The role of constitutional genetic defects in idiopathic pulmonary fibrosis (IPF) is increasingly appreciated. Monogenic disorders associated with IPF affect two pathways: telomere maintenance, accounting for approximately 10% of all patients with IPF, and surfactant biology, responsible for 1%–3% of cases and often co-occurring with lung cancer. We examined the prevalence of rare variants in five surfactant-related genes, SFTPA1, SFPTA2, SFTPC, ABCA3, and NKX2-1, that were previously linked to lung disease in whole genome sequencing data from 431 patients with IPF. We identified functionally deleterious rare variants in SFTPA2 with a prevalence of 1.3% in individuals with and without a family history of IPF. All individuals had no personal history of lung cancer, but substantial bronchiolar metaplasia was noted on lung explants and biopsies. Five patients had novel missense variants in NKX2-1, but the contribution to disease is unclear. In general, patients were younger and had longer telomeres compared with the majority of patients with IPF suggesting that these features may be useful for identifying this subset of patients in the clinic. These data suggest that SFTPA2 variants may be more common in unselected IPF cohorts and may manifest in the absence of personal/family history of lung cancer or IPF.

中文翻译：

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家族性和散发性肺纤维化中罕见的表面活性剂相关变异

体质性遗传缺陷在特发性肺纤维化 (IPF) 中的作用越来越受到重视。与 IPF 相关的单基因疾病影响两个途径：端粒维持，约占所有 IPF 患者的 10%，以及表面活性剂生物学，占病例的 1%–3%，并且通常与肺癌同时发生。我们检查了 5 个表面活性剂相关基因SFTPA1、SFPTA2、SFTPC、ABCA3和NKX2-1中罕见变异的普遍性，这些基因之前在来自 431 名 IPF 患者的全基因组测序数据中与肺部疾病相关。我们在SFTPA2中发现了功能有害的罕见变体在有和没有 IPF 家族史的个体中患病率为 1.3%。所有个体都没有肺癌的个人病史，但在肺外植体和活组织检查中发现大量细支气管化生。五名患者在NKX2-1中有新的错义变异，但对疾病的贡献尚不清楚。一般来说，与大多数 IPF 患者相比，患者更年轻且端粒更长，这表明这些特征可能有助于在临床上识别这部分患者。这些数据表明，SFTPA2变体可能在未选择的 IPF 队列中更常见，并且可能在没有肺癌或 IPF 个人/家族史的情况下出现。