RBM20 mutations in left ventricular non‐compaction cardiomyopathy

Cardiomyopathies are among the most prevalent causes of premature death in the Western world. A significant amount of cardiomyopathies has a genetic etiology. Currently, mutations in more than 170 genes associated with different cardiomyopathies, channelopathies, or syndromes with cardiac involvement are described.1 Left ventricular non-compaction (LVNC) is a rare cardiomyopathy and characterized by the presence of excessive left ventricular trabeculation, deep intra-trabecular recesses, and a thin compacted myocardial layer2 with a >2-fold thickening of the noncompacted endocardium compared with the compacted epicardium (NC/C>2).3-5 Currently, the pathogenesis of LVNC is incompletely understood. Especially, it is unclear if LVNC is just an anatomical phenotype or a pathological entity as 1.3%–2.3% of the asymptomatic population fulfill all four current cardiac magnetic resonance (CMR) imaging criteria for diagnosis of LVNC.6 Interestingly, while the American Heart Association (AHA) classifies LVNC as an independent genetic cardiomyopathy, the European Society of Cardiology (ESC) defines it as an unclassified entity.4 Nevertheless LVNC has gained attention because of improvements in cardiac imaging that allow more detailed visualization and clinical awareness of this disease.7, 8 Genetics play an important role in LVNC because 17%–50% of patients have a family member with cardiomyopathy.9, 10 It is supposed that the inherited phenotype can arise due to a gene mutation, which disrupts the physiological compaction of the developing embryonic myocardium.11 Mutations are identified in 17%–41% of LVNC cases, indeed.12, 13 Most of the LVNC-associated genetic defects have also been reported in patients with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM) and arrhythmogenic cardiomyopathy (ACM) sometimes in combination with LVNC and even within the same family.12, 14, 15 These findings might indicate a genetic overlap of different cardiomyopathies. Additionally, LVNC shares several symptoms and clinical findings with other cardiomyopathies. Characterization of the phenotypic expression of LVNC identified distinct subtypes including benign LVNC with preserved systolic and diastolic function, dilated, hypertrophic, restrictive, and arrhythmogenic LVNC.16 The reasons for the clinical variability are widely unknown and might be influenced by the genetic background. Otherwise it may be that patients currently diagnosed with LVNC are those with an anatomical LVNC phenotype, who subsequently develop DCM or HCM.6 In more than 80% of genetic LVNC the specific mutation can be identified in sarcomeric genes (MYH7, MYBPC3 or TTN).15 However, also rare pathogenic mutations in other genes, like RBM20 are associated with LVNC.11, 15, 17 Nevertheless, the majority of the known pathogenic RBM20-mutations is associated with DCM.18-21 RBM20 encodes the vertebrate specific RNA Binding Motif Protein 20 (RBM20), which is involved in post-transcriptional splicing of many sarcomeric and calcium-handling genes in the cardiomyocyte.22-24 Loss of RBM20 function leads to mis-splicing of target genes in humans and rodent models.22-25 RBM20 is composed of two zink finger domains, one RNA-recognition motif (RRM)-type RNA binding domain and an arginine-/serine-(RS)-rich region. In 2019, two mutational hot spot regions in exons 9 and 11 of RBM20 have been recognized.26 The majority of pathogenic RBM20 mutations is localized in the RS domain.11, 18, 19, 23 Nevertheless, a global understanding of variant pathogenicity across the RBM20-coding transcript remains elusive. An RBM20 patient registry has been assembled and reveals a high prevalence of sudden cardiac deaths and early onset cardiomyopathies.26 In this clinical context, Sun et al27 describe in the current issue of Pediatric Investigation two independent young LVNC patients carrying RBM20 missense mutations. Both mutations have been identified before in DCM patients.18, 19, 28 Furthermore, the mutation RBM20-p.R636H was described in one case with LVNC29 but in contrast to the present manuscript by Sun et al27 without detailed clinical description. Interestingly, the authors used trio whole exome sequencing and discovered that both mutations occurred de novo in the pediatric index patients. No further cardiomyopathy associated mutations were discovered. In conclusion, the manuscript by Sun et al emphasizes the clinical need for genetic testing even in cases without a known family history and RBM20 should be considered as a LVNC associated gene as previously suggested.11, 15 Especially in children with genetic forms of LVNC the risk for major adverse cardiac events might be increased.15 Hence, the genetic diagnosis of LVNC might have relevance for risk prediction and clinical management of patients and their relatives.15 None.