Key result
A novel frameshift variation in the BAG3 gene (p.H243Tfr*64) was identified as the cause of familial dilated cardiomyopathy, correlating with a severe phenotype and early onset.
Observational (n=100)
No
The identification of the novel p.H243Tfr*64_BAG3 frameshift mutation expands the genetic basis of familial dilated cardiomyopathy and enables early identification of at-risk individuals.
Supports expanding genetic panels for familial DCM; leaves open confirmation in independent cohorts before clinical adoption.
BACKGROUND: Dilated cardiomyopathy, a major cause of chronic heart failure and cardiac transplantation, is characterized by left ventricular or biventricular heart dilatation. In nearly 50% of cases the pathology is inherited, and more than 60 genes have been reported as disease-causing. However, in 30% of familial cases the mutation remains unidentified even after comprehensive genetic analysis. This study clinically and genetically assessed a large Spanish family affected by dilated cardiomyopathy to search for novel variations. METHODS AND RESULTS: Our study included a total of 100 family members. Clinical assessment was performed in alive, and genetic analysis was also performed in alive and 1 deceased relative. Genetic screening included resequencing of 55 genes associated with sudden cardiac death, and Sanger sequencing of main disease-associated genes. Genetic analysis identified a frame-shift variation in BAG3 (p.H243Tfr*64) in 32 patients. Genotype-phenotype correlation identified substantial heterogeneity in disease expression. Of 32 genetic carriers (one deceased), 21 relatives were clinically affected, and 10 were asymptomatic. Seventeen of the symptomatic genetic carriers exhibited proto-diastolic septal knock by echocardiographic assessment. CONCLUSIONS: We report p.H243Tfr*64_BAG3 as a novel pathogenic variation responsible for familial dilated cardiomyopathy. This variation correlates with a more severe phenotype of the disease, mainly in younger individuals. Genetic analysis in families, even asymptomatic individuals, enables early identification of individuals at risk and allows implementation of preventive measures.
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Toro et al. (2016) conducted an observational in Familial Dilated Cardiomyopathy (n=100). BAG3 gene frameshift variation (p.H243Tfr*64) vs. Non-carriers was evaluated on Presence of dilated cardiomyopathy phenotype. A novel frameshift variation in the BAG3 gene (p.H243Tfr*64) was identified as the cause of familial dilated cardiomyopathy, correlating with a severe phenotype and early onset.
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