Abstract 4145070: Genetic and Family Analysis of Probands with Peripartum Cardiomyopathy and Dilated Cardiomyopathy and Their First-Degree Relatives

Introduction: Peripartum cardiomyopathy (PPCM) presents as left ventricular systolic dysfunction (LVSD) during pregnancy or the post-partum interval. The underlying cause of PPCM remains incompletely defined, with hypotheses suggesting either pregnancy-related environmental (e.g., hormonal, hemodynamic) cause or genetic cause similar to dilated cardiomyopathy (DCM). Hypothesis: If PPCM results principally from pregnancy-related environmental cause, then first-degree relatives (FDRs) of women with PPCM will have lower risk of DCM than FDRs of women with DCM because they cannot share this risk. Conversely, if DCM genetics underlies both PPCM and DCM, then FDRs of women with PPCM or DCM are equally likely to share these genetic factors and will have comparable risks. Aims: In female probands with PPCM or DCM from the DCM Precision Medicine Study, evaluate proband DCM-relevant rare variant genetics; in their FDRs, compare the age-specific cumulative risk of DCM, LVSD, or LV enlargement [LVE]. Methods: Of 452 female probands with DCM, 72 met criteria for PPCM; all underwent exome sequencing and analysis of rare variants in 36 DCM genes. Their 665 FDRs were assessed for DCM, LVSD, or LVE. Hierarchical logit models were used to describe the distribution of the most deleterious variant identified (none, variant of uncertain significance, or pathogenic/likely pathogenic) in probands. For FDRs, binary data on the presence or absence of DCM, LVSD, or LVE at enrollment were used to model age-specific cumulative risk in a Weibull proportional hazards model. Models accounted for site heterogeneity and, in FDRs, intrafamilial correlation. Results: The odds of finding a DCM-relevant rare variant were comparable between female probands with PPCM and DCM (OR=1.07, 95% CI: 0.37-3.11, p=0.90) adjusting for ancestry, ethnicity, and diagnosis age. DCM-relevant rare variants of PPCM probands were similar to those of DCM probands for ClinGen gene evidence category (p=0.55) and variant predicted impact (loss-of-function, missense, or other; p=0.90). Age-specific cumulative risk of DCM, LVSD, or LVE was not different among FDRs of women with PPCM or DCM (HR=0.96, 95% CI: 0.59-1.57, p=0.87) adjusting for proband ancestry and diagnosis age and FDR sex. Conclusion: Data from female probands indicate that PPCM and DCM have a similar rare variant genetic basis. FDRs of both PPCM and DCM probands show similar risks of DCM, LVSD, or LVE, further supporting an underlying genetic cause for PPCM.