Background The left ventricular noncompaction cardiomyopathy (LVNC) is a rare subtype of cardiomyopathy associated with a high risk of heart failure (HF), thromboembolism, arrhythmia, and sudden cardiac death. Methods The proband with overlap phenotypes of LVNC and hypertrophic cardiomyopathy (HCM) complicates atrial fibrillation (AF), ventricular tachycardia (VT), and HF due to the diffuse myocardial lesion, which were diagnosed by electrocardiogram, echocardiogram and cardiac magnetic resonance imaging. Peripheral blood was collected from the proband and his relatives. DNA was extracted from the peripheral blood of proband for high-throughput target capture sequencing. The Sanger sequence verified the variants. The protein was extracted from the skin of the proband and healthy volunteer. The expression difference of desmocollin2 was detected by Western blot. Results The novel heterozygous truncated mutation (p.K47Rfs*2) of the DSC2 gene encoding an important component of desmosomes was detected by targeted capture sequencing. The western blots showed that the expressing level of functional desmocollin2 protein (~ 94kd) was lower in the proband than that in the healthy volunteer, indicating that DSC2 p.K47Rfs*2 obviously reduced the functional desmocollin2 protein expression in the proband. Conclusion The heterozygous DSC2 p.K47Rfs*2 remarkably and abnormally reduced the functional desmocollin2 expression, which may potentially induce the overlap phenotypes of LVNC and HCM, complicating AF, VT, and HF.

Overlap phenotypes of the left ventricular noncompaction and hypertrophic cardiomyopathy with complex arrhythmias and heart failure induced by the novel truncated DSC2 mutation.

Importance Pathogenic variants in the RBM20 gene are associated with aggressive dilated cardiomyopathy (DCM). Recently, RBM20 was found to be associated with left ventricular non-compaction cardiomyopathy (LVNC). Thus far, only five families with LVNC have been reported to carry variants in RBM20. It remains unknown whether the variants in RBM20 associated with DCM can also cause LVNC. Objective To elucidate the causative RBM20 variant in two unrelated patients with both LVNC and DCM, and to identify the clinical characteristics associated with variants in RBM20. Methods Trio whole-exome sequencing (WES) was performed. Variants were filtered and classified in accordance with the guidelines of the American College of Medical Genetics and Genomics (ACMG). Results We identified two distinct de novo variants in RBM20 (one per patient) in these two patients with LVNC. Both variants have been reported in patients with DCM, without the LVNC phenotype. Patient 1 was an 11-year-old girl who had DCM, LVNC, and heart failure; the ratio of noncompacted-to-compacted myocardium was 2.7:1. A de novo heterozygous variant c.1907G>A (p.Arg636His) in exon 9 was identified in this patient. Patient 2 was a 13-year-old boy who had clinical phenotypes identical to those of Patient 1; the ratio of noncompacted-to-compacted myocardium was 3.2:1 in this patient. WES revealed a de novo heterozygous variant c.1909A>G (p.Ser637Gly) in exon 9. Both variants were previously characterized as pathogenic, and our study classified them as pathogenic variants based on the ACMG guidelines. Interpretation We found that two patients with LVNC had variants in RBM20. Our results extended the clinical spectrum of the two RBM20 variants and illustrated that the same variant in RBM20 can cause DCM, with or without the LVNC phenotype.

Whole-exome sequencing reveals two de novo variants in the RBM20 gene in two Chinese patients with left ventricular non-compaction cardiomyopathy.

Dilated cardiomyopathy (DCM) is characterized by the dilation and impaired contraction of 1 or both ventricles and can be caused by a variety of disorders. Up to 50% of idiopathic DCM cases have heritable familial diseases, and the clinical screening of family members is recommended. Identifying a genetic cause that can explain the DCM risk in the family can help with better screening planning and clinical decision-making. Whole-exome sequencing (WES) has aided significantly in the detection of causative genes in many genetically heterogeneous diseases. In the present study, we applied WES to identify the causative genetic variant in a family with heritable DCM.WES was applied to identify genetic variants on a 26-year-old man as the proband of a family with DCM. Subsequently, Sanger sequencing was performed to confirm the variant in the patient and all the available affected and unaffected family members. The pathogenicity of the variant was evaluated through co-segregation analysis in the family and employment of in silico predictive software.WES demonstrated the missense pathogenic heterozygous nucleotide variant, c.1907G > A, (p.Arg636His, rs267607004, NM_0011343), in exon 9 of the RBM20 gene in the proband. The variant was co-segregated in all the affected family members in a heterozygous form and the unaffected family members. The in silico analysis confirmed the variant as pathogenic.Pathogenic RBM20 nucleotide variants are associated with arrhythmogenic DCM. We believe that our report is the first to show an RBM20 variant in Iranian descent associated with DCM. 

/pdf/dilated-cardiomyopathy-caused-by-a-pathogenic-nucleotide-2i6g6tmd.pdf

Dilated cardiomyopathy caused by a pathogenic nucleotide variant in RBM20 in an Iranian family

/pdf/dilated-cardiomyopathy-caused-by-a-pathogenic-nucleotide-1sbfd2ja.pdf

RBM20 (RNA-binding motif protein 20) is a vertebrate- and muscle-specific RNA-binding protein that belongs to the serine-arginine-rich family of splicing factors. The RBM20 gene was first identified as a dilated cardiomyopathy–linked gene over a decade ago. Early studies in Rbm20 knockout rodents implicated disrupted splicing of RBM20 target genes as a causative mechanism. Clinical studies show that pathogenic variants in RBM20 are linked to aggressive dilated cardiomyopathy with early onset heart failure and high mortality. Subsequent studies employing pathogenic variant knock-in animal models revealed that variants in a specific portion of the arginine-serine-rich domain in RBM20 not only disrupt splicing but also hinder nucleocytoplasmic transport and lead to the formation of RBM20 biomolecular condensates in the sarcoplasm. Conversely, mice harboring a disease-associated variant in the RRM (RNA recognition motif) do not show evidence of adverse remodeling or exhibit sudden death despite disrupted splicing of RBM20 target genes. Thus, whether disrupted splicing, biomolecular condensates, or both contribute to dilated cardiomyopathy is under debate. Beyond this, additional questions remain, such as whether there is sexual dimorphism in the presentation of RBM20 cardiomyopathy. What are the clinical features of RBM20 cardiomyopathy and why do some individuals develop more severe disease than others? In this review, we summarize the reported observations and discuss potential mechanisms of RBM20 cardiomyopathy derived from studies employing in vivo animal models and in vitro human-induced pluripotent stem cell–derived cardiomyocytes. Potential therapeutic strategies to treat RBM20 cardiomyopathy are also discussed. 

Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems

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Whole-exome sequencing reveals two de novo variants in the RBM20 gene in two Chinese patients with left ventricular non-compaction cardiomyopathy.