Familial Dilated Cardiomyopathy Caused by a Novel Frameshift in the BAG3 Gene
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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 frameshift
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