A recent study shows that 80% of multiplex families with epilepsy could be successfully classified into clinical syndromes using molecular genetics. Understanding the genetic component of epilepsy could strengthen genetic counseling and provide opportunity for improved intervention (Afawi Z, et al. Neurology. 2016;86:713-722).
Massively parallel gene-sequencing studies have already demonstrated the importance of gene mutations in the etiology of epilepsy, suggesting that many forms of epilepsy are likely to have a genetic basis. For example, idiopathic (genetic) generalized epilepsy is known to have a strong genetic component.
“A better understanding of the inheritance patterns underlying the common epilepsies, including those reported here, will assist strategies to understand the elusive molecular basis of common complex epilepsies,” particularly the genetic generalized epilepsies, suggested Zaid Afawi, MD, PhD, Tel Aviv University, Ramat Aviv, Israel, and colleagues.
Dr Afawi and colleagues conducted clinical interviews and genetic analyses of 211 families with ≥2 affected relatives with epilepsy to determine whether syndromes in individuals segregated in families: 857 family members had epilepsy.
Of the 211 families, 169 were classified into 5 broad familial epilepsy groups—generalized (N = 61), focal (N = 22), genetic epilepsy with febrile seizures plus and pure febrile seizures (N = 24), mixed (N = 29), and special (N = 33). Overall, 42 (20%) families remained unclassified.
“Variants deemed causative of the epilepsy syndrome were identified in 49/211 families,” noted the investigators. The majority of the variants were found in established epilepsy genes, including SCN1A, KCNQ2, and CSTB, “but in 11 families, this cohort contributed to the initial [gene] discovery (e.g., KCNT1, PCDH19, TBC1D24).”
Unexpected molecular genetic findings in 2 families led to an expanded phenotypic spectrum of 2 established genes, including a familial LAMC3 homozygous variant, where the predominant phenotype was epilepsy with myoclonic-atonic seizures, and an SCN1A pathogenic variant that was found in a family in 5 siblings in which the phenotype was broadly consistent with Dravet syndrome.
Of the classified families, 83% comprised affected relatives concordant for the same broad epilepsy group, which is consistent with syndromic groups being relatively distinct genetic entities.
Although the cohort involving family members with generalized epilepsy accounted for the largest number of families, genetic findings in this group were rare. Outside of this cohort, however, “considerable molecular success was realized, emphasizing the progress made for monogenic epilepsies and reinforcing the integration of genetic testing into standard clinical care practices,” Afawi and colleagues concluded. “As the revolutionary technology of massively parallel sequencing moves us toward large cohort studies, we expect intermediate-sized families will continue to contribute strongly to these efforts.”