Pathogenic RBM20-Variants Are Associated With a Severe Disease Expression in Male Patients With Dilated Cardiomyopathy.

BACKGROUND: As pathogenic variants in the gene for RBM20 appear with a frequency of 6% among Danish patients with dilated cardiomyopathy (DCM), it was the aim to investigate the associated disease expression in affected families. METHODS AND RESULTS: Clinical investigations were routinely performed in DCM index-patients and their relatives. In addition, >= 76 recognized and likely DCM-genes were investigated. DNA-sequence-variants within RBM20 were considered suitable for genetic testing when they fulfilled the criteria of (1) being pathogenic according to the American College of Medical Genetics and Genomics-classification, (2) appeared with an allele frequency of <1:10.000, and (3) segregated with DCM in >= 7 affected individuals. A total of 80 individuals from 15 families carried 5 different pathogenic RBM20-variants considered suitable for genetic testing. The penetrance was 66% (53/80) and age-dependent. Males were both significantly younger and had lower ejection fraction at diagnosis than females (age, 29 +/- 11 versus 48 +/- 12 years; P<0.01; ejection fraction, 29 +/- 13% versus 38 +/- 9%; P<0.01). Furthermore, 11 of 31 affected males needed a cardiac transplant while none of 22 affected females required this treatment (P<0.001). Thirty percent of RBM20-carriers with DCM died suddenly or experienced severe ventricular arrhythmias although no adverse events were identified among healthy RBM20-carriers with a normal cardiac investigation. The event-free survival of male RBM20-carriers was significantly shorter compared with female carriers (P<0.001). CONCLUSIONS: The disease expression associated with pathogenic RBM20-variants was severe especially in males. The findings of the current study suggested that close clinical follow-up of RBM20-carriers is important which may ensure early detection of disease development and thereby improve management.