Phenotypic analysis of 303 multiplex families with common epilepsies

Abstract

Gene identification in epilepsy has mainly been limited to large families segregating genes of major effect and de novo mutations in epileptic encephalopathies. Many families that present with common non-acquired focal epilepsies and genetic generalized epilepsies remain unexplained. We assembled a cohort of 'genetically enriched' common epilepsies by collecting and phenotyping families containing multiple individuals with unprovoked seizures. We aimed to determine if specific clinical epilepsy features aggregate within families, and whether this segregation of phenotypes may constitute distinct 'familial syndromes' that could inform genomic analyses. Families with three or more individuals with unprovoked seizures were studied across multiple international centres. Affected individuals were phenotyped and classified according to specific electroclinical syndromes. Families were categorized based on syndromic groupings of affected family members, examined for pedigree structure and phenotypic patterns and, where possible, assigned specific familial epilepsy syndromes. A total of 303 families were assembled and analysed, comprising 1120 affected phenotyped individuals. Of the 303 families, 117 exclusively segregated generalized epilepsy, 62 focal epilepsy, and 22 were classified as genetic epilepsy with febrile seizures plus. Over one-third (102 families) were observed to have mixed epilepsy phenotypes: 78 had both generalized and focal epilepsy features within the same individual (n = 39), or within first or second degree relatives (n = 39). Among the genetic generalized epilepsy families, absence epilepsies were found to cluster within families independently of juvenile myoclonic epilepsy, and significantly more females were affected than males. Of the 62 familial focal epilepsy families, two previously undescribed familial focal syndrome patterns were evident: 15 families had posterior quadrant epilepsies, including seven with occipito-temporal localization and seven with temporo-parietal foci, and four families displayed familial focal epilepsy of childhood with multiple affected siblings that was suggestive of recessive inheritance. The findings suggest (i) specific patterns of syndromic familial aggregation occur, including newly recognized forms of familial focal epilepsy; (ii) although syndrome-specificity usually occurs in multiplex families, the one-third of families with features of both focal and generalized epilepsy is suggestive of shared genetic determinants; and (iii) patterns of features observed across families including pedigree structure, sex, and age of onset may hold clues for future gene identification. Such detailed phenotypic information will be invaluable in the conditioning and interpretation of forthcoming sequencing data to understand the genetic architecture and inter-relationships of the common epilepsy syndromes.

Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery

“…A role for such complex, non-Mendelian genetic factors in epilepsy has been hypothesised from epidemiological data, for example, the observation that most family pedigrees are not consistent with a monogenic (dominant or recessive) mechanism. 6 , 12 , 30…”

“…Individuals with and without epilepsy from families with epilepsy were ascertained from the Epi4K Consortium 12 and The University of Melbourne's Epilepsy Genetics Program. Singleton patients with epilepsy were also ascertained from the Epi4K Consortium and from tertiary hospitals in Australia, New Zealand and the US.…”

“…People with epilepsy who did not have a known family history of epilepsy were classified as sporadic. We further divided our familial group into individuals from multiplex families with ≥3 affected relatives (as defined previously) 12 versus individuals from non-multiplex families (with only two affected relatives) or a positive family history with unknown number of affected relatives.…”

Semantic Similarity Analysis Reveals Robust Gene-Disease Relationships in Developmental and Epileptic Encephalopathies

“…Description of the recruitment and phenotyping of the Epi4K dbGaP cohort (phs000653.v1.p1) has been reported previously. 24 , 25 …”

Exome sequencing in 57 patients with self-limited focal epilepsies of childhood with typical or atypical presentations suggests novel candidate genes

“…[4][5][6] The ongoing genetic dissection of epilepsy phenotypes, based on large datasets, necessarily modify our conceptual approach of epilepsies but also confirm the dichotomy: generalized versus focal; SFEC are clearly distinctive from other non-acquired focal epilepsies (NAFE) with onset in childhood, such as sleep-related hypermotor epilepsy or familial focal epilepsy with variable foci that usually do not have the same evolution with age. 7 Atypical SFEC exist having in common an age-specific seizure onset, a seizure resolution related to brain maturation, an absence of structural brain abnormalities, a rather characteristic EEG spike and wave element of variable expression, and a supposed genetic origin. Atypical Rolandic epilepsies cover atypical benign focal epilepsy of childhood (aBFEC), status of RE, Landau-Kleffner (LKS) and Continuous Spike-Wave during Sleep (CSWS) syndromes.…”