Abstract
BACKGROUND: Rare variant genetics have been associated with peripartum cardiomyopathy (PPCM), but the role of genetics remains unsettled. The study sought to compare dilated cardiomyopathy (DCM) genetic risk in first-degree relatives (FDRs) of female patients (probands) with DCM or PPCM to gain causal inference, and to assess DCM-relevant rare variant prevalence in DCM/PPCM probands and population controls. METHODS: Clinical and genetic data were analyzed from the DCM Precision Medicine Study. Risk of DCM or partial DCM, where partial DCM was defined as left ventricular enlargement or a left ventricular ejection fraction of <50%, was estimated in 665 FDRs from 452 female probands, all of whom had been pregnant; 67 had PPCM and 385 had DCM; prevalence of pathogenic, likely pathogenic, or uncertain significance variants was estimated among probands. RESULTS: The risk of DCM/partial DCM for FDRs of PPCM probands was similar to that for FDRs of DCM probands (hazard ratio, 0.77 [95% CI, 0.47-1.28]). Estimated DCM prevalence among the lowest-risk FDRs of non-Hispanic European ancestry probands with PPCM (7.0% [95% CI, 0%-14.1%] females, 9.0% [95% CI, 1.6%-16.3%] males) exceeded population estimates from a UK Biobank study (0.30% females, 0.63% males). Estimated prevalences of a pathogenic, likely pathogenic, or uncertain significance variant among African ancestry and European ancestry probands with PPCM were 55.4% (95% CI, 33.1%-77.7%) and 66.0% (95% CI, 38.6%-93.3%), respectively. The estimated prevalence of pathogenic/likely pathogenic variants among European ancestry PPCM probands (26.6% [95% CI, 12.6%-40.6%]) exceeded a population estimate from a UK Biobank study (0.6%). CONCLUSIONS: The risk of DCM/partial DCM among FDRs was similar regardless of whether their probands had PPCM or DCM. Also, DCM-relevant rare variant findings for females with PPCM or DCM were similar and greater than in population controls, suggesting a similar causal basis for PPCM and DCM. These findings underscore the need for genetic evaluations in all patients with PPCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037632.