Variable neurologic phenotype in a GEFS+ family with a novel mutation in SCN1A.
OBJECTIVE
To describe the spectrum of clinical disease in a mutliplex family with an autosomal dominant form of generalized epilepsy with febrile seizures plus (GEFS+) and determine its genetic etiology.


METHODS
Medical and family history was obtained on 11 clinically affected individuals and their relatives across three generations through medical chart review and home visits. A candidate gene approach including haplotype analysis and direct sequencing was used.


RESULTS
An epilepsy-associated haplotype was identified on 2q24. Direct sequencing of the entire SCN1A gene identified seven sequence variants. However, only one of these, c.1162 T>C, was not found in population controls. This transition in exon 8 of SCN1A predicts a substitution (Y388H) of a highly conserved tyrosine residue in the loop between transmembrane segments S5 and S6 of the sodium channel protein (Na(v)1.1). Clinical features in mutation carriers of this novel missense mutation were highly variable, ranging from febrile seizures to severe refractory epilepsy.


CONCLUSIONS
A novel missense mutation in the pore-forming region of the sodium channel gene SCN1A causes GEFS+ with a variable phenotype that includes mood and anxiety disorders, as well as ataxia, expanding the GEFS+ spectrum to include neuropsychiatric disease.
Mahoney
Krista
K
Clinical Epidemiology Unit, Faculty of Medicine, Memorial University, St. John's, NL, Canada. kmahoney@mun.ca
Moore
Susan J
SJ
Buckley
David
D
Alam
Muhammed
M
Parfrey
Patrick
P
Penney
Sharon
S
Merner
Nancy
N
Hodgkinson
Kathy
K
Young
Terry-Lynn
TL
D000328:Adult; D001007:Anxiety / Q000209:etiology / Q000235:genetics; D001259:Ataxia / Q000209:etiology / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004829:Epilepsy, Generalized / Q000150:complications / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D003294:Seizures, Febrile / Q000150:complications / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics*
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels