Abstracts

Rationale: Recent gene discovery and genetic diagnosis in the epilepsies has focused on epileptic encephalopathies caused by de novo pathogenic variants. Familial epilepsies are presumably caused by genetic factors, yet the majority remain unexplained by known genetic causes. We performed systematic genetic analysis of a large cohort of familial epilepsies, including single nucleotide variants, copy number variants, and polygenic risk scores.

Methods: Familial epilepsies, defined as two or more affected first-degree relatives or three or more total affected relatives, were ascertained from epilepsy clinics in Israel. DNA samples were collected from affected and unaffected relatives in each family. Exome sequencing was performed on at least one affected individual per family. Variant pathogenicity was evaluated by ACMG criteria. Candidate variants were segregated by Sanger sequencing. Genome-wide microarray was performed for all available DNA samples and analyzed for pathogenic copy number variants and polygenic risk scores. Polygenic risk scores were derived from the largest epilepsy genome-wide association study and calculated for all sampled individuals in our cohort. Affected individuals were compared to their unaffected relatives using methods accounting for familial relatedness

Results: The cohort included 124 families, containing 541 affected individuals (median 3 affected individuals per family, range 2-17). DNA analysis included 382 affected and 372 unaffected relatives. Pathogenic variants were identified in 22/124 families (18%). These were single nucleotide variants in 19 families and recurrent copy number variants in 3 families. Candidate variants in established and candidate genes were identified in an additional 13/124 families (10%). Incomplete penetrance of pathogenic variants was common, with total aggregate penetrance 78% across all families. The number of affected individuals in a family was not associated with the likelihood of identifying a pathogenic variant (p = 0.97). Polygenic risk for generalized epilepsy was significantly higher in affected individuals compared to their unaffected relatives (OR 1.12, p = 0.04), and this enrichment in polygenic risk was strongest in the 36 families with generalized epilepsies (OR 1.41, p = 0.001). There was no difference in polygenic risk scores between solved versus unsolved families (OR = 1.05, p = 0.42).

Conclusions: Familial epilepsies have a substantial yield of identifiable genetic causes from a broad range of epilepsy-associated genes and copy number variants. These findings have clinical implications for genetic testing in familial epilepsies. Non-Mendelian forms of inheritance such as polygenic risk scores will advance our understanding of the complex genetic basis of familial epilepsies.

Funding: Please list any funding that was received in support of this abstract.: American Academy of Neurology, Hartwell Foundation, National Institute of Neurological Disorders and Stroke, German Research Foundation.