The prevalence of pathogenic variants in the BMPR2 gene in patients with idiopathic pulmonary arterial hypertension in the Russian population: sequencing data and meta-analysis

Background Idiopathic pulmonary arterial hypertension (IPAH) is a rare and severe form of pulmonary hypertension. Genetic predisposition, especially rare variants in the BMPR2 gene, plays a significant role in IPAH development, influencing disease onset and progression. More than 600 unique variants of this gene have been reported in the literature as being associated with IPAH. No systematic studies have been conducted to estimate the frequency of pathogenic variants in BMPR2 in the Russian population. It is recommended to reevaluate IPAH variants every three years in order to incorporate newly available data from the literature. Thus, to compare the prevalence of the discovered pathogenic variants in IPAH patients in the Russian population we need to re-evaluate pathogenicity of the published BMPR2 variants and then to perform meta-analysis based on the reassessed data. Methods Whole-genome sequencing was done for a cohort of 74 adult IPAH patients in Russia. Variant identification in BMPR2 gene was done with the standard bioinformatic pipeline. Literature analysis was done by a curated search for BMPR2 variants in PAH patients in public databases. A meta-analysis of the frequency of pathogenic variants was conducted in accordance with the MOOSE (Meta-Analysis of Observational Studies in Epidemiology) guidelines. Reassessment of pathogenicity was performed with InterVar software that incorporate ACMG criteria. Results Analysis of the BMPR2 gene from 74 adult IPAH patients in Russia revealed that 6 out of 74 patients (8.11%) carried pathogenic or likely pathogenetic variants. The reassessment of 665 variants found by us in the literature revealed that only 70% of PAH variants in BMPR2 are now classified as pathogenic or likely pathogenic. Meta-analysis based on the reevaluated pathogenic variants showed that even though the frequency of 8.11% of pathogenic or likely pathogenic variants in our cohort is lower than the overall average of 17,75% from the meta-analysis, the difference is not statistically significant (p = 0.052). We also report de novo found deletion in the 6th exon of the BMPR2 gene. Conclusion For the first time we present the results of the sequencing study of IPAH patients in the Russian population. Despite the substantial heterogeneity observed in the data, the prevalence of pathogenic mutations in BMPR2 gene in IPAH patients in the Russian population does not significantly differ from the average from the meta-analysis. It is essential to periodically revise the pathogenicity of the published variants since only 70% of PAH variants in BMPR2 were classified as pathogenic or likely pathogenic.