Purpose: Dilated cardiomyopathy (DCM) is a major cause of chronic heart failure and the most common indication for cardiac transplantation. 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.
Methods: We studied 105 unrelated probands by direct sequencing of BAG3 exons and splice sites. Large deletions/insertions were screened for by real time polymerase chain reaction (RT-PCR).
Results: We found 6 different mutations in 7 families with familial DCM: the known p.Glu455Lys mutation (2 families) and 5 novel mutations: p.Gln353ArgfsX10 (c.1055delC), p.Gly379AlafsX45 (c.1135delG), p.Tyr451X (c.1353C>A), p.Glu456AspfsX3 (c.1368delG) and a large deletion of 17,990bp removing BAG3 exons 3-4. The Gln353ArgfsX10, Gly379AlafsX45, and the large deletion are likely to be pathogenic as they are predicted to remove a large C-terminal part of the protein, including the entire BAG domain. The Tyr451X and Glu456AspfsX3 are also likely to be pathogenic as they remove more than half of the BAG domain.
There were 31 BAG3 mutation carriers; mean age at the time of diagnosis/screening was 30.4±12.6 years, 20 (64.5%) were male. 10 subjects were asymptomatic (32.3%), 20 (64.5%) had heart failure symptoms; mean NYHA class was 2.5±1.1, 1 (3.2%) had palpitations. Of the 31 carriers 28 (90%) were in sinus rhythm, 2 were in atrial fibrillation (6.5%), 1 had junctional rhythm (3.2%). DCM was diagnosed in 20 patients (65%), 11 BAG3 carriers (35%) had normal cardiac function. Over mean 95.3±81.9 months of follow-up (median 95.3 months) there were 7 (22.6%) serious adverse events: 3 patients received heart transplant (9.7%), 3 died of heart failure (9.7%), 1 died suddenly (3.7%). Persistent LV dysfunction (LVEF<45%) was present in 9 (29%) patients, 4 had significant improvement in LV function on treatment 4 (12.9%), and 11 BAG3 carriers had persistent normal LV function (35.5%). Among members of screened families there were no cases of DCM without BAG3 mutation. Of interest, all BAG3 carriers with persistent normal LV function had BAG3 truncating mutations.
Conclusions: BAG3 mutations are relatively frequent cause of DCM (6.7%). We report five novel pathogenic BAG3 variants including a large deletion Our observations highlight the necessity for screening BAG3 in DCM patients for copy number variations (CNV) variants in addition to point mutations.