Association of a synonymous SCN1B variant affecting splicing efficiency with Benign Familial Infantile Epilepsy (BFIE)

•In a large BFIE family, whole genome linkage analysis showed significant linkage to chromosome 19p12-q13 with a LOD score of 3.48.•Sequence analysis of the SCN1B gene, identified a synonymous variant c.492T>C/p.Tyr164Tyr segregating with the disease phenotype and affecting splicing efficiency.•WES analysis identified a common PRRT2 c.649dupC/Arg217Profs*8 mutation, showing incomplete penetrance with the disease in the family.•Synonymous SCN1B variant most probably contributes to the BFIE phenotype as part of an oligogenic predisposition or as a modifier.•Signifies the importance of evaluation of potentially pathogenic effects of synonymous variants.

Benign Familial Infantile Epilepsy (BFIE) is clinically characterized by clusters of brief partial seizures progressing to secondarily generalized seizures with onset at the age of 3-7 months and with favorable outcome. PRRT2 mutations are the most common cause of BFIE, and found in about 80% of BFIE families. In this study, we analyzed a large multiplex BFIE family by linkage and whole exome sequencing (WES) analyses. Genome-wide linkage analysis revealed significant evidence for linkage in the chromosomal region 19p12-q13 (LOD score 3.48). Mutation screening of positional candidate genes identified a synonymous SCN1B variant (c.492T>C, p.Tyr164Tyr) affecting splicing by the removal of a splicing silencer sequence, shown by in silico analysis, as the most likely causative mutation. In addition, the PRRT2 frameshift mutation (c.649dupC/p.Arg217Profs*8) was observed, showing incomplete, but high segregation with the phenotype. In vitro splicing assay of SCN1B expression confirmed the in silico findings showing a splicing imbalance between wild type and mutant exons. Herein, the involvement of the SCN1B gene in the etiology of BFIE, contributing to the disease phenotype as a modifier or part of an oligogenic predisposition, is shown for the first time.