Prenatal trio-based whole exome sequencing in fetuses with congenital pulmonary airway malformation
Original Article

Prenatal trio-based whole exome sequencing in fetuses with congenital pulmonary airway malformation

Qi Yu1#, Junxian Chen2#, Haibo Li3, Jiangyang Xue3, Cuiju Meng1, Haifa Hong4, Wenjun Qin4, Changshui Chen5

1Screening Center Office, The Affiliated Women and Children’s Hospital of Ningbo University, Ningbo, China; 2Pediatric Cardiothoracic Surgery, The Affiliated Women and Children’s Hospital of Ningbo University, Ningbo, China; 3The Central Laboratory of Birth Defects Prevention and Control, The Affiliated Women and Children’s Hospital of Ningbo University, Ningbo, China; 4Department of Pediatric Cardiothoracic Surgery, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; 5Ningbo Key Laboratory of Genomic Medicine and Birth Defects Prevention, The Affiliated Women and Children’s Hospital of Ningbo University, Ningbo, China

Contributions: (I) Conception and design: C Chen, W Qin, Q Yu; (II) Administrative support: C Chen, W Qin; (III) Provision of study materials or patients: Q Yu, J Chen; (IV) Collection and assembly of data: H Li, J Xue; (V) Data analysis and interpretation: Q Yu, C Meng, H Hong; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to: Wenjun Qin, PhD. Department of Pediatric Cardiothoracic Surgery, Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, 355 Lu-ding Rd., Shanghai 200032, China. Email: qwj0130@163.com; Changshui Chen, MD. Ningbo Key Laboratory of Genomic Medicine and Birth Defects Prevention, The Affiliated Women and Children’s Hospital of Ningbo University, 339 Liu-ting Rd., Ningbo 315000, China. Email: chencs@139.com.

Background: 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).

Methods: 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.

Results: A total of 23 rare variants were identified in 11 fetuses with CPAM, including 3 homozygous mutations and 19 heterozygous mutations. EYA1, FAP, THAP4 and ALDH1B1, all with extremely low population frequencies, were predicted to be deleterious. Notably, mutations in the mucin genes (MUC3A and MUC6) 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.

Conclusions: 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.

Keywords: Congenital pulmonary airway malformation (CPAM); whole exome sequencing (WES); prenatal diagnosis; genetic mutations

Submitted Apr 21, 2025. Accepted for publication Jul 10, 2025. Published online Aug 26, 2025.

doi: 10.21037/tp-2025-271

Highlight box

Key findings

• Congenital pulmonary airway malformation (CPAM) may involve epithelial barrier dysfunction cause by mucin gene mutations and be associated with potential immune–metabolic crosstalk.

What is known and what is new?

• CPAM is a rare congenital lung malformation potentially associated with deleterious genetic variants disrupting critical developmental pathways essential for normal airway morphogenesis.

• This is the first comprehensive investigation of prenatal trio-based whole exome sequencing in CPAM, revealing that CPAM may involve epithelial barrier dysfunction driven by mucin gene mutations and potential immune–metabolic crosstalk.

What is the implication, and what should change now?

• This research suggests that CPAM may result from interactions among developmental, metabolic, and immune pathways, with rare mucin gene variants implicating epithelial barrier dysfunction, providing a basis for future validation and clinical translation.

Introduction

Congenital pulmonary airway malformation (CPAM) is a rare congenital anomaly of the lower respiratory tract characterized by the formation of cystic or solid masses of abnormal lung tissue (1-4). The clinical presentation of CPAM is highly variable, ranging from severe cases that may lead to hydrops fetalis and necessitate pregnancy termination, to completely asymptomatic forms identified antenatally via routine prenatal ultrasound. Newborns with CPAM may exhibit severe respiratory distress immediately after birth or remain asymptomatic until symptoms manifest later in life (5). Although prenatal ultrasound is the primary tool for CPAM detection, overlapping imaging features with those of other lesions and the limited clinical data obtainable during gestation result in inaccurate prenatal diagnosis and challenges in effective genetic counseling (6,7).

CPAM has a low incidence rate, ranging from 1 in 8,300 to 1 in 35,000 live births (5). To date, the research on CPAM genetic mechanism remains limited, possibly due to the lack of evidence for classic inheritance patterns, coupled with its low incidence and sporadic occurrence. Karyotype analysis and chromosome microarray analysis are the most common molecular genetic tests in clinical practice. However, these methods frequently fail to elucidate the underlying genetic etiology in many cases (8,9). With the development of molecular genetic technology, whole exome sequencing (WES) has gradually become a powerful tool for identifying single gene mutations in fetal abnormalities (10-12). Notably, trio-based WES studies in CPAM have revealed pathogenic mutations in genes critical for lung development, suggesting that some variants are involved in molecular pathways related to cancer development (5,9,13). These findings suggest that although CPAM primarily occurs sporadically, the presence of familial cases and rare mutations indicates that deleterious genetic variants may disrupt critical developmental pathways essential for normal airway morphogenesis (14,15). Nevertheless, existing studies have primarily focused on postnatal cases (16,17), and prenatal trio-based WES investigations remain rare in the literatures.

In this study, we performed prenatal trio-based WES on thirteen fetuses affected by CPAM and their parents to expand the spectrum of genetic variants associated with CPAM and to provide further insights into the underlying pathogenic mechanisms. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-271/rc).

Methods

Recruitment of family

We recruited 13 fetuses with CPAM who were referred to the Screening Center Office at The Affiliated Women and Children’s Hospital of Ningbo University from July 2023 to July 2024, including 6 male fetuses and 7 female fetuses.

Genomic DNA collection

The amniotic fluid samples and peripheral blood samples from their parents were collected. Genomic DNA was extracted using the TIANamp Blood DNA Kit (Tiangen, China), according to the manufacturer’s instructions. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The present study received ethical approval from the Medical Ethics Committee at The Affiliated Women and Children’s Hospital of Ningbo University (No. 23KYSL-094). All participating individuals gave their informed consent for inclusion before they participated in the study.

Genetic analysis

DNA libraries were constructed as stated in previous studies (18,19). Indels, copy number variants (CNVs), and single-nucleotide variants (SNVs) were identified as described in previous studies (18,19). Each variant was compared in public databases, including exome aggregation consortium (ExAC, https://gnomad.broadinstitute.org/) and gnomAD (https://gnomad.broadinstitute.org/). Additionally, variants underwent pathogenic prediction with tools freely available online such as Sorting Intolerant From Tolerant (SIFT), Polymorphism Phenotyping v2 (PolyPhen-2) and meta-support vector machine (MetaSVM). WEB-based GEne SeT AnaLysis Toolkit (WebGestalt) (https://www.webgestalt.org/) was used for Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the variants identified in fetuses (20).

Statistical analysis

Rare variants were defined as those with minor allele frequency (MAF) <0.1% in population databases, including gnomAD or ExAC. Functional impact of variants was predicted using SIFT, PolyPhen-2 HDIV, and MetaSVM. KEGG pathway enrichment analysis was performed using WebGestalt, and pathways with a P value <0.01 were considered significantly enriched.

Results

Proband clinical characteristics

WES was performed on 13 fetuses diagnosed with CPAM along with their parents. Clinical characteristics including gender, CPAM location, and pregnancy outcome are listed in Table 1. Of the 13 fetuses included in the study (6 males, 7 females), 12 were delivered as live births, and one underwent medical termination. The fetus CPAM6 was excluded from this study following termination of pregnancy because of other severe congenital malformations.

Table 1

Clinical characteristics of fetuses with CPAM

Fetus number Gender Location Pregnancy outcome
CPAM1 Male Right lobe Live birth
CPAM2 Female Left lobe Live birth
CPAM3 Female Left lobe Live birth
CPAM4 Female Right lobe Live birth
CPAM5 Female Left lobe Live birth
CPAM6 Female Left lobe Induced abortion
CPAM7 Male Left lobe Live birth
CPAM8 Male Right lobe Live birth
CPAM9 Male Left lobe Live birth
CPAM10 Female Right lobe Live birth
CPAM11 Female Left lobe Live birth
CPAM12 Male Right lobe Live birth
CPAM13 Male Right lobe Live birth

CPAM, congenital pulmonary airway malformation.

WES identified variants

After stringent quality control, there were 23 rare variants identified exclusively in 11 affected fetuses, as shown in Table 2. No variants were identified in one fetus CPAM10. Homozygous variants NBPF10, MAGEC1, and TAF4 were identified. Additionally, 20 heterozygous variants were identified, including EYA1, PDS5B, MUC3A, NPTXR, NBPF1, THAP4, GNA12, MUC6, PDE4DIP, SRRD, FAP, PLEKHH2, ALDH1B1, KIAA0319, PRDM12, GOLGA6L1, GOLGA6L22, HLA-DRB5, FOXI3, HCN2.

Table 2

Genetic profile of the 11 fetuses with CPAM included in this study

Fetus number Gender Homozygous Heterozygous
CPAM1 Male EYA1
CPAM2 Female NBPF10 PDS5B
CPAM3 Female MUC3A, NPTXR
CPAM4 Female NBPF1, THAP4, GNA12
CPAM5 Female MUC6, PDE4DIP
CPAM7 Male MAGEC1 SRRD
CPAM8 Male FAP
CPAM9 Male PLEKHH2, ALDH1B1
CPAM11 Female TAF4 KIAA0319, MUC3A, PRDM12, GOLGA6L1, GOLGA6L22
CPAM12 Male HLA-DRB5
CPAM13 Male FOXI3, MUC3A, HCN2

CPAM, congenital pulmonary airway malformation.

EYA1, THAP4, FAP, and ALDH1B1 were predicted to be deleterious by multiple bioinformatics tools (SIFT, PolyPhen-2, and MetaSVM) and found at extremely low population frequencies (gnomAD/ExAC <0.1%) as shown in Table 3. Among these, the mutation in EYA1, a gene widely reported to be associated with Branchio-Oto-Renal syndrome (21,22), suggesting its possible role in congenital developmental anomalies. FAP encodes a transmembrane serine protease that has been reported as a specific marker of cancer-associated fibroblasts, playing a critical role in tissue remodeling, extracellular matrix degradation, and cell migration (23,24). ALDH1B1, a key gene in aldehyde metabolism, has also been shown to be essential for the maintenance of cancer stem cells and tumor progression (25). This is also consistent with previous studies, which observed oncogene mutations in CPAM (5,9).

Table 3

Summary of the mutated genes in 11 fetuses with CPAM included in this study

Gene Genomic coordinates Variant type ExAC_ALL gnomAD_AF SIFT/PolyPhen-2_HDIV/MetaSVM _pred
EYA1 chr8:71299070 Nonsynonymous SNV 0 0 T/D/D
NBPF10 chr1:146074349 Nonsynonymous SNV 0
PDS5B chr13:32770441 Frameshift deletion 0.0007 7.168e−05
MUC3A chr7:100955628 Frameshift insertion 0
NPTXR chr22:38843700 Frameshift deletion 0
NBPF1 chr1:16589962 – 5.952e−05 3.696e−05
THAP4 chr2:241602972 Nonsynonymous SNV 0 0 T/D/D
GNA12 chr7:2844151 Frameshift deletion 0
PDE4DIP chr1:149005125 Nonsynonymous SNV 0
MUC6 chr11:1017046 Frameshift deletion 0
SRRD chr22:26484008 Frameshift deletion 0
MAGEC1 chrX:141906382 Frameshift deletion 0
FAP chr2:162225499 Nonsynonymous SNV 8.36e−06 8.292e−06 D/D/D
PLEKHH2 chr2:43694467 Stop-gained 0
ALDH1B1 chr9:38395998 Nonsynonymous SNV 4.96e−05 4.484e−05 D/D/D
KIAA0319 chr6:24579941 Frameshift deletion 3.601e−05 1.46e−05
PRDM12 chr9:130681622 Frameshift deletion 0
GOLGA6L1 chr15:23129938 Nonsynonymous SNV 0 9.595e−05
GOLGA6L12 chr15:23129938 Nonsynonymous SNV 0 9.595e−05
TAF4 chr20:62065486 Frameshift insertion 0
HLA-DRB5 chr6: 32518555 – 0 0
FOXI3 chr2:88452479 Frameshift deletion 0
HCN2 chr19:590300 Frameshift deletion 0

CPAM, congenital pulmonary airway malformation; D, deleterious; ExAC, exome aggregation consortium; MetaSVM, meta-support vector machine; PolyPhen-2, Polymorphism Phenotyping v2; SIFT Sorting, Intolerant From Tolerant; SNV, single nucleotide variant; T, tolerated.

Notably, frameshift mutations were detected in mucin genes MUC3A and MUC6 in four fetuses. MUC3A and MUC6 encode mucins, a group of glycoproteins located on the surface of epithelial tissues, which play crucial roles in protection and lubrication (26). Mutations or abnormal expression of these genes have been reported to be associated with a variety of diseases, particularly in immunological disorders and cancers (27-29). Thus, mutations in these mucin genes may impair epithelial barrier function and contribute to structural abnormalities during fetal lung development.

Enriched analysis of these variants

In order to fully understand the potential function of the identified mutations, we conducted GO enrichment analysis of these 23 mutated genes in the fetuses on WebGestalt. The biological process (BP), cellular component (CC), and molecular function (MF) databases were selected as references, and Over-Representation Analysis (ORA) was performed using protein-coding genes as the background set. Processes with a P value less than 0.01 were considered significantly enriched. As shown in Figure 1A, the top 10 enriched processes were related to developmental regulation, metabolic activity, and CC organization. Among them, melanocyte proliferation and epidermal cell fate specification showed the highest enrichment ratios, suggesting that these mutated genes may play critical roles in embryonic development and the formation of ectoderm-derived structures. Additionally, processes related to epigenetic modification, such as peptidyl-lysine dimethylation and non-phosphorylating glycolytic enzyme activity, indicating potential involvement in metabolic reprogramming. Enrichment in terms such as pharyngeal system development, Golgi lumen localization, and components of clathrin-coated vesicles further support the involvement of these genes in cell fate determination, protein processing and transport, and tissue morphogenesis. These findings provide a foundation for understanding the potential roles of the mutated genes in CPAM.

Figure 1 Enriched analysis of the variants. (A) The top 10 enriched processes in GO analysis. (B) The top 10 enriched pathways in KEGG analysis. CoA, coenzyme A; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.

Then, the mutated genes were submitted to the WebGestalt to determine the KEGG enrichment. Pathways with a P value less than 0.01 were considered significantly enriched. The top 10 enriched pathways were shown in Figure 1B. This KEGG enrichment analysis elucidates that these mutated genes are involved immunometabolism regulation. The results demonstrate that the pantothenate and coenzyme A (CoA) pathway is critically involved in energy metabolism and lipid homeostasis, while histidine metabolism and its sub-pathways (ascorbate and β-alanine metabolism) show significant associations with immunometabolism disorders. These findings provide novel insights into metabolic-immune crosstalk in CPAM.

Discussion

In this study, WES was conducted in 13 CPAM-affected fetuses and their parents. A total of 23 rare variants were identified in fetuses, including 3 homozygous mutations and 20 heterozygous mutations. Notably, several variants such as EYA1, FAP, THAP4 and ALDH1B1 were predicted to be deleterious and are known to participate in congenital developmental anomalies, metabolic homeostasis, and cancer progression (21-25). These findings are consistent with previous studies that oncogenic mutations have been identified in CPAM (5,9), suggesting that such genetic alterations may not only impair lung development but also pose long-term risks, highlighting the importance of careful monitoring and follow-up in clinical diagnosis and management.

Interestingly, several of these mutated genes such as EYA1 are recurrently mutated at different sites in independent patients, suggesting its potential role as key genetic contributors to disease susceptibility (as listed in Table S1). The recurrence of mutations within the same gene at distinct sites strengthens the evidence for their functional significance and pathogenic potential. EYA1 is well-known for its role in organogenesis and has been reported implicating in congenital syndromes such as Branchio-Oto-Renal syndrome (21,22). Notably, the gene MUC3A is mutated at different sites in different patients (as listed in Table S1). It encodes mucins, which are essential components of the epithelial barrier, and their dysregulation has been implicated in a variety of immune-related and neoplastic disorders (27-29). Their involvement in CPAM may reflect a previously unrecognized mechanism whereby epithelial barrier defects, possibly through impaired mucosal signaling or cell adhesion, contribute to abnormal branching morphogenesis and airway cyst formation.

The GO enrichment analysis of the 23 mutated genes showed significant enrichment in embryonic development, cell fate specification, and epigenetic modification. Our KEGG pathway enrichment analysis revealed the enriched pathways are not only associated with cellular energy metabolism and lipid regulation, but are also closely linked to immune signaling and inflammatory responses. The observed associations suggest a possible crosstalk between immune and metabolic dysfunctions in CPAM.

The inherent limitation of our study is the relatively small sample size and the absence of large pedigrees with clear disease segregation, which is common to most researches involving rare, genetically heterogeneous, and oligo/polygenic disorders (5). Moreover, our study is also limited by the lack of definitive postnatal histological classification of CPAM tissues and functional validation, which may affect the generalizability of the findings and hinder in-depth comparisons of phenotypic characteristics and prognostic differences among distinct histologic subtypes. Future studies with larger cohorts, complete pathological data, and experimental validation are needed to further clarify the genetic mechanisms underlying CPAM. Nevertheless, despite these shortcomings, the results remain highly significant. In particular, we identified several common pathways involved in metabolic-immune crosstalk and epithelial barrier dysfunction, which provides new directions for further elucidating the molecular mechanisms of CPAM and improving its clinical management.

Conclusions

In summary, our study provides novel genetic insights into the etiology of CPAM through trio-based WES of fetuses affected with CPAM and their unaffected parents. We detected 23 rare variants in CPAM-affected fetuses that have not been previously described. GO and KEGG enrichment analyses revealed significant associations with pathways related to cell fate determination, epigenetic modification, and immunometabolism processes, suggesting a multifactorial genetic basis underlying CPAM pathogenesis. Our study highlights the potential roles of metabolic-immune crosstalk and epithelial barrier dysfunction in CPAM. The findings from our study can be helpful in precision medicine interventions and genetic counseling in CPAM affected families.

Acknowledgments

We would like to take this opportunity to extend our deepest appreciation to all the individuals who have generously lent their time, knowledge, and skills to the creation and refinement of our article. Their contributions have been instrumental in its success.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-271/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-271/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-271/prf

Funding: The study was funded by Municipal Key Research and Development Plan of Ningbo (No. 2023Z178), Ningbo Medica and Health Brand Discipline (No. 2022020405), National Natural Science Foundation of China (No. 32201046), and the Clinical Research Plan of Shenkang Hospital Development Center of Shanghai (No. SHDC2023CRD011).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-271/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and the protocol was approved by the Medical Ethics Committee at The Affiliated Women and Children’s Hospital of Ningbo University (No. 23KYSL-094). All participating individuals gave their informed consent for inclusion before they participated in the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Yu Q, Chen J, Li H, Xue J, Meng C, Hong H, Qin W, Chen C. Prenatal trio-based whole exome sequencing in fetuses with congenital pulmonary airway malformation. Transl Pediatr 2025;14(8):1888-1895. doi: 10.21037/tp-2025-271

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