Background: non-syndromic dilated cardiomyopathy (DCM) is found to correlate with a genetic cause in 30-40 % of cases. The identification of a causative gene variant can guide treatment options and cascade testing of at-risk family members. Cardiomyopathy multigene panels are routinely used to identify the genetic cause, but often detect variants of uncertain significance (VUS). Pathogenic variants in RBM20 have been reported to account for 2-6 % of familial DCM, but geographic differences can be relevant.
Methods: we collected clinical information, cardiac imaging and family history of 101 individuals with DCM, non-dilated left ventricular cardiomyopathy (NDLVC) and isolated left ventricular dilatation from the Emilia-Romagna Region of Italy. Every subject underwent genetic testing through a next generation sequencing panel of genes related to cardiomyopathies. Analysis of single nucleotide polymorphisms (SNP) was used for haplotype analyses.
Results and conclusions: in our cohort, seven individuals (7 %) carried the same heterozygous variant in RBM20 (chr10-110,821,350-G-A; c.2731G > A; p.Val911Met). The referring laboratories reported four further subjects, for a total of 11 unrelated individuals with DCM or isolated left ventricular dilatation from the same geographical area carrying the same variant. These individuals showed high arrhythmic burden and a possible unfavorable evolution towards advanced heart failure. According to guidelines, this variant is classified as VUS; however, its absence in a large local control database and its clinical consistency among affected subjects supports its contributing role. SNP analysis unveiled a common haplotype in the carriers of this variant, suggesting a founder effect. We emphasize the importance of this finding in terms of diagnosis, management and cascade testing of family members.
Keywords: Dilated cardiomyopathy; Founder effect; Genetic diagnosis; Heart failure; RBM20; Transplantation.
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