Genetic Spectrum of Arrhythmogenic Cardiomyopathy (original) (raw)

. Author manuscript; available in PMC: 2020 Mar 1.

The morphologically distinct forms of cardiomyopathy, dilated, hypertrophic, right ventricular arrhythmogenic and restrictive (DCM, HCM, ARVC and RCM, respectively), each have high heritable component, and the precise genes implicated help predict arrhythmia complications and progression.1 When evaluating the patient with cardiomyopathy, the probability of an informative genetic test ranges from 20–60%, depending on the presence of family history and type of cardiomyopathy. HCM is more genetically restricted, dividing HCM into sarcomere-HCM and non-sarcomere-HCM, with clear differences in outcome.2 DCM is more genetically heterogeneous with truncations of the TTN gene accounting for 20% of DCM.3 The next most frequently implicated genes in DCM each account for 2–8% of cases and include LMNA, SCN5A, and RBM20.4 The precise frequency of each gene’s contribution evolves as datasets enlarge and with increased use of genetic testing in clinical practice. Mutations in the RBM20 gene encoding RNA Binding Motif Protein 20 were initially described in two large families with DCM.5 RBM20 is an RNA splicing regulator and among its targets is the TTN gene encoding titin.6 RBM20 mutations were suggested to indicate a rapid progression to heart failure and the presence of life-threatening arrhythmias.7 Early genetic reports may overestimate clinical findings due to ascertainment bias in which the most severely affected families are overrepresented in genetic research. Over time, especially if genotype status leads the investigation, genotype-phenotype correlations reveal a broader phenotype with milder presentations. The gnomAD dataset indicates that RBM20 is particularly intolerant of loss of function variation (http://gnomad.broadinstitute.or/gene/ENSG00000203867),8 and that some RBM20 exons are not well covered with exome sequencing possibly underestimating RBM20 in DCM. RBM20 was included on targeted cardiomyopathy gene sequencing panels in 2012–2014, and with this inclusion, more data has become available on RBM20’s role DCM.

Parikh et al. now describe a larger cohort of RBM20 gene mutation carriers ascertained from two clinical US testing laboratories.9 The study captured 171 unique RBM20 variants from 403 clinical genetic tests. They observed significant enrichment of cardiomyopathy-associated RBM20 variants in exons 9 and 11, similar to earlier studies.5, 10 Exon 9 encodes an RNA binding domain of the RBM20 protein, while no function is ascribed to the exon 11 encoded region, and these regions were not enriched with variation in gnomAD. ClinVar, a public database of clinically relevant genetic variants, reports 12 RBM20 missense gene variants classified as likely pathogenic or pathogenic with 11 falling within the pathogenic regions (https://www.ncbi.nlm.nih.gov/clinvar/?term=RBM20%5Bgene%5D). An additional seven variants in these regions are classified as variants uncertain significance (VUS). Three exon 9 variants have conflicting reports of pathogenicity, while four exon 11 variants are uncertain significance. These inconsistencies highlight the difficulty of defining pathogenicity in single probands.

Parikh et al. found RBM20 variants in exons 9 and 11 associated with more severe clinical phenotypes. In particular, these patients were more likely to have a non-sustained ventricular tachycardia (NSVT), atrial fibrillation, a shorter PR interval, and a family history of cardiac death. Although variation in exons 9 and 11 may be easier to interpret as pathogenic, this does not exclude variants in other regions of RBM20 as causing disease. Interpreting RBM20 variation outside these regions is aided by family segregation analysis. In family-based studies, arrhythmia phenotypes like increased NSVT may serve as milder presentations of cardiac findings in gene-positive family members. In a related study, 80 RBM20 gene carriers from 15 families highlighted male sex as a risk factor for faster progression.11

In addition to rare pathogenic variants, there are GWAS signals for RBM20 in cardiac dysrhythmias. Specifically, two intronic RBM20 variants associate with atrial fibrillation and QRS complex measures.12 One of these variants, rs10749053, falls within intron 9, which is close to the regions identified by Parikh et al. The finding that RBM20 variants associate with atrial fibrillation and QRS interval further underscores the importance of RBM20 function for cardiac conduction system and arrhythmia risk.

RMB20 is in the subset of cardiomyopathy genes associated with increased risk for arrhythmias. This increased arrhythmia risk is best described for LMNA in which the risk for arrhythmias occurs in the absence of cardiomyopathy LMNA gene mutations are associated with atrioventricular nodal heart block and atrial fibrillation, as well as increased risk for ventricular arrhythmias.1, 4 Parikh et al. observed that RBM20 cardiomyopathy patients have comparable ventricular arrhythmia risk to LMNA cardiomyopathy patients and a trend towards reduced atrial fibrillation. However, the GWAS link between RBM20 intronic SNPs and atrial fibrillation may suggest the absence of association could relate to the small sample size.12

The AHA/ACC/HRS guidelines for managing ventricular arrhythmias recommend placement of an implantable cardiac defibrillator (ICD) in patients with LMNA cardiomyopathy and ≥ 2 risk factors (NSVT, EF < 45%, nonsense mutations, or male sex).13 Cardiomyopathy patients with pathogenic mutations in RBM20 appear to be at similar ventricular arrhythmia risk as LMNA cardiomyopathy patients. As such, these gene carriers should be monitored closely, and standard guidelines for primary prevention ICD placement may be inadequate. Due to the high penetrance of RBM20 mutations, family members of affected individuals should have site-specific genetic testing and managed based on genotype (Figure 1).

Figure 1:

Figure 1:

Basic Workflow for Evaluating Patients with Genetic Cardiomyopathy.

Mutations in the DCM genes, SCN5A and FLNC, are also associated with higher rates of arrhythmias.14, 15 These specific arrhythmia associations with pathogenic mutations in LMNA, RBM20, SCN5A, or FLNC are of urgent importance, and genetic evaluation should be standard of care for DCM patients to better delineate this risk. The growing use of genome sequencing in medicine allows the use of personalized genetic information to inform clinical care of patients and family members. While it can be difficult to find clinically actionable associations, RBM20 mutations and arrhythmia risk is an excellent example. Genetic testing for DCM is at the forefront of personalized genomic medicine in predicting medically manageable risk.

Footnotes

Conflict of Interest Statement

EMM serves as a consultant to Invitae Inc, Tenaya Therapeutics, Exonics, AstraZeneca, and Cytokinetics. AMG has no conflicts of interest to report.

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