Widening the landscape of heritable pulmonary hypertension mutations in paediatric and adult cases

Heritable forms of pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis (PVOD/PCH) diverge by lung histopathological lesions, clinical and para-clinical presentation, their responsible genes, and mode of transmission. Since the identification of the gene in families affected by PAH, mutations in several other genes have been discovered for both forms. The mutation landscape in these new genes is not yet well known. We set up a next-generation sequencing-based targeted sequencing gene panel allowing known genes for PAH and PVOD/PCH to be analysed simultaneously Genetic analysis was prospectively performed on 263 PAH and PVOD/PCH patients (adult and paediatric cases). Pathogenic mutations were identified in 19.5% of sporadic PAH patients (n=180), 54.5% of familial PAH patients and 13.3% of PVOD/PCH patients. was the most frequently mutated gene, followed by in both paediatric and adult PAH. mutations were identified in 1.2% of adult PAH cases. biallelic mutations were restricted to PVOD/PCH. A truncating mutation and a predicted loss-of-function variant were also identified in in two severely affected sporadic PAH female patients. Our results confirm that mutations are found in genes beyond in heritable PAH, emphasise the role of and , and designate as a new PAH gene.