Okhrimenko Galina, Borovikova Irina, Dankovtseva Elena, Zamyatin Vladimir, Nikulin Dmitry, Zobova Ekaterina, Lyzhenkova Anna, Danilova Anna, Osipova Natalia, Minushkina Larisa, Zateyshchikov Dmitry, Poptsova Maria
Bioinformatics Lab, Institute of Artificial Intelligence and Digital Sciences, HSE University, Moscow, Russia.
Faculty of Physics, Lomonosov Moscow State University, Moscow, Russia.
Respir Res. 2025 Apr 14;26(1):146. doi: 10.1186/s12931-025-03214-9.
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.
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.
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.
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.
特发性肺动脉高压（IPAH）是一种罕见且严重的肺动脉高压形式，其遗传基础最常与BMPR2基因突变相关。然而，俄罗斯人群中尚未有关于IPAH患者基因检测的报道，也未进行系统研究来评估该群体中致病变异的频率。
研究队列包括105例IPAH患者，其中男性23例，女性82例，于2014年至2024年在俄罗斯莫斯科的肺动脉高压护理中心接受治疗。使用全基因组测序进行基因检测。使用GATK、DeepVariant、VEP、sv - callers和AnnotSV进行变异鉴定和注释。使用MOOSE进行的荟萃分析纳入了24项研究，涉及3124例IPAH患者和470个可能致病（P/LP）变异。使用纳入ACMG标准的InterVar进行致病性重新评估。
对105例俄罗斯成年IPAH患者的分析显示，11例患者（10.48%）为致病性或可能致病性（P/LP）BMPR2变异的携带者。重新评估的结果是，P/LP BMPR2变异的数量从394个（59%）增加到445个（67%），其中80个致病变异的意义变得不确定，152个未分类变异变为P/LP。对这些重新评估的致病变异的荟萃分析表明，虽然我们队列中P/LP变异的频率（10.48%）低于荟萃分析的总体平均值17.75%，但差异无统计学意义（p = 0.062）。此外，我们报告了3个文献中未报道的P/LP BMPR2变异，其中1个为结构变异，在3例患者的27个IPAH相关基因中的TBX4、ATP13A3和AQP1基因中发现了4个P/LP变异。
我们首次展示了俄罗斯人群中IPAH患者的基因检测结果。尽管全球数据存在相当大的异质性，但俄罗斯人群中IPAH患者致病性BMPR2突变的患病率与荟萃分析中的总体平均值无显著差异。定期重新评估已发表变异的致病性至关重要，因为一半的致病性BMPR2 - IPAH变异被重新分类为可能致病或意义不确定。
