Center for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Röntgenstraße 1, 69126, Heidelberg, Germany.
Laboratory for Molecular Genetic Diagnostics, Institute of Human Genetics, Heidelberg University, Röntgenstraße 1, 69126, Heidelberg, Germany.
Respir Res. 2022 Mar 27;23(1):74. doi: 10.1186/s12931-022-01987-x.
A genetic predisposition can lead to the rare disease pulmonary arterial hypertension (PAH). Most mutations have been identified in the gene BMPR2 in heritable PAH. However, as of today 15 further PAH genes have been described. The exact prevalence across these genes particularly in other PAH forms remains uncertain. We present the distribution of mutations across PAH genes identified at the largest German referral centre for genetic diagnostics in PAH over a course of > 3 years.
Our PAH-specific gene diagnostics panel was used to sequence 325 consecutive PAH patients from March 2017 to October 2020. For the first year the panel contained thirteen PAH genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4. These were extended by the three genes ATP13A3, AQP1 and SOX17 from March 2018 onwards following the genes' discovery.
A total of 79 mutations were identified in 74 patients (23%). Of the variants 51 (65%) were located in the gene BMPR2 while the other 28 variants were found in ten further PAH genes. We identified disease-causing variants in the genes AQP1, KCNK3 and SOX17 in families with at least two PAH patients. Mutations were not only detected in patients with heritable and idiopathic but also with associated PAH.
Genetic defects were identified in 23% of the patients in a total of 11 PAH genes. This illustrates the benefit of the specific gene panel containing all known PAH genes.
遗传易感性可能导致罕见疾病肺动脉高压（PAH）。大多数突变已在遗传性 PAH 的 BMPR2 基因中被发现。然而，截至今天，已经描述了另外 15 个 PAH 基因。这些基因在其他 PAH 形式中的确切患病率仍然不确定。我们展示了在最大的德国 PAH 遗传诊断转诊中心，在超过 3 年的时间里，在 PAH 基因中发现的突变在各种基因中的分布。
我们使用特定于 PAH 的基因诊断面板对 2017 年 3 月至 2020 年 10 月的 325 名连续 PAH 患者进行了测序。第一年，该面板包含 13 个 PAH 基因：ACVRL1、BMPR1B、BMPR2、CAV1、EIF2AK4、ENG、GDF2、KCNA5、KCNK3、KLF2、SMAD4、SMAD9 和 TBX4。自 2018 年 3 月以来，随着这三个基因的发现，该面板又扩展到了 ATP13A3、AQP1 和 SOX17 这三个基因。
在 74 名患者（23%）中发现了 79 个突变。在这些变体中，51 个（65%）位于 BMPR2 基因中，而另外 28 个变体则位于另外 10 个 PAH 基因中。我们在至少有两名 PAH 患者的家族中发现了 AQP1、KCNK3 和 SOX17 基因中的致病变体。突变不仅在遗传性和特发性 PAH 患者中被检测到，也在与其他因素相关的 PAH 患者中被检测到。
在总共 11 个 PAH 基因中，有 23%的患者存在遗传缺陷。这说明了包含所有已知 PAH 基因的特定基因面板的益处。
