title: Variable epilepsy phenotypes associated with a familial intragenic deletion of the SCN1A gene.
abstract: 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.
authors.affiliation: Child Neurology Unit, Children's Hospital A. Meyer - University of Florence, Florence, Italy. r.guerrini@meyer.it
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Elena
authors.initials: E
authors.lastname: Cellini
authors.forename: Davide
authors.initials: D
authors.lastname: Mei
authors.forename: Tiziana
authors.initials: T
authors.lastname: Metitieri
authors.forename: Cristina
authors.initials: C
authors.lastname: Petrelli
authors.forename: Daniela
authors.initials: D
authors.lastname: Pucatti
authors.forename: Carla
authors.initials: C
authors.lastname: Marini
authors.forename: Nelia
authors.initials: N
authors.lastname: Zamponi
mesh_terms: D000328:Adult; D000368:Aged; D002648:Child; D004569:Electroencephalography / Q000706:statistics & numerical data; D004831:Epilepsies, Myoclonic / Q000175:diagnosis / Q000235:genetics; D004829:Epilepsy, Generalized / Q000175:diagnosis / Q000235:genetics*; D005190:Family; D005260:Female; D017353:Gene Deletion; D018740:Genetic Heterogeneity; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D003294:Seizures, Febrile / Q000175:diagnosis / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels