Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies

Abstract

BACKGROUND Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin. METHODS In 172 women with peripartum cardiomyopathy, we sequenced 43 genes with variants that have been associated with dilated cardiomyopathy. We compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in persons with dilated cardiomyopathy and with population controls. RESULTS We identified 26 distinct, rare truncating variants in eight genes among women with peripartum cardiomyopathy. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than that in a reference population of 60,706 persons (4.7%, P = 1.3×10−7) but was similar to that in a cohort of patients with dilated cardiomyopathy (55 of 332 patients [17%], P = 0.81). Two thirds of identified truncating variants were in TTN, as seen in 10% of the patients and in 1.4% of the reference population (P = 2.7×10−10); almost all TTN variants were located in the titin A-band. Seven of the TTN truncating variants were previously reported in patients with idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of 83 women with peripartum cardiomyopathy, the presence of TTN truncating variants was significantly correlated with a lower ejection fraction at 1-year follow-up (P = 0.005). CONCLUSIONS The distribution of truncating variants in a large series of women with peripartum cardiomyopathy was remarkably similar to that found in patients with idiopathic dilated cardiomyopathy. TTN truncating variants were the most prevalent genetic predisposition in each disorder.

Peripartum Cardiomyopathy

“…Equally strikingly, 14 of these 17 TTN truncating variants were located in the A band of titin (P=0.0018 versus the reference population; Figure 5). 120 Variants in subjects with DCM show a similar predilection for affecting the A band. 121,122 These surprising findings indicate that PPCM often has a genetic cause and that PPCM shares a genetic origin with familial and sporadic DCM.…”

“…120 Targeted sequencing of 43 genes known to associate with DCM revealed a striking 15% prevalence in the patients with PPCM of high-impact nonsense, frameshift, and splicing variants (P=1.3×10 −7 compared with the control group). Interestingly, the prevalence was similar to that found in a large cohort of DCM cases (17%; P=0.81).…”

Impact of Demographic Features, Lifestyle, and Comorbidities on the Clinical Expression of Hypertrophic Cardiomyopathy

“…In a landmark study, a common 25 mb MYBPC3 deletion was associated with increased risk of heart failure in South Asians exposed to secondary risk factors, such as hypertension and hypercholesterolemia, posing a lifelong threat to carriers 76. Furthermore, a role for truncating titin mutations has been recently proposed in the development of peripartum cardiomyopathy,77 suggesting the possible interaction between a genetic predisposition and additional environmental (pregnancy) or genetic stimuli. These observations add a broader dimension to the interactions between cardiomyopathies and the environment: from relatively uncommon, genetically driven diseases that are only modestly influenced by external stimuli, to a common genetic trait that is not pathogenic per se, but may provide predisposition to cardiac disease in the presence of risk factors and high‐risk lifestyles (Figure 4).…”

Peripartum cardiomyopathy

“…Analysis of pedigrees affected by the condition and registries of dilated cardiomyopathy (DCM) identified variants in genes that encode the sarcomeric proteins titin, myosin, and troponin 54849. Subsequently, the sequencing of 43 genes associated with DCM in 172 women with PPCM detected 26 truncating variants, 65% of which occurred in TTN, the gene that encodes titin 50. Identifiable variants were present in 15% of women with PPCM, which is similar to the 17% prevalence in women with DCM and significantly higher than that seen in the reference population 50.…”