Multiplex families with epilepsy: Success of clinical and molecular genetic characterization

Abstract

Objective: To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis.

Methods: 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.

Results: 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., SCN1A, KCNQ2, CSTB), but in 11 families, this cohort contributed to the initial discovery (e.g., KCNT1, PCDH19, TBC1D24). We expand the phenotypic spectrum of established epilepsy genes by reporting a familial LAMC3 homozygous variant, where the predominant phenotype was epilepsy with myoclonic-atonic seizures, and a pathogenic SCN1A variant in a family where in 5 siblings the phenotype was broadly consistent with Dravet syndrome, a disorder that usually occurs sporadically.

Conclusion: 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.

Figure 1. Understanding the genetic architecture to the epilepsies; variant segregation in select pedigrees

Family pedigrees with molecular findings that contribute to our understanding of the genetic basis to mixed epilepsy families (A: families A–E) with both chance occurrence and variable expressivity evident. Three families with likely susceptibility variants (B: families F–H) support the concept of an epileptic diathesis that presumably has a polygenic basis. *Family data used from previous publications; see table e-2 for full references. Family A: Heron et al. (2007) J Med Genet; pedigree A. Family B: Afawi et al. (2010) Epilepsia. Family C: Harkin et al. (2007) Brain; patient 48. Family D: Berkovic et al. (2004) Neurology; pedigree ref A. Family E: Arsov, Mullen et al. (2012) Ann Neurol; pedigree ref B. Family G: Arsov, Mullen et al. (2012) Ann Neurol; pedigree ref G. Family H: Heron et al. (2004) Ann Neurol; pedigree ref A.

Figure 2. Special family with occipital dysplasia due to LAMC3 mutation

LAMC3-positive family pedigree and MRI from IV-13 show occipital dysplasia (white arrows). The primary clinical presentation in this family was that of epilepsy with myoclonic-atonic seizures.

Figure 3. Unclassified family with SCN1A mutation

SCN1A-positive family pedigree with limited electroclinical data. The phenotype was broadly consistent with Dravet syndrome in severe cases.