Multiplex families with epilepsy

Abstract

<h3>Objective:</h3> To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis. <h3>Methods:</h3> Following the referral of families with 2 or more relatives with epilepsy, individuals were classified into epilepsy syndromes. Families were classified into syndromes where at least 2 family members had a specific diagnosis. Pedigrees were analyzed and molecular genetic studies were performed as appropriate. <h3>Results:</h3> A total of 211 families were ascertained over an 11-year period in Israel. A total of 169 were classified into broad familial epilepsy syndrome groups: 61 generalized, 22 focal, 24 febrile seizure syndromes, 33 special syndromes, and 29 mixed. A total of 42 families remained unclassified. Pathogenic variants were identified in 49/211 families (23%). The majority were found in established epilepsy genes (e.g., <i>SCN1A</i>, <i>KCNQ2</i>, <i>CSTB</i>), but in 11 families, this cohort contributed to the initial discovery (e.g., <i>KCNT1</i>, <i>PCDH19</i>, <i>TBC1D24</i>). We expand the phenotypic spectrum of established epilepsy genes by reporting a familial <i>LAMC3</i> homozygous variant, where the predominant phenotype was epilepsy with myoclonic-atonic seizures, and a pathogenic <i>SCN1A</i> variant in a family where in 5 siblings the phenotype was broadly consistent with Dravet syndrome, a disorder that usually occurs sporadically. <h3>Conclusion:</h3> A total of 80% of families were successfully classified, with pathogenic variants identified in 23%. The successful characterization of familial electroclinical and inheritance patterns has highlighted the value of studying multiplex families and their contribution towards uncovering the genetic basis of the epilepsies.