RBM20 – Dilated Cardiomyopathy

RBM20 encodes an RNA-binding protein crucial for cardiac alternative splicing. Heterozygous variants in RBM20 cause autosomal dominant dilated cardiomyopathy (DCM) characterized by left ventricular dilation, systolic dysfunction, and a high arrhythmic burden. The inheritance is autosomal dominant with age-dependent penetrance and frequent ventricular arrhythmias (HP:0001644; HP:0011675).

Early linkage in two large unrelated families mapped DCM to chromosome 10q25–q26, where exon 9 missense variants in RBM20 co-segregated with disease in >7 affected relatives (LOD >11) [PMID:19712804]. In a cohort of 312 idiopathic DCM probands, six unique RBM20 rare variants were identified (1.9%), confirming a mutation hotspot in the RS-rich domain [PMID:20590677].

The variant spectrum is dominated by missense changes in the conserved RS domain of exon 9, including c.1907G>A (p.Arg636His) [PMID:19712804], c.1900C>T (p.Arg634Trp) [PMID:30557877], and c.1913C>A (p.Pro638Gln) [PMID:29367541]. Recurrent variants are found across diverse populations, accounting for ~2–3% of DCM cases.

Functional studies demonstrate that RBM20 haploinsufficiency disrupts titin (TTN) splicing, shifting isoforms from stiff N2B to compliant N2BA, impairing sarcomere mechanics and the Frank–Starling response in patient cardiomyocytes and knock-in mice (RSRSP stretch mutations S637A/S639G) [PMID:27496873; PMID:35394688]. Patient-derived iPSC-CMs with p.Ser635Ala exhibit sarcomeric disarray and altered calcium handling [PMID:28941705].

A variant outside the RS domain (p.Ile536Thr) alters TTN splicing but lacks overt DCM phenotype in DM1 patients, highlighting allele-specific penetrance and the need for comprehensive clinical correlation [PMID:31419596].

Collectively, definitive human genetic evidence from multiplex families, replication in cohorts, and concordant in vitro and in vivo functional data establish RBM20 as a causal DCM gene. RBM20 genetic testing enables early diagnosis, family screening, and personalized risk stratification. Key take-home: RBM20 testing should be integrated into DCM gene panels to guide surveillance and ICD decisions.

References

• Journal of the American College of Cardiology • 2009 • Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. PMID:19712804
• Clinical and Translational Science • 2010 • Identification of novel mutations in RBM20 in patients with dilated cardiomyopathy. PMID:20590677
• Cardiovascular Research • 2016 • A mutation in the glutamate-rich region of RNA-binding motif protein 20 causes dilated cardiomyopathy through missplicing of titin and impaired Frank-Starling mechanism. PMID:27496873
• FASEB Journal • 2022 • RBM20 phosphorylation and its role in nucleocytoplasmic transport and cardiac pathogenesis. PMID:35394688
• Journal of Molecular and Cellular Cardiology • 2017 • Severe DCM phenotype of patient harboring RBM20 mutation S635A can be modeled by patient-specific induced pluripotent stem cell-derived cardiomyocytes. PMID:28941705
• Forensic Science International • 2019 • RNA sequencing reveals abnormal LDB3 splicing in sudden cardiac death. PMID:31419596

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