101/2023.01.17.23284702
• Publication Date: 2023-01-19T00:55:19Z
• Authors: Linnaeus Bundalian; Yin-Yuan Su; Siwei Chen; Akhil Velluva; Anna Sophia Kirstein; Antje Garten; Saskia Biskup; Florian Battke; Dennis Lal; Henrike O. Heyne; Konrad Platzer; Chen-Ching Lin; Johannes R. Lemke; Diana Le Duc
• Keywords: Etiology

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 variants could contribute to the phenotype. To determine importance of for different epilepsy types, we analyzed a whole-exome sequencing cohort 9,170 epilepsy-affected individuals 8,436 controls. Here, separately three groups : DEEs, generalized (GGE), non-acquired focal (NAFE). We required qualifying (QRVs) occur in controls at minor allele frequency ≤ 1:1,000, be predicted as deleterious (CADD≥20), have an odds ratio cases ≥2. identified genes enriched with QRVs DEE (n=21), NAFE (n=72), GGE (n=32) - number found greatest least DEE. This suggests may play more important role causality than Moreover, QRV-carrying HSGP2, FLNA or TNC involved structuring brain extracellular matrix. The present study confirms involvement NAFE, while GGE, contribution such appears limited.