Familial pulmonary arterial hypertension by KDR heterozygous loss of function.

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.
Competing Interests: Conflict of interest: M. Eyries has nothing to disclose. D. Montani reports grants and personal fees from Actelion and Bayer, personal fees from GSK, Pfizer and MSD, outside the submitted work. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: N. Favrolt has nothing to disclose. Conflict of interest: M. Riou has nothing to disclose. Conflict of interest: L. Faivre has nothing to disclose. Conflict of interest: G. Manaud has nothing to disclose. Conflict of interest: F. Perros has nothing to disclose. Conflict of interest: S. Gräf has nothing to disclose. Conflict of interest: M.W. Morrell is an employee of Morphogen-IX. Conflict of interest: M. Humbert reports personal fees from Acceleron, Actelion, Merck and United Therapeutics, grants and personal fees from Bayer and GSK, outside the submitted work. Conflict of interest: F. Soubrier has nothing to disclose.
(Copyright ©ERS 2020.)