Rare variants in STAB2 in patients with chronic thromboembolic pulmonary hypertension

The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is poorly understood. Studies of the genetic risk factors for CTEPH are likely to improve our understanding of CTEPH pathogenesis and may lead to novel treatment and prevention strategies. Genetic analysis focused on shared gene variants in high-risk disease pedigrees can aid in the identification of rare variants with a strong effect on disease risk.

We identified 13 CTEPH high-risk pedigrees and performed whole-exome sequencing in 22 CTEPH cases from these pedigrees, focusing on rare and deleterious variants that were shared between related CTEPH cases. We validated CTEPH candidate gene variants in two independent CTEPH cohorts, one from Utah (n=78) and one from the University of California San Diego (n=238), and compared them to controls from the UK Biobank.

A rare and predicted deleterious missense variant in STAB2 was identified in two related CTEPH cases. Qualifying STAB2 variant alleles were observed more frequently in both CTEPH cohorts (pooled allele frequency 4.6%) than in subjects from the UK Biobank with a history of pulmonary embolism (PE) (allele frequency 2.2%, p=0.0002) or without a history of PE (allele frequency 1.9%, p<0.0001). CTEPH subjects with qualifying STAB2 variants had elevated levels of plasma von Willebrand Factor (vWF) and factor VIII, consistent with the known role of STAB2 as a genetic regulator of circulating vWF levels.

Rare variants in STAB2 are identified in a CTEPH high-risk pedigree and are over-represented in nonrelated CTEPH cases compared to controls with PE. These data suggest that STAB2 is a CTEPH risk gene.