Heritable pulmonary arterial hypertension: new genetic findings and environmental triggers

Abstract

Abstract Our goal was to identify new environmental or genetic causes in heritable pulmonary arterial hypertension (HPAH) families outside the 18 known diagnostics PAH genes. PAH gene panel sequencing was performed for 47 HPAH families which revealed pathogenic variants in 39 families. Five of the remaining families agreed to whole exome sequencing and to fill in a drug and toxin exposure questionnaire. In Family 1 and 2, mother and daughter with HPAH carried a likely pathogenic variant in the CYBA gene and a variant of uncertain significance in the FKBP1A gene, respectively, following ACMG guidelines. In Family 3, we detected a likely pathogenic variant in the PTGR2 gene. These genes could play part in PAH pathogenesis but further functional analyses are required to corroborate these findings. In the remaining two families, we could not identify any plausible genetic cause. However, a father and son with PAH reported exposure to trichloroethylene, asbestos and tramadol in Family 4. In Family 5, two brothers with pulmonary veno-occlusive disease showed occupational toxin exposure. Thus, our findings indicate that not only a genetic predisposition but also environmental triggers should be investigated for HPAH patients.