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

March 10, 2023

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

Abstract

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., HSGP2, FLNA 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.

  1. Institute of Human Genetics, University of Leipzig Medical Center, 4103 Leipzig, Germany.
  2. Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan.
  3. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  4. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  5. Division of General Biochemistry, Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, 04103, Leipzig, Germany.
  6. Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103, Leipzig, Germany.
  7. Pediatric Research Center, University Hospital for Children and Adolescents, Leipzig University, 04103, Leipzig, Germany.
  8. CeGaT GmbH, 72076, Tuebingen, Germany.
  9. Hertie-Institute for Clinical Brain Research, 72070, Tubingen, Germany.
  10. Cologne Center for Genomics, University of Cologne, 50937 Cologne, Germany.
  11. Hasso-Plattner-Institut for Digital Engineering, University of Potsdam, Potsdam, Germany.
  12. Hasso Plattner Institute at Mount Sinai, Mount Sinai School of Medicine, NY, US.
  13. Institute for Molecular Medicine Finland: FIMM, University of Helsinki, Helsinki, Finland.
  14. Center for Rare Diseases, University of Leipzig Medical Center, 4103 Leipzig, Germany.