BACKGROUND A variant of c.14429G>A (p.Arg4810Lys, rs112735431) in the ring finger protein 213 gene (RNF213; NM_001256071.2) has been recently identified as a risk allele for pulmonary arterial hypertension (PAH). PAH can be added as a new member of RNF213-associated vascular diseases, which include Moyamoya disease and peripheral pulmonary stenosis. Our aim was to identify the clinical features and outcomes of PAH patients with this variant. METHODS Whole-exome sequencing was performed in 139 idiopathic (or possibly heritable) PAH patients. RESULTS The RNF213 p.Arg4810Lys variant was identified in a heterozygous state in 11 patients (7.9%). Time-course changes in hemodynamics after combination therapy in the patients with the RNF213 p.Arg4810Lys variant were significantly poorer compared with those carrying the bone morphogenic protein receptor type 2 (BMPR2) mutation (n = 36) (comparison of changes in mean pulmonary arterial pressure, p = 0.007). The event-free rate of death or lung transplantation was significantly poorer in RNF213 p.Arg4810Lys variant carriers than in BMPR2 mutation carriers (5-year event-free rate since the introduction of prostaglandin I2 infusion, 0% vs 93%, respectively; p < 0.001). CONCLUSIONS Idiopathic PAH patients with the RNF213 p.Arg4810Lys variant are associated with poor clinical outcomes even in recent times. Earlier consideration of lung transplantation might be required for RNF213 p.Arg4810Lys variant carriers who are developing PAH. Documentation of the RNF213 p.Arg4810Lys variant, as well as already known pathogenic genes, such as BMPR2, can provide clinically relevant information for therapeutic strategies, leading to a personalized approach for the treatment of PAH.

中文翻译：

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RNF213变体（p.Arg4810Lys）携带者患有肺动脉高压的预后不良。

背景技术最近已鉴定出无名指蛋白213基因（RNF213； NM_001256071.2）中c.14429G＞ A（p.Arg4810Lys，rs112735431）的变体为肺动脉高压（PAH）的风险等位基因。PAH可以作为RNF213相关血管疾病的新成员而添加，其中包括Moyamoya疾病和周围性肺狭窄。我们的目的是确定具有这种变异的PAH患者的临床特征和结局。方法对139名特发性（或可能遗传）的PAH患者进行了全外显子测序。结果在11例患者中（7.9％）鉴定出RNF213 p.Arg4810Lys变体处于杂合状态。RNF213 p患者在联合治疗后血液动力学的时程变化。与携带2型骨形态发生蛋白受体（BMPR2）突变的患者相比，Arg4810Lys变异体显着更差（n = 36）（比较平均肺动脉压，p = 0.007）。与BMPR2突变携带者相比，RNF213 p.Arg4810Lys变异携带者的无事件死亡或肺移植的发生率要差得多（自引入前列腺素I2输注以来的5年无事件发生率，分别为0％和93％； p <0.001）。结论具有RNF213 p.Arg4810Lys变异的特发性PAH患者即使在最近的时间也与不良的临床预后相关。正在发展PAH的RNF213 p.Arg4810Lys变异携带者可能需要更早考虑肺移植。有关RNF213 p.Arg4810Lys变体以及已知的致病基因（例如BMPR2）的文档，