Abstract 16991: Rare Variants in BMP10 Confer Risk of Pulmonary Arterial Hypertension

Abstract

Background: Genetic mutations in the genes of BMPR2 pathway are the most crucial cause of pulmonary arterial hypertension. BMP10 is the major ligand of BMPR2, but it remains elusive that whether BMP10 mutation are associated with pulmonary arterial hypertension (PAH). Methods: Whole exome sequencing was applied to screen the BMP10 mutations in 378 patients with congenital heart disease associated with pulmonary arterial hypertension (CHD-PAH). The pathogenicity of variants was assessed by ACMG guideline. Pedigree structures and familial transmission of variants were analyzed for the case who carried the BMP10 mutation. The deleterious function of BMP10 mutations were analyzed via in vitro experiments. Results: Five rare and pathogenic BMP10 variants were identified in five patients with CHD-PAH, including three missense mutations (p.Q74R, p.R96Q, p.I335S) and two nonsense mutations (p.Q116Ter, p.R313Ter). These five cases did not carry mutation in other known PAH risk genes. Five BMP10 mutations were classified as uncertain significance(UVS) or likely pathogenic(LP) variants according to ACMG guideline. It was notworthy that the high impact likely loss-of-function variants in BMP10 were found in 0.53% (2 out of 378) of cases, which was significiantly hihger than those of 0.002% (4 out 251106) in the general population from the GnomAD database (P<10 -4 ). Familial analysis revealed that a case had inherited the heterozygous BMP10 p.I335S missense variant from her affected mother, strongly indicating the co-segregation of BMP10 mutaiton and PAH phenotype. Functional experiments implied that the missense mutation p.I335S and the nonsense mutation p.Q116Ter both resulted in reduced BMP10 protein expression in 293T cells. Conclusion: We identified strong association between rare damaging variants in BMP10 and PAH. The novel BMP10 mutations found in this study will provide new insights into the genetic mechanism of PAH.