Variable epilepsy phenotypes associated with a familial intragenic deletion of the SCN1A gene

• Published in: Epilepsia (Copenhagen) Vol. 51; no. 12; pp. 2474 - 2477
• Main Authors: Guerrini, Renzo, Cellini, Elena, Mei, Davide, Metitieri, Tiziana, Petrelli, Cristina, Pucatti, Daniela, Marini, Carla, Zamponi, Nelia
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2010
• Subjects: Adult; Aged; Child; Dravet syndrome; Electroencephalography - statistics & numerical data; Epilepsies, Myoclonic - diagnosis; Epilepsies, Myoclonic - genetics; Epilepsy, Generalized - diagnosis; Epilepsy, Generalized - genetics; Family; Female; Gene Deletion; Genetic Heterogeneity; Heterozygote; Humans; Intrafamilial heterogeneity; Male; Middle Aged; MLPA; Mutation, Missense - genetics; NAV1.1 Voltage-Gated Sodium Channel; Nerve Tissue Proteins - genetics; Pedigree; Phenotype; SCN9A; Seizures; Seizures, Febrile - diagnosis; Seizures, Febrile - genetics; Sodium Channels - genetics
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/j.1528-1167.2010.02790.x

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.