Familial pulmonary arterial hypertension by KDR heterozygous loss of function

• Published in: The European respiratory journal Vol. 55; no. 4; p. 1902165
• Main Authors: Eyries, Mélanie, Montani, David, Girerd, Barbara, Favrolt, Nicolas, Riou, Marianne, Faivre, Laurence, Manaud, Grégoire, Perros, Frédéric, Gräf, Stefan, Morrell, Nicholas W., Humbert, Marc, Soubrier, Florent
• Format: Journal Article
• Language: English
• Published: England European Respiratory Society 01.04.2020
• Subjects: Cardiology and cardiovascular system; Familial Primary Pulmonary Hypertension - genetics; Genetic Association Studies; Genetic Predisposition to Disease; Human health and pathology; Humans; Life Sciences; Mutation; Vascular Endothelial Growth Factor Receptor-2 - genetics
• ISSN: 0903-1936; 1399-3003; 1399-3003
• DOI: 10.1183/13993003.02165-2019

Beyond the major gene BMPR2 , several new genes predisposing to PAH have been identified during the last decade. Recently, preliminary evidence of the involvement of the KDR gene was found in a large genetic association study. We prospectively analysed the KDR 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 KDR gene. These two index cases were clinically characterised by low diffusing capacity for carbon monoxide adjusted for haemoglobin ( D LCO c) and interstitial lung disease. In one family, segregation analysis revealed that variant carriers are either presenting with PAH associated with low D LCO c, or have only decreased D LCO c, whereas non-carrier relatives have normal D LCO c. In the second family, a single affected carrier was alive. His carrier mother was unaffected with normal D LCO c. We provided genetic evidence for considering KDR as a newly identified PAH-causing gene by describing the segregation of KDR mutations with PAH in two families. In our study, KDR mutations are associated with a particular form of PAH characterised by low D LCO c and radiological evidence of parenchymal lung disease including interstitial lung disease and emphysema.