Epilepsies of presumed genetic etiology show enrichment of rare variants that occur in the general population

June 22, 2023

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

Abstract

Previous studies suggested that severe epilepsies, e.g., developmental and epileptic encephalopathies (DEEs), are mainly caused by ultra-rare de novo genetic variants. For milder disease, 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 control individuals. 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 control individuals with an allele count ≥ 1 and a minor allele frequency ≤ 1:1,000, to be predicted as deleterious (CADD ≥ 20), and to have an odds ratio in individuals with epilepsy ≥ 2. We identified genes enriched with QRVs primarily in NAFE (n = 72), followed by GGE (n = 32) and DEE (n = 21). This suggests that rare variants may play a more important role for causality of NAFE than for DEE. Moreover, we found that genes harboring QRVs, e.g., HSGP2, FLNA, or TNC, encode proteins that are involved in structuring the brain extracellular matrix. The present study confirms an involvement of rare variants for NAFE that occur also in the general population, while in DEE and GGE, the contribution of such variants appears more limited.

Keywords: NAFE; epilepsy; rare genetic variants.

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