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Phenotypic analysis of 303 multiplex families with common epilepsies

Lookup NU author(s): Dr Douglas Crompton, Dr Rhys ThomasORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: 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.

Publication metadata

Author(s): Abou-Khalil B, Afawi Z, Allen AS, Bautista JF, Bellows ST, Berkovic SF, Bluvstein J, Burgess R, Cascino G, Cops EJ, Cossette P, Cristofaro S, Crompton DE, Delanty N, Devinsky O, Dlugos D, Epstein MP, Fountain NB, Freyer C, Garry SI, Geller EB, Glauser T, Glynn S, Goldberg-Stern H, Goldstein DB, Gravel M, Haas K, Haut S, Heinzen EL, Kirsch HE, Kivity S, Knowlton R, Korczyn AD, Kossoff E, Kuzniecky R, Loeb R, Lowenstein DH, Marson AG, McCormack M, McKenna K, Mefford HC, Motika P, Mullen SA, O'Brien TJ, Ottman R, Paolicchi J, Parent JM, Paterson S, Petrovski S, Pickrell WO, Poduri A, Rees MI, Sadleir LG, Scheffer IE, Shih J, Singh R, Sirven J, Smith M, Smith PEM, Thio LL, Thomas RH, Venkat A, Vining E, Von Allmen G, Weisenberg J, Widdess-Walsh P, Winawer MR

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2017

Volume: 140

Issue: 8

Pages: 2144-2156

Print publication date: 01/08/2017

Online publication date: 03/07/2017

Acceptance date: 24/04/2017

Date deposited: 08/09/2017

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press


DOI: 10.1093/brain/awx129


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Funder referenceFunder name
Epilepsy Research UK
National Institute of Hea lth grant (ID: U01NS077367)
National Institute of Social Ca re and Health Research
NHMRC Program Grant (ID: APP1091593; ID: 628952).
NIH grant R01 GM117946
Waterloo Foundation