Background: Peripartum cardiomyopathy (PPCM) shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in over 40 genes, including TTN, which encodes the sarcomere protein titin.
Methods: We sequenced 43 genes, with variants that have been associated with dilated cardiomyopathy, in 172 women with peripartum cardiomyopathy. We compared the prevalence of different types of variant (nonsense, frameshift, and splicing) in these women with the prevalence of these variants in persons with dilated cardiomyopathy and population controls.
Results: We identified 26 distinct rare truncating variants in eight genes in women with PPCM. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than in a reference population of 60,706 individuals (4.7%, P=1.3x10-7), but was similar to a cohort of 332 dilated cardiomyopathy cases (55 in 332 [17%], P=0.81). Two thirds of identified truncating variants were in TTN ([10%], P=2.7x10-10 versus 1.4% in reference population), almost all located in the titin A-band. Seven of the TTN truncating variants were previously reported in cases of idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of women with PPCM (n=83), the presence of TTN truncating variants correlated with lower ejection fraction at one-year follow-up (P=0.005).
Conclusions: The distribution of truncating variants in a large series of women with PPCM is remarkably similar to that found in idiopathic dilated cardiomyopathy. TTN truncating variants are the most prevalent genetic predisposition of each disorder.