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.

Figure 1. Titin Protein and Spatial Distribution of Variants in the Protein

Titin, a protein encoded by TTN, makes up one of the three major filaments of the cardiac sarcomere, the basic unit of striated muscle tissue. Regions of the sarcomere are designated as the Z-disk (red), I-band (named for its isotropic properties under a polarizing microscope, shown in blue), A-band (named for its anisotropic properties, shown in green), and M-band (from the German mittelscheibe, the disk in the middle of the sarcomere, shown in purple). The spatial distributions of the truncating variants that were found in samples obtained from patients with peripartum cardiomyopathy (PPCM) and dilated cardiomyopathy (DCM) are indicated, along with the distributions of such variants in healthy controls. At the bottom of the diagram, the genomic locus of TTN is shown. N2BA and N2B denote the exons (vertical lines) encoding the two main cardiac transcripts. For PSI (i.e., the proportion spliced in), the height of the vertical line indicates the proportion of cardiac transcripts obtained from patients with dilated cardiomyopathy that contain the exon. Images are adapted from Herman et al. and Roberts et al.