Expanding the genetic burden of low-evidence genes in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a severe disease characterized by elevated pulmonary artery pressure, leading to heart failure and premature death if untreated. Genetic factors significantly contribute to PAH, and several genes have been linked to its development. According to the ClinGen PH-GCEP group, 12 genes have definitive evidence of association with PAH, three have moderate evidence, six have limited evidence, and five remain disputed due to insufficient genetic data. The aim of this study was to analyze variants in genes without definitive evidence in a cohort of 1480 individuals (954 PAH patients and 526 relatives) by next-generation sequencing (NGS). Variants were prioritized through a custom pipeline developed in-house and classification was performed according to ACMG guidelines. A total of 32 different variants were identified in 42 individuals (32 patients and 10 relatives, five of whom developed the disease): Two pathogenic or likely pathogenic variants in ABCC8 and 30 variants of unknown significance (VUS) in 10 genes (ABCC8, AQP1, BMPR1A, BMPR1B, BMP10, FBLN2, NOTCH3, SMAD1, SMAD4 and TET2). On the opposite, no candidate variants were detected in GGCX, KLF2, KLK1 or PDGFD genes. These findings provide further genetic evidence supporting the association of ABCC8 and related genes with PAH, while no candidate variants were detected in GGCX, KLF2, KLK1, or PDGFD. Further research is needed to confirm the functional impact of these variants.