Dilated Cardiomyopathy via the RBM20 Gene

Dilated cardiomyopathy (DCM) is a heterogeneous disease of the cardiac muscle. It is characterized by dilatation of the left, right, or both ventricles, systolic dysfunction, and diminished myocardial contractility. Symptoms include arrhythmia, dyspnea, chest pain, palpitation, fainting, and congestive heart failure (Ikram et al. 1987). Additional features may include woolly hair and myopathy (Møller et al. 2009). Sudden death occurs in ~30% of patients with DCM (Tamburro and Wilber 1992). Although symptoms of DCM usually begin in adulthood, an extensive clinical variability between individuals concerning the age of onset, penetrance, and extent of structural and functional abnormality has been documented. The prevalence of DCM has been estimated at ~1/2700 (Codd et al. 1989).

Up to 30% of DCM cases are familial (Grünig et al. 1998). In about half of these families, DCM is inherited in an autosomal dominant manner (AD-DCM). In rare families, the disease is transmitted with an autosomal recessive, X-linked or mitochondrial inheritance. The RBM20 gene is highly expressed in striated muscle, particularly the heart and is strongly associated with autosomal dominant DCM (Brauch et al. 2009; Li et al. 2010). The RBM20 gene encodes RNA-binding Motif Protein 20 (RBM20), which binds RNA and regulates splicing. Alternative splicing plays a major role in the adaptation of cardiac function exemplified by the isoform switch of titin. The RBM20 protein represses splicing to coordinate cardiac pre-mRNA processing (Maatz et al. 2014). Reduced activity of RBM20 results in altered isoforms of proteins (titin, LDB3, CACNA1C etc) that maintain sarcomeric structure and cardiac function. These changes eventually lead to cardiomyopathy and heart failure (Guo et al. 2012). So far, all causative variants reported in RBM20 are missense (Human Gene Mutation Database).

RBM20-associated DCM occurs in ~3% of DCM patients (Refaat et al. 2012).

This test provides full coverage of all coding exons of the RBM20 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).