Evaluation of Women with Peripartum or Dilated Cardiomyopathy and Their First-Degree Relatives: The DCM Precision Medicine Study

Background: Rare variant genetics have been associated with peripartum cardiomyopathy (PPCM) but the role of genetics remains unsettled. Objective: The study sought to compare dilated cardiomyopathy (DCM) genetic risk in first-degree relatives (FDRs) of female patients with DCM or PPCM (probands), 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 pDCM was defined as left ventricular (LV) enlargement or a LV ejection fraction of <50%, was estimated in 665 FDRs from 452 female probands, all of whom had been pregnant, of which 67 had PPCM and 385 had DCM; prevalence of pathogenic, likely pathogenic or uncertain significance variants (P/LP/VUS) was estimated among probands. Results: The risk of DCM/pDCM for FDRs of PPCM probands was similar to that for FDRs of DCM probands (HR, 0.77; 95% CI, 0.47 - 1.28). Estimated DCM prevalence among the lowest-risk FDRs of non-Hispanic EA 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 P/LP/VUS among AA and EA 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 P/LP variants among EA PPCM probands (26.6%; 95% CI, 12.6%-40.6%) exceeded a population estimate from a UK Biobank study (0.6%). Conclusion: The risk of DCM/pDCM 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 shared genetic basis for PPCM and DCM. These findings underscore the need for genetic evaluations in all PPCM patients.