Yu Qi, Chen Junxian, Li Haibo, Xue Jiangyang, Meng Cuiju, Hong Haifa, Qin Wenjun, Chen Changshui
Screening Center Office, The Affiliated Women and Children's Hospital of Ningbo University, Ningbo, China.
Pediatric Cardiothoracic Surgery, The Affiliated Women and Children's Hospital of Ningbo University, Ningbo, China.
Transl Pediatr. 2025 Aug 31;14(8):1888-1895. doi: 10.21037/tp-2025-271. Epub 2025 Aug 26.
Congenital pulmonary airway malformation (CPAM) is a rare lung abnormality characterized by the formation of cystic or solid masses in lung tissues. To date, the genetic etiology of CPAM has not been well described. The objective of this study is to explore the potential genetic etiology of CPAM through trio-based whole exome sequencing (WES).
We performed WES on 13 fetuses diagnosed with CPAM and their parents. The filtered variants were further analyzed using bioinformatic prediction tools and enrichment analyses.
A total of 23 rare variants were identified in 11 fetuses with CPAM, including 3 homozygous mutations and 19 heterozygous mutations. , , and , all with extremely low population frequencies, were predicted to be deleterious. Notably, mutations in the mucin genes ( and ) were identified in four cases, suggesting potential impairment of epithelial barrier function. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed significant involvement in embryonic development, epigenetic regulation, cellular morphogenesis and immunometabolism-related pathways, highlighting potential immune-metabolic crosstalk in CPAM.
In this study, we provide novel insights into the genetic architecture of CPAM and revealed a multifactorial etiology involving developmental, metabolic, and immune-related mechanisms, which can provide a foundation for future functional studies and genetic counseling in CPAM-affected families.
先天性肺气道畸形（CPAM）是一种罕见的肺部异常，其特征是肺组织中形成囊性或实性肿块。迄今为止，CPAM的遗传病因尚未得到充分描述。本研究的目的是通过基于三联体的全外显子组测序（WES）探索CPAM的潜在遗传病因。
我们对13例诊断为CPAM的胎儿及其父母进行了WES。使用生物信息学预测工具和富集分析对过滤后的变异进行进一步分析。
在11例患有CPAM的胎儿中总共鉴定出23个罕见变异，包括3个纯合突变和19个杂合突变。 、 、 和 ，所有这些在人群中的频率极低，被预测为有害的。值得注意的是，在4例病例中鉴定出粘蛋白基因（ 和 ）的突变，提示上皮屏障功能可能受损。基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析显示，显著参与胚胎发育、表观遗传调控、细胞形态发生和免疫代谢相关途径，突出了CPAM中潜在的免疫-代谢相互作用。
在本研究中，我们对CPAM的遗传结构提供了新的见解，并揭示了涉及发育、代谢和免疫相关机制的多因素病因，这可为未来CPAM受累家庭的功能研究和遗传咨询提供基础。
