In contrast to hereditary pulmonary veno-occlusive disease (PVOD) for which a single gene (EIF2AK4) has been identified and whose mutations provoke a recessively transmitted disease with high penetrance, several genes have been implicated in pulmonary arterial hypertension (PAH) since the discovery of BMPR2 mutations in 2000. Here, we sought to determine the genetic architecture of pulmonary hypertension (PH) according to gene mutations found in a cohort of French patients.
Genetic analysis was prospectively performed on 263 PAH and PVOD patients (adult and pediatric cases). We developed NGS-based targeted sequencing gene panel allowing known genes for PAH and PVOD/PCH to be analyzed simultaneously (BMPR2, TBX4, EIF2AK4, CAV1, KCNK3, SMAD9, ACVRL1, ENG, BMP9). The BMP10 gene, a BMP9 paralog, was also included in the capture design.
A pathogenic mutation was identified in 49 of the 263 analyzed patients. Mutations were identified in 19.5 % of sporadic PAH patients, 54.5% in familial PAH and 13.5% in PVOD/PCH patient. BMPR-2 is the most frequently mutated gene, followed by TBX4 in both pediatric and
adult PAH. BMP9 mutations were identified in 1.2% of adult PAH cases. EIF2AK4 bi-allelic mutations are restricted to PVOD/PCH. A truncating mutation and a predicted loss of function variant were also identified in the BMP10 gene in two severely affected sporadic PAH patients.
Gene panel sequencing is an efficient tool to improve the knowledge of PH genetic architecture. Our results confirm that mutations are found in genes beyond BMPR2 in PAH, reveal the emerging role of TBX4 in adult PAH while this gene was initially described as a major gene in pediatric PAH and designate BMP10 as a new candidate