RBM20 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2009 (Brauch et al, 2009, PMID: 19712804). To date, a large number of studies have reported over 25 RBM20 variants in DCM patients (Key papers include 26084686, Hey et al, 2019, PMID: 30871348; Li et al, 2010, PMID: 20590677; Millat et al, 2011, PMID: 21846512). Human evidence supporting this gene-disease relationship includes case-level data and segregation data, including 55 index cases with DCM carrying RBM20 variants. Brauch et al (2009, PMID: 19712804) performed linkage analysis on two large DCM families to identify RBM20 as the disease locus and subsequent screening of 8 DCM families identified a total of 5 RBM20 variants (p.Pro638Leu, p.Arg636His, p.Arg636Ser, p.Ser637Gly, p.Arg634Gln). In addition, this gene-disease association is supported by experimental evidence reported in several studies. In particular, Beqqali et al (2016, PMID: 27496873) performed functional studies on the p.E913K variant. They investigated human cardiac tissue with p.E913K and U-2 OS transfected cells and observed down-regulation of the RBM20 protein by Western blot. They also showed by RNA-seq analysis that p.E913K affects titin splicing. In RBM20 deficient rats, the observed phenotype resembled human DCM with arrhythmia and sudden cardiac death (Guo et al, 2012, PMID: 22466703). The same study also identified the p.S635A variant which in splice reporter assays rendered RBM20 inactive. Human induced pluripotent stem cells (iPSC) carrying the p.S636A variant showed abnormal distribution of alpha-actinin and defective calcium handling (Streckfuss-Bömekeet al, 2017, PMID: 28941705). Gene expression analysis in iPSCs carrying the p.S636A variant showed dysregulated sarcomeric (TTN and LDB3) and calcium handling (CAMK2D and CACNA1C) genes (Oishi et al, 2016, PMID: 26604126). In summary, there is strong evidence to support the relationship between RBM20 and autosomal dominant DCM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Therefore, the classification has been revised to definitive. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on October 11, 2019 (SOP Version 7).
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