No association between SCN9A and monogenic human epilepsy disorders

Abstract

Many studies have demonstrated the clinical utility and importance of epilepsy gene panel testing to confirm the specific aetiology of disease, enable appropriate therapeutic interventions, and inform accurate family counselling. Previously, SCN9A gene variants, in particular a c.1921A>T p.(Asn641Tyr) substitution, have been identified as a likely autosomal dominant cause of febrile seizures/febrile seizures plus and other monogenic seizure phenotypes indistinguishable from those associated with SCN1A, leading to inclusion of SCN9A on epilepsy gene testing panels. Here we present serendipitous findings of genetic studies that identify the SCN9A c.1921A>T p.(Asn641Tyr) variant at high frequency in the Amish community in the absence of such seizure phenotypes. Together with findings in UK Biobank these data refute an association of SCN9A with epilepsy, which has important clinical diagnostic implications.

Fig 1. Family pedigrees showing SCN9A NM_002977 c.1921A>T p.(Asn641Tyr) genotype data.

(A). Kinship 1: A simplified pedigree of the extended Amish family investigated, showing relationships between 18 distantly related individuals found to be heterozygous for the SCN9A p.(Asn641Tyr) variant. Individuals shaded black are affected with afebrile seizures. Kinship 2: An additional Amish family comprising of one individual with no history of seizures for whom exome data was available, found to be heterozygous for the SCN9A p.(Asn641Tyr) variant (II:1). Kinships 1 and 2 likely share common ancestry, but could not be connected through available records. Genotype is shown under individuals (variant: +, wild type: -). (B). Electropherogram showing the DNA sequence at the position of SCN9A c.1921A>T in a heterozygous individual.