Shared genetic predisposition in Peripartum and dilated cardiomyopathies

James S. Ware, Jian Li, Erica Mazaika, Christopher M. Yasso, Tiffany De Souza, Thomas P. Cappola, Emily J. Tsai, Denise Hilfiker-Kleiner, Chizuko A. Kamiya, Francesco Mazzarotto, Stuart A. Cook, Indrani Halder, Sanjay K. Prasad, Jessica Pisarcik, Karen Hanley-Yanez, Rami Alharethi, Julie Damp, Eileen Hsich, Uri Elkayam, Richard SheppardAngela Kealey, Jeffrey Alexis, Gautam Ramani, Jordan Safirstein, John Boehmer, Daniel F. Pauly, Ilan S. Wittstein, Vinay Thohan, Mark J. Zucker, Peter Liu, John Gorcsan, Dennis M. McNamara, Christine E. Seidman, Jonathan G. Seidman, Zoltan Arany

Research output: Contribution to journalArticlepeer-review

366 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)233-241
Number of pages9
JournalNew England Journal of Medicine
Issue number3
StatePublished - Jan 21 2016

All Science Journal Classification (ASJC) codes

  • General Medicine


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