In the present study, our genetic data showed the significant deleterious effect of rare PTGIS variants on the development of IPAH independent of BMPR2. Given the strong association between rare PTGIS variants and IPAH, further studies are needed to assess whether these variants represent a true PAH disease state that is distinct from a grayer area or a potential contamination with secondary pulmonary hypertension. Here, PTGIS is linked to pulmonary arterial hypertension.