A novel splicing variant in FLNC gene responsible for a highly penetrant familial dilated cardiomyopathy in an extended Iranian family

Abstract

Recent achievements in the genetic diagnosis of Dilated Cardiomyopathy (DCM) have disclosed rare variants in numerous genes encoding different types of myocardial proteins. However, the causative gene underlying the pathogenesis of about 60% of familial cases with DCM has not been identified. One novel gene introduced in 2016 for cardiac-restricted DCM is FLNC. In this study, we applied Whole Exome Sequencing (WES) and bioinformatics-based methods to a member of an extended non-consanguineous family with DCM history accompanied with fatal arrhythmia in at least four consecutive generations. We found a novel splice-site mutation in FLNC gene (c.2389+1G>A) which cosegregated with all symptomatic individuals in the family. Computational prediction software tools as well as RT-PCR method were used to evaluate the impact of the FLNC splice site mutation. This substitution leads to exon 15th donor-site disruption and exon skipping, which would result in a premature stop codon three aminocids downstream of the mutation site. The aberrantly mRNA transcript can induce nonsense-mediated mRNA decay. Although carrier individuals show remarkable variable expression regarding the severity of DCM as well as the disease age of onset, a highly penetrant fatal arrhythmia was found to be shared between them. We strongly suggest that the involvement of FLNC gene, due to haploinsufficiency, should be considered in familial cases with DCM, especially if accompanied with arrhythmia and increased incidence of sudden cardiac death.

Keywords: FLNC gene; Familial dilated cardiomyopathy; Splicing mutation; Whole Exome Sequencing.