Department of Pulmonology, St. Antonius ILD Center of Excellence, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands.
Department of Clinical Chemistry, St. Antonius ILD Center of Excellence, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands.
Int J Mol Sci. 2023 Feb 1;24(3):2790. doi: 10.3390/ijms24032790.
In only around 40% of families with pulmonary fibrosis (PF) a suspected genetic cause can be found. Genetic overlap analysis of Whole Exome Sequencing (WES) data may be a powerful tool to discover new shared variants in novel genes for PF. As a proof of principle, we first selected unrelated PF patients for whom a genetic variant was detected (n = 125) in established PF genes and searched for overlapping variants. Second, we performed WES (n = 149) and identified novel potentially deleterious variants shared by at least two unrelated PF patients. These variants were genotyped in validation cohorts (n = 2748). In 125 unrelated patients, a potentially deleterious variant was detected in known PF genes of which 15 variants in six genes overlapped, involving 51 patients. Overlap analysis of WES data identified two novel variants of interest: c.421T > C p.(Y141H) and c.1373dupG p.(S459fs*5), neither gene had been related to pulmonary fibrosis before. Both proteins were present in the alveolar epithelium. No apparent characteristics of telomere disease were observed. This study underlines the potential of searching for overlapping rare potentially deleterious variants to identify disease-associated variants and genes. A previously unreported variant was found in two putative new PF genes, but further research is needed to determine causality.
在仅有约 40%的肺纤维化 (PF) 患者的家庭中可以发现疑似遗传原因。全外显子组测序 (WES) 数据的遗传重叠分析可能是发现 PF 新基因中共享新变异的有力工具。作为原理验证，我们首先选择了已发现遗传变异（n = 125）的不相关 PF 患者，这些变异存在于已建立的 PF 基因中，并搜索重叠变异。其次，我们进行了 WES（n = 149），并确定了至少两个不相关的 PF 患者共享的新的潜在有害变异。这些变异在验证队列（n = 2748）中进行了基因分型。在 125 个不相关的患者中，在已知的 PF 基因中检测到潜在有害的变异，其中六个基因中的 15 个变异重叠，涉及 51 个患者。WES 数据的重叠分析确定了两个新的感兴趣的变异：c.421T > C p.(Y141H) 和 c.1373dupG p.(S459fs*5)，这两个基因以前都与肺纤维化无关。这两种蛋白质都存在于肺泡上皮细胞中。没有观察到明显的端粒疾病特征。本研究强调了寻找重叠的罕见潜在有害变异以识别疾病相关变异和基因的潜力。在两个推定的新 PF 基因中发现了一个以前未报道的变异，但需要进一步研究来确定因果关系。
