BACKGROUND

Idiopathic pulmonary arterial hypertension (IPAH) is a rare and severe form of pulmonary hypertension, with a genetic basis most commonly associated with mutations in the BMPR2 gene. However, no genetic testing has been reported for IPAH patients in the Russian population, nor have systematic studies been conducted to assess the frequency of pathogenic variants in this group.

METHODS

The study cohort included 105 IPAH patients, consisting of 23 males and 82 females, who were managed at the PH care center in Moscow, Russia, from 2014 to 2024. Genetic testing was performed using whole-genome sequencing. Variant identification and annotation were conducted using GATK, DeepVariant, VEP, sv-callers and AnnotSV. A meta-analysis, performed with MOOSE, included 24 studies involving 3124 IPAH patients and 470 P/LP variants. Pathogenicity reassessment was carried out using InterVar, which incorporates ACMG criteria.

RESULTS

Analysis of 105 adult IPAH patients in Russia revealed 11 patients (10.48%) as carriers of pathogenic or likely pathogenetic (P/LP) BMPR2 variants. As the result of reassessment, the number of P/LP BMPR2 variants raised from 394 (59%) to 445 (67%) with 80 pathogenic variants became of uncertain significance, and 152 unclassified variants became P/LP. The meta-analysis of these reevaluated pathogenic variants showed that while the frequency of P/LP variants in our cohort (10.48%) is lower than the overall average of 17.75% from the meta-analysis, the difference is not statistically significant (p = 0.062). Additionally, we report three P/LP BMPR2 variants, not reported in literature, with one being structural, and four P/LP variants in TBX4, ATP13A3 and AQP1 genes from 27 IPAH genes in 3 patients.

CONCLUSIONS

For the first time, we present the results of genetic testing in IPAH patients from the Russian population. Despite the considerable heterogeneity in the world-wide data, the prevalence of pathogenic BMPR2 mutations in IPAH patients from the Russian population does not significantly differ from the overall average in the meta-analysis. It is crucial to periodically reassess the pathogenicity of published variants, as half of the pathogenic BMPR2 IPAH variants were reclassified as LP or of uncertain significance.