ABCA3 c.838C>T (p.Arg280Cys, R280C) and c.697C>T (p.Gln233Ter, Q233X, Q233*) as Causative Variants for RDS: A Family Case Study and Literature Review

Abstract

Background: Respiratory distress syndrome (RDS) is the primary cause of respiratory failure in preterm infants, but it also affects 5-7% of term infants. Dysfunctions in pulmonary surfactant metabolism, resulting from mutations of the lung surfactant genes, are rare diseases, ranging from fatal neonatal RDS to interstitial lung disease, associated with increased morbidity and mortality. This study aims to clarify the clinical significance of ABCA3 variants found in a specific family case, as existing data in the literature are inconsistent. Material and Methods: A family case report was conducted; targeted panel genetic testing identified a variant of the SFTPB gene and two variants of ABCA3 genes. Comprehensive research involving a systematic review of PubMed, Google Scholar databases, and genome browsers was used to clarify the pathogenicity of the two ABCA3 variants found in the index patient. Advanced prediction tools were employed to assess the pathogenicity of the two ABCA3 variants, ensuring the validity and reliability of our findings. Results: The index case exhibited fatal neonatal RDS. Genetic testing revealed the presence of the SFTPB p.Val267Ile variant, which was not previously reported but is a benign variant based on family genetic testing and history. Additionally, two ABCA3 gene variants were identified: c.697C>T, not yet reported, and c.838C>T. These variants were found to affect ABCA3 protein function and were likely associated with neonatal RDS. Prediction tools and data from nine other cases in the literature supported this conclusion. Conclusions: Based on in silico predictors, an analysis of the presented family, and cases described in the literature, it is reasonable to consider reclassifying the two ABCA3 variants identified in the index case as pathogenic/pathogenic. Reclassification will improve genetic counseling accuracy and facilitate correct diagnosis.

Keywords: ABCA3 Q233X; ABCA3 R280C; ABCA3 c.697C>T; ABCA3 c.838C>T; ABCA3 p.Arg280Cys; ABCA3 p.Gln233Ter; SFTPB p.Val267Ile; genetic testing; interstitial lung disease; neonatal RDS.

Figure 1

The flow chart of the systematic review on ABCA3 c.838C>T (p.Arg280Cys, R280C) and c.697C>T (p.Gln233Ter, Q233X, Q233*).

Figure 2

Anterior-posterior thoracic X-rays of the index patient in the supine position. (A) DOL 1—small perihilar distelectatic foci. (B) DOL 5—reticular, micronodular lung interstitium, confluent along the hilum and in the area corresponding to the superior right lung, air bronchogram. (C) DOL 40—diffuse bilateral, symmetrical opacification of the lungs with a granular aspect, extended air bronchogram. (D) DOL 60—diminished lung fields, diffuse, symmetrical, almost complete opacification, disappearance of the mediastinum and diaphragm outline (DOL—day of life).

Figure 3

Structure 7W01 of the Cryo-EM structure of nucleotide-free ABCA3. (A) A crystal 7W01 structure at a resolution of 3.3 Å. (B) The changes are highlighted in green within the 7W01 structure, marked by red circles, and were visualized using Mol* Viewer, a modern web app for 3D visualization and analysis [59].

Figure 4

A structural model of the ABCA3 protein, showing the distribution of the compound heterozygous c.838C>T (p.Arg280Cys, R280C) and c.697C>T (p.Gln233Ter, Q233X, Q233*) variants detected in ABCA3 in this study. The ABCA3 protein comprises 12 putative membrane-spanning helices along the NH2- and COOH- terminal domains, two extracellular domains (ECDs), and two nucleotide-binding domains (NBDs). The critical conserved Walker A and Walker B motifs are indicated as A and B, respectively, within the nucleotide-binding domains. The red asterisk marks the ABCA3 c.838C>T (p.Arg280Cys, R280C) and c.697C>T (p.Gln233Ter, Q233X, Q233*) variants identified in this study.

Figure 5

Lung histology—microscopic examination: (A) Alveolar proteinosis (×100)—fine, granular, eosinophilic material inside the alveoli, some with a compact aspect; (B) thickened alveolar septae and vascular stasis (×200)—additionally, mononuclear cells and fibroblast are present; (C) alveoli and bronchiole filled with eosinophilic material (×200)—additionally, atelectatic and emphysematous areas; (D) alveoli with pseudostratified AEC II (×200); (E,F) alveolar proteinosis (×100)—amorphous or granular PAS-positive material inside the alveoli is suggestive of lung alveolar proteinosis; (A–D) hematoxylin-eosin staining; (E,F) periodic-acid Schiff (PAS) staining.

Figure 6

Segregation analysis within the family studied: the squares represent males, and the circles represent females; the arrow points to the index case; the slashed symbols indicate deceased individuals; the black-filled symbols denote individuals with fatal neonatal respiratory distress syndrome; the half-filled symbols represent carriers. Generations are denoted using Roman numerals, while individuals are identified by Arabic numerals.