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

BackgroundRare variant genetics have been associated with peripartum cardiomyopathy (PPCM) but the role of genetics remains unsettled. ObjectiveThe 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. MethodsClinical 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. ResultsThe 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%). ConclusionThe 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. Condensed AbstractThis is the first study to assess and compare dilated cardiomyopathy (DCM) risk in first-degree relatives (FDRs) of females with peripartum cardiomyopathy (PPCM) and (DCM). The similar risk of DCM or a partial phenotype of DCM in FDRs of females with PPCM and DCM suggests a common genetic contribution to PPCM and DCM. Also, the prevalence of DCM-relevant rare genetic variants was similar between FDRs of females probands diagnosed with PPCM and DCM within European and African ancestry groups and much higher than in population controls. These findings underscore the need of a genetics evaluation for all females with PPCM. Clinical Trialclinicaltrials.gov, NCT03037632