3947Yield of clinical and genetic cascade screening among 436 relatives of 111 consecutive index-patients with dilated cardiomyopathy

Hey, Thomas Morris; Harbo, Maria; Aagaard, Mads M.; Madsen, Trine; Rasmussen, Torsten Bloch; Gadgaard, Tenna; Moêlgaard, H.; Moeller, J E; Eiskjær, Hans

doi:10.1093/eurheartj/ehx504.3947

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“…Initially clinical and genetic investigations of ≥76 potential DCM related genes were performed in 111 DCM-index patients including 436 of their relatives at risk of having inherited the condition. 32 Familial DCM occurred in 34% (38/111) of cases. A total of 14 different pathogenic DNA-sequence-variants suitable for genetic testing were identified in 19 apparently unrelated index-patients (17%) with a frequency of 45% (17/38) in familial DCM and 3% (2/73) in sporadic DCM.…”

Section: Genetic Investigationsmentioning

confidence: 99%

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

Hey

Rasmussen

Madsen

et al. 2019

Circ: Heart Failure

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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.

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Section: Genetic Investigationsmentioning

confidence: 99%