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A follow-up study of a large Utah family with significant linkage to chromosome 2q24 led us to identify a new febrile seizure (FS) gene,  SCN9A  encoding Na v 1.7. In 21 affected members, we uncovered a potential mutation in a highly conserved amino acid, p.N641Y, in the large cytoplasmic loop between transmembrane domains I and II that was absent from 586 ethnically matched population control chromosomes. To establish a functional role for this mutation in seizure susceptibility, we introduced the orthologous mutation into the murine  Scn9a  ortholog using targeted homologous recombination. Compared to wild-type mice, homozygous  Scn9a   N641Y/N641Y  knockin mice exhibit significantly reduced thresholds to electrically induced clonic and tonic-clonic seizures, and increased corneal kindling acquisition rates. Together, these data strongly support the  SCN9A  p.N641Y mutation as disease-causing in this family. To confirm the role of  SCN9A  in FS, we analyzed a collection of 92 unrelated FS patients and identified additional highly conserved Na v 1.7 missense variants in 5% of the patients. After one of these children with FS later developed Dravet syndrome (severe myoclonic epilepsy of infancy), we sequenced the  SCN1A  gene, a gene known to be associated with Dravet syndrome, and identified a heterozygous frameshift mutation. Subsequent analysis of 109 Dravet syndrome patients yielded nine Na v 1.7 missense variants (8% of the patients), all in highly conserved amino acids. Six of these Dravet syndrome patients with  SCN9A  missense variants also harbored either missense or splice site  SCN1A  mutations and three had no  SCN1A  mutations. This study provides evidence for a role of  SCN9A  in human epilepsies, both as a cause of FS and as a partner with  SCN1A  mutations.

A Role of SCN9A in Human Epilepsies, As a Cause of Febrile Seizures and As a Potential Modifier of Dravet Syndrome