Cardiomyopathy and Preeclampsia: Shared Genetics? [Original Research Article]

Background—Preeclampsia (PE), is associated with diastolic dysfunction, peripartum cardiomyopathy (CM), and both preexisting and subsequent maternal cardiovascular disease (CVD). Gene mutations causing idiopathic CM were recently implicated in peripartum CM. We sought to determine whether CM gene mutations are also a contributory factor in PE. Methods—Subjects were participants in The Preeclampsia Registry and Biobank. After providing informed consent, subjects with a history of PE completed a detailed questionnaire and provided medical records for diagnostic confirmation. Saliva samples were collected for DNA isolation. Whole exome sequencing (WES) was performed to detect rare variants (minor allele frequency of <0.1%) in 43 genes associated with CM. Missense variants were deemed "damaging missense" if so classified by any of 7 standard function prediction algorithms. Variants were defined as "loss-of-function" if they caused a stop-gain, splicing, or frame-shift insertion or deletion. Results were compared with data from two control groups: unrelated women with a gynecologic disorder sequenced using the same methods and instruments (n=530) as well as published variant data from 33,000 subjects in the Exome Aggregation Consortium (ExAC). PE was not excluded in control groups. Results—Of 181 subjects with confirmed PE, 96% were Caucasian. 72% had ≥1 preterm PE delivery <37 weeks. Among PE subjects, WES demonstrated 10 rare loss-of-function variants and 228 rare damaging missense variants in the 43 CM genes considered. The prevalence of these loss-of-function variants was significantly higher in PE subjects (5.5%) compared to the local control (2.5%) population (p=0.014). 68% of women with PE carried ≥1 loss-of-function or damaging missense variant (mean of 1.94 mutations). As seen with peripartum CM, most mutations (55%) were found in the TTN gene. 73% of PE subjects had TTN mutations in PE cohort versus 48% in local controls (p=1.36E-11). Conclusions—Women who develop PE are more likely to carry protein-altering mutations in genes associated with CM, particularly in TTN. Mutations promoting CM are prevalent in PE, idiopathic CM, and peripartum CM, and they are important risk factors for a widening spectrum of cardiovascular disorders. Detecting these variants should allow more specific diagnosis, classification, counseling, and management of women at risk.