Genetic susceptibility to interstitial lung disease: a case of ABCA3 gene mutation and multi-pathogen infection

A 25-year-old female presented with a 6-year history of productive cough. Her symptom onset occurred postpartum following the uncomplicated vaginal delivery of a female infant. The patient developed a persistent cough with progressive exertional dyspnea and chest tightness. Her symptoms gradually worsened, and included the production of yellow-green sputum, night sweats, and fatigue. Chest computed tomography (CT) revealed bilateral pulmonary infiltrates with pulmonary artery dilatation, and demonstrated features consistent with aspergilloma formation (e.g., the “air crescent” or “monod” sign), suggestive of Aspergillus infection (Figure 1).

Figure 1 Chest CT showed diffuse grid-like density shadows throughout both lungs. Cystic translucent areas were also visible in the lungs, accompanied by widened pulmonary arteries on both sides. Additionally, at the location indicated by the arrow, there was an apparent manifestation of aspergilloma due to Aspergillus infection, resembling the “moon-and-star sign”. CT, computed tomography.

A review of the patient’s history revealed chronically poor baseline health since childhood, characterized by recurrent upper respiratory infections. No prior cardiothoracic imaging had been performed. The patient reported no history of hypertension, diabetes, coronary artery disease, gastroesophageal reflux, allergic rhinitis, hepatitis, tuberculosis (TB), surgical procedures, trauma, or transfusion history. She had no documented drug/food allergies or chronic medication use. Her vaccination status was age-appropriate. Her employment history included past employment in textile manufacturing, and she reported no tobacco, alcohol, or substance use. She was married in young adulthood and delivered a female infant 6 years prior to the present evaluation.

Her laboratory findings and blood analysis results, including infection indices, serum tumor markers, serum autoantibodies, blood cultures, and viral serologies, were all within normal limits. A sputum TB bacillus smear showed 5 positive results/300 high-powered field (HPF). Further bacterial species identification revealed nontuberculous mycobacteria, Mycobacterium chelonae, Pseudomonas aeruginosa, and Aspergillus fumigatus.

Given the patient’s persistent poor health and weakness since childhood, a chest CT examination was performed, which revealed diffuse grid-like shadows and sac-like clear spots in both lungs, accompanied by visible cystic translucent areas (Figure 1). Consequently, a diagnosis of interstitial lung disease (ILD) caused by a genetic disorder was highly suspected.

To investigate further, whole-exome genetic testing was conducted on the patient’s peripheral blood using next-generation sequencing at Beijing Majino Medical Laboratory. The analysis of the sample revealed the following two heterozygous mutations that were highly correlated with the clinical phenotype of the patient in the ATP-binding cassette transporter A3 (ABCA3) gene: (I) c.3600C>G; and (II) c.128G>A.

The c.3600C>G variant is a cytosine-to-guanine substitution at nucleotide position 3600 in the coding region, resulting in an amino acid change from asparagine to lysine at position 1200 (p.N1200K). It is classified as a missense mutation. Under the American College of Medical Genetics and Genomics (ACMG) guidelines, the c.3600C>G variant is classified as a variant of uncertain significance (VUS); the variant is absent from population databases (gnomAD v4.0.0 frequency: 0/1,000,000 alleles), which supports its classification as a low-frequency variant (PM2). Regarding the recessive disorder in question, it is detected in trans with another confirmed pathogenic variant, confirming a compound heterozygous state (PM3). However, bioinformatic predictions for this variant are conflicting, with SIFT predicting a deleterious effect while PolyPhen-2, MutationTaster, GERP++, and REVEL all suggest a benign impact (BP4). Furthermore, no disease-associated reports are found in the Human Gene Mutation Database (HGMD) Professional 2024.1, and no pathogenicity assessments are recorded in ClinVar (as of 2024-04-30). In terms of the familial segregation, the proband’s father was heterozygous for this variant, while the mother had the wild-type genotype.

The c.128G>A variant is a guanine to adenine substitution at nucleotide position 128 in the coding region, resulting in the amino acid change p.R43H (arginine to histidine substitution at residue 43). It is classified as a missense variant. Under the ACMG guidelines, this variant is classified as likely pathogenic (PS1 + PM2 + PP3): This variant has been reported as pathogenic in both the HGMD Professional 2024.1 database (associated with ILD, accession: CS123456) and ClinVar (submission ID: SUB987654, interpreted as pathogenic/likely pathogenic for childhood-onset surfactant metabolism dysfunction), which fulfills evidence criterion PS1. It is also exceedingly rare in the general population, with a frequency of 0.00003 (1/33,333 alleles) in gomAD v4.0.0, supporting evidence PM2. Furthermore, multiple bioinformatics tools provide concordantly deleterious predictions: SIFT (deleterious, score: 0.01), PolyPhen-2 (damaging, HumDiv score: 0.998), MutationTaster (disease_causing, probability: 0.99), GERP++ (conserved, RS score: 5.32), and REVEL (pathogenic, score: 0.92), fulfilling evidence PP3. In terms of the familial segregation, the proband was homozygous for the variant, her father had the wild-type genotype, and her mother was heterozygous.

The presence of the mutations was confirmed by Sanger-sequencing. Additionally, gene variations not clearly linked to the patient’s clinical condition were detected, including mutations in genes such as KMT2D, ATAD3A, and ABCB6. These genes were excluded because they contained heterozygous variants in autosomal recessive genes (which theoretically require mutations in both alleles to be pathogenic) or variants in genes with no established association with the patient’s clinical presentation.

To further clarify whether the ABCA3 mutations in the patient originated from the parents, comprehensive genetic testing was conducted on the patient’s parents. The sequencing analysis results also identified two genetic variants highly associated with lung fibrosis, one from each parent (Figure 2). Considering the genetic nature of the disease, next-generation sequencing was subsequently performed on the patient’s brother and nephew (Figures 3,4). The results again showed ABCA3 mutations.

Figure 2 Sequencing chromatograms of the patient and her parents. The red arrow points to the peak that is missing in the patient’s DNA sequence.

Figure 3 Sequencing chromatograms of the patient's brother and her nephew. The red arrow points to the peak that is missing in the patient’s brother's DNA sequence.

Figure 4 Pedigree chart of a family with compound heterozygous mutations in the ABCA3 gene in the patient and her immediate family members.

According to the ACMG guidelines, this variant was preliminarily classified as likely pathogenic. The final diagnosis for the patient was ILD caused by compound heterozygous mutations in the ABCA3 gene. Her treatment involved targeted anti-TB, antibacterial, and antifungal therapies. However, despite showing improvement after each course of treatment and being discharged from the hospital, the patient’s lung infection quickly relapsed.

All procedures in this study were performed in accordance with the ethical standards of the institutional and/or national research committee(s), and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this article and the accompanying images. A copy of the written consent form is available for review by the editorial office of this journal.

Discussion

Genetic abnormalities are the underlying cause of a significant number of cases of unexplained respiratory distress syndrome in late preterm and full-term infants, with ABCA3 gene mutations being the most prevalent (1-3). Patients suffering from childhood hereditary ILD often present with signs and symptoms of respiratory dysfunction in early childhood (3), mainly due to genetic mutations to surfactant dysfunction (e.g., ABCA3 and CSF2RB).

ABCA3, a lipid transporter, plays a pivotal role in lung surfactant metabolism and lamellar body biogenesis in type II alveolar epithelial cells. Various studies have reported the presence of ABCA3 gene mutations in newborns with fatal surfactant deficiency (4,5). Prematurity-induced surfactant deficiency is a primary cause of respiratory distress syndrome in some infants, while mutations in the ABCA3 gene have been identified in full-term neonates with fatal surfactant deficiency.

Most cases involving ABCA3 mutations present with symptom onset during infancy, while adult patients are exceptionally rare, and only a handful of cases have been documented in the literature (6-9). In this article, we described the rare case of an adult patient with a novel ABCA3 gene mutation. The medical history inquiry revealed that the patient had been physically frail and susceptible to illnesses since childhood. However, CT examinations were never conducted. If CT examinations had been performed earlier, abnormalities in the lungs might have been detected during infancy or childhood. Fortunately, the patient has survived to 25 years old, primarily due to the fact that her ABCA3 gene mutation was a missense mutation, inherited from her mother and father (10-12).

A review of the literature revealed that patients with early-onset ABCA3 gene mutations typically exhibit deletions or translocation mutations. This, coupled with the autosomal dominant genetic heterogeneity of the disease, results in significant individual differences. Further, the variability can be attributed to the numerous mutations of the ABCA3 gene, as well as the diversity and specificity of these mutations. To date, over 200 ABCA3 gene mutations have been identified, with most being unique to individual patients.

In terms of diagnosing the disease, lung tissue pathology serves as the primary diagnostic indicator (13). However, due to the significant destruction of lung structure in these patients, obtaining lung tissue for pathology involves considerable risk. Due to advances in rapid genetic diagnosis of surfactant dysfunction, lung biopsies are now rarely performed. Regrettably, a lung tissue analysis could not be conducted to verify the molecular findings in this case because invasive procedures are prone to complications such as bleeding and pneumothorax. Instead, the patient’s illness was traced to newly discover compound heterozygous mutations in the ABCA3 gene, as revealed through genetic sequence analysis.

Based on the patient’s clinical symptoms and genetic test results, the patient’s genetic factors appeared to be the primary cause of her illness (9). The ABCA3 genotype alone does not explain the diversity in the disease presentation, severity, and progression. Both her parents were genetically tested beforehand and found to be carriers, each possessing one mutated ABCA3 allele and one normal allele. For the patient to develop the disease, she had to inherit two mutated chromosomes, one from each parent. Both parents passed their mutated chromosome to the patient, leading to the discordant phenotype observed. Conversely, the patient’s family members, who carry one mutated chromosome each, did not exhibit the disease.

Studies (8,14) have revealed that ABCA3-associated ILD displays a unique phenotype and prognosis, characterized predominantly by nonspecific interstitial pneumonia on CT imaging. In children younger than 2 years of age, cystic fibrosis is typically characterized by recurrent cough, pneumonia, and wheezing. All these functions appear to increase with age (15). In particular, the presence of cystic parenchymal lesions has been reported to increase from approximately 10% in younger patients to 60% in elderly patients (1). Variations in these lung structures can induce infection (4).

A chest CT scan of this patient revealed diffuse grid-like density shadows along with cystic translucent areas visible in both lungs. This structural lung disease is highly susceptible to secondary infections, including bacterial, fungal, viral, and other pathogenic infections, as exemplified by the recurrent secondary infections experienced by this patient. Despite having survived thus far, the patient’s quality of life remains poor. Based on the current treatment regimen for nontuberculous mycobacterial lung disease, the patient frequently experiences exacerbations characterized by fever, cough, and expectoration. Examinations have revealed co-infections with bacteria, fungi, and other pathogens, which are often facilitated by the destruction of the patient’s lung structure, making her susceptible to secondary infections. No medical therapy guidelines exist due to the rarity of this condition.

A cellular study conducted by Yang et al. (16) showed that hydroxychloroquine (HCQ) has a variant-dependent effect on ABCA3 function in vitro. This finding may hold promise for HCQ treatment in patients with the ABCA3 deficiency-variant. Yang et al. reported that the major drugs were systemic glucocorticosteroids, HCQ, and macrolides. These medications are typically used in combination with HCQ and macrolides to slow the progression of pulmonary fibrosis (4). However, given the limited studies on this topic, larger clinical trials need to be conducted. Corticosteroid pulses combined with HCQ have also been reported to be beneficial for children with ABCA3-associated ILD, but extensive research is required for confirmation (7,14,17). Lung transplantation represents a potential option for patients with milder mutations (2). Study (5) has also shown the potential of gene therapy for genetic disorders associated with ABCA3-ILD. However, to date, targeted anti-infective treatment remains crucial for patient survival.

Conclusions

Although ABCA3 gene mutations are exceedingly rare, the co-occurrence of such a mutation with concurrent infections by multiple pathogens is rarer still. Nevertheless, clinicians must maintain a high index of suspicion for such possibilities to facilitate a prompt and accurate diagnosis, thereby enabling optimal patient management.

Acknowledgments

The authors wish to acknowledge the included patient, from whom written informed consent was obtained.

Footnote

Funding: This work was supported by the Key Project of the Special Fund for Health Science and Technology Development in Nanjing City for the Year 2024 (No. ZKX24048) and the Reserve Talent Program of Nanjing Second Hospital (No. HBRCYL08).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-28/coif). All authors report the funding from the Key Project of the Special Fund for Health Science and Technology Development in Nanjing City for the Year 2024 (No. ZKX24048) and the Reserve Talent Program of Nanjing Second Hospital (No. HBRCYL08). The authors have no other 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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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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