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首页> 外文期刊>BMC Pulmonary Medicine >A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension
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A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension

机译：BMPR2和KCNK3中罕见变体的负担有助于家族肺动脉高血压的风险

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Background Pulmonary arterial hypertension (PAH) is a severe lung disease with only few effective treatments available. Familial cases of PAH are usually recognized as an autosomal dominant disease, but incomplete penetrance of the disease makes it difficult to identify pathogenic variants in accordance with a Mendelian pattern of inheritance. Methods To elucidate the complex genetic basis of PAH, we obtained whole exome- or genome-sequencing data of 17 subjects from 9 families with heritable PAH and applied gene-based association analysis with 9 index patients and 300 PAH-free controls. Results A burden of rare variants in BMPR2 significantly contributed to the risk of the disease ( p =?6.0?×?10?8). Eight of nine families carried four previously reported single nucleotide variants and four novel insertion/deletion variants in the gene. One of the novel variants was a large 6.5 kilobase-deletion. In the remaining one family, the patient carried a pathogenic variant in a member of potassium channels, KCNK3, which was the first replicative finding of channelopathy in an Asian population. Conclusions The variety of rare pathogenic variants suggests that gene-based association analysis using genome-wide sequencing data from increased number of samples is essential to tracing the genetic heterogeneity and developing an appropriate panel for genetic testing.
机译：背景技术肺动脉高压（PAH）是一种严重的肺病，只有很少有效治疗。 PAH的家族病例通常被认为是常染色体的显性疾病，但疾病的不完全渗透性使得难以根据孟德尔的遗传模式鉴定病原变体。方法阐明PAH的复杂遗传基础，我们获得了来自9个家庭的全部外销或基因组测序数据，其中来自9个家庭，其中包含遗传性PAH和应用基因的关联分析，具有9名指数患者和300种无磷油对照。结果BMPR2中罕见变体的负担显着导致疾病的风险（p = 6.0？×10 ？8 ）。九个家族中的八个先前报道的单一核苷酸变体和基因中的四种新插入/缺失变体。其中一种新型变异是大6.5千碱基缺失。在剩下的一个家庭中，患者在钾通道的成员中携带致病变体，KCNK3是亚洲人口中的第一个复制的分子病变。结论各种稀有致病变体表明，基于基因的基因关联分析来自增加的样本数量的基因组测序数据对于追踪遗传异质性并开发适当的基因检测组是必不可少的。

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