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Variable epilepsy phenotypes associated with a familial intragenic deletion of the SCN1A gene
Author(s) -
Guerrini Renzo,
Cellini Elena,
Mei Davide,
Metitieri Tiziana,
Petrelli Cristina,
Pucatti Daniela,
Marini Carla,
Zamponi Nelia
Publication year - 2010
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1167.2010.02790.x
Subject(s) - dravet syndrome , genetics , phenotype , missense mutation , epilepsy , biology , loss function , haploinsufficiency , gene , haplotype , mutation , ube3a , allele , neuroscience , ubiquitin ligase , ubiquitin
Summary Deletions and duplications/amplifications of the α1‐sodium channel subunit ( SCN1A ) gene occur in about 12% of patients with Dravet syndrome (DS) who are otherwise mutation‐negative. Such genomic abnormalities cause loss of function, with severe phenotypes, reproductive disadvantage and, therefore, sporadic occurrence. Inherited mutations, occurring in ∼5% of patients with DS, are usually missense; transmission occurs from a mildly affected parent exhibiting febrile seizures (FS) or the generalized epilepsy with febrile seizures plus (GEFS+) spectrum. We identified an intragenic SCN1A deletion in a three‐generation, clinically heterogeneous family. Sequence analysis of SCN9A , a putative modifier, ruled out pathogenic mutations, variants, or putative disease–associated haplotype segregating with phenotype severity. Intrafamilial variability in phenotype severity indicates that SCN1A loss of function causes a phenotypic spectrum in which seizures precipitated by fever are prominent and schematic syndrome subdivisions would be inappropriate. SCN1A deletions should be ruled out even in individuals with mild phenotypes.