Rare variant mutations in pregnancy-associated or peripartum cardiomyopathy

Abstract

Background: The term peripartum cardiomyopathy (PPCM) describes dilated cardiomyopathy (DCM) without known cause that occurs during the last month of pregnancy to 5 months postpartum. A related term, pregnancy-associated cardiomyopathy (PACM), refers to DCM onset earlier in pregnancy. Multiple studies have focused on inflammatory, immunologic, and environmental causes. An alternative hypothesis is that PPCM and PACM result, in part, from a genetic cause. In this study, we sought to test the hypothesis that rare DCM-associated mutations underlie a proportion of PACM or PPCM cases.

Methods and results: A systematic search of our DCM database designed for family-based genetic studies was undertaken for cases associated with pregnancy and the postpartum period; in the identified cases, clinical and molecular genetic data, including exonic and near intron/exon boundaries of DCM genes, were analyzed. Of 4110 women from 520 pedigrees in the Familial Dilated Cardiomyopathy Research Project database, we identified 45 cases of PPCM/PACM. Evidence of familial clustering with DCM was present in 23 unrelated cases. Of the 45 cases, 19 had been resequenced for known DCM genes, and 6 carried mutations. Five had PPCM, of which 3 were familial with mutations found in MYH7, SCN5A, and PSEN2, and 2 were sporadic with mutations in MYH6 and TNNT2. One case had PACM and carried a mutation in MYBPC3.

Conclusions: These findings suggest that a proportion of PPCM/PACM cases results from a genetic cause.

Figure 1. PPCM/PACM Pedigrees Associated with DCM Mutations

Pedigrees have been labeled by letter, which correspond to their respective mutation as shown in Table 3. Pedigree D has been previously published and is not shown. Squares represent males, circles females. An arrowhead denotes the proband. A diagonal line marks deceased individuals. Solid symbols indicate confirmed or possible PPCM/PACM or IDC with or without heart failure; shaded symbols represent a family history suggestive of DCM that was not confirmed with medical records. Open symbols represent unaffected individuals. For PPCM/PACM or IDC cases, the current age or age at death, the age at diagnosis (in parenthesis), and the clinical presentation are shown. The presence or absence of a mutation is indicated by a + or − symbol, respectively. An asterisk represents a homozygous or hemizygous subject. Arrh=arrhythmia; asym=asymptomatic; HF= heart failure; ICD=implantable cardiac defibrillator; MI= myocardial infarction; PPCM=peripartum cardiomyopathy; PACM=pregnancy associated cardiomyopathy; SCD=sudden cardiac death; trx=heart transplant.