Familial pulmonary arterial hypertension by heterozygous loss of function.

Beyond the major gene , several new genes predisposing to PAH have been identified during the last decade. Recently, preliminary evidence of the involvement of the gene was found in a large genetic association study.We prospectively analysed the gene by targeted panel sequencing in a series of 311 PAH patients referred to a clinical molecular laboratory for genetic diagnosis of PAH.Two index cases with severe PAH from two different families were found to carry a loss-of-function mutation in the gene. These two index cases were clinically characterised by low diffusing capacity for carbon monoxide adjusted for haemoglobin ( c) and interstitial lung disease. In one family, segregation analysis revealed that variant carriers are either presenting with PAH associated with low c, or have only decreased c, whereas non-carrier relatives have normal c. In the second family, a single affected carrier was alive. His carrier mother was unaffected with normal c.We provided genetic evidence for considering as a newly identified PAH-causing gene by describing the segregation of mutations with PAH in two families. In our study, mutations are associated with a particular form of PAH characterised by low c and radiological evidence of parenchymal lung disease including interstitial lung disease and emphysema.