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Abstract
BackgroundBAG3 gene mutations have been recently implicated as a novel cause of dilated cardiomyopathy (DCM). Our aim was to evaluate the prevalence of BAG3 mutations in Polish patients with DCM and to search for genotype-phenotype correlations.MethodsWe studied 90 unrelated probands by direct sequencing of BAG3 exons and splice sites. Large deletions/insertions were screened for by quantitative real time polymerase chain reaction (qPCR).ResultsWe found 5 different mutations in 6 probands and a total of 21 mutations among their relatives: the known p.Glu455Lys mutation (2 families), 4 novel mutations: p.Gln353ArgfsX10 (c.1055delC), p.Gly379AlafsX45 (c.1135delG), p.Tyr451X (c.1353C>A) and a large deletion of 17,990 bp removing BAG3 exons 3–4. Analysis of mutation positive relatives of the probands from this study pooled with those previously reported showed higher DCM prevalence among those with missense vs. truncating mutations (OR = 8.33, P = 0.0058) as well as a difference in age at disease onset between the former and the latter in Kaplan-Meier survival analysis (P = 0.006). Clinical data from our study suggested that in BAG3 mutation carriers acute onset DCM with hemodynamic compromise may be triggered by infection.ConclusionsBAG3 point mutations and large deletions are relatively frequent cause of DCM. Delayed DCM onset associated with truncating vs. non-truncating mutations may be important for genetic counseling.
Highlights
BAG3 gene mutations have been recently implicated as a novel cause of dilated cardiomyopathy (DCM)
Medical records of hospitalized patients were reviewed, in particular we reviewed: (1) histopathologic data of endomyocardial biopsy in two DCM patients - in one patient biopsy was performed based on clinical indications and in the other two pieces of endomyocardial tissue were obtained during ventricular assist device implantation due to fulminant heart failure, (2) cardiovascular magnetic resonance (CMR) data of one patient (CMR performed due to clinical suspicion of myocarditis)
The findings that truncating BAG3 mutations cause disease with later onset than missense variants may be important for genetic counselling. It should be confirmed by a study addressing disease severity, our results suggest that missense BAG3 mutations may have a stronger pathogenic effect than the truncating variants
Summary
BAG3 gene mutations have been recently implicated as a novel cause of dilated cardiomyopathy (DCM). Our aim was to evaluate the prevalence of BAG3 mutations in Polish patients with DCM and to search for genotype-phenotype correlations. Dilated cardiomyopathy (DCM) is a major cause of chronic heart failure and the most common indication for cardiac transplantation [1]. In a substantial number of cases DCM is familial with autosomal dominant inheritance. Whereas a large number of genes have been shown to harbor mutations causing DCM [2] novel disease loci are continuously being reported. One interesting gene which recently has been implicated as a novel DCM locus is BAG3 [3,4]. The purpose of our study was to evaluate the prevalence of BAG3 mutations in Polish patients with DCM and to search for genotype-phenotype correlations A specific BAG3 mutation virtually always occurring de novo (Pro209Leu) causes a severe childhood myofibrillar myopathy which is regarded as a distinct disease from that caused by other known BAG3 mutations [9,10,11].
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