Surfactant Deficiency via the ABCA3 Gene

Surfactant deficiency is a severe respiratory disorder due to dysfunction in the production or function of pulmonary surfactants. Surfactant is a lipid and protein mixture lining the lung tissue that lowers alveolar surface tension and prevents atelectasis during expiration. Loss of surfactant function results in alveoli collapse following expiration leading to shortness of breath and impaired oxygen delivery. In severe forms, respiratory failure occurs shortly after birth with infants requiring mechanical ventilation and lung transplantation for survival (Nogee et al. 2000. PubMed ID: 10712351; Tredano et al. 2003. PubMed ID: 12784301). Pathogenic variants in the ABCA3, SFTPB, SFTPC, and NKX2-1 genes have been reported to be causative for surfactant deficiency with patients with SFTPB-related surfactant deficiency being the most severely affected. Genetic testing is helpful in the differential diagnosis of ABCA3-related surfactant deficiency from other surfactant deficiencies, respiratory infections, cardiac disorders with obstructed pulmonary venous return, and other respiratory distress syndromes (Hamvas 2006. PubMed ID: 17142157).

Surfactant dysfunction may be inherited in an autosomal dominant manner through pathogenic variants in the SFTPC and NKX2-1 genes or an autosomal recessive manner through pathogenic variants in the ABCA3 or SFTPB genes (Hamvas 2006. PubMed ID: 17142157). To date over 150 different causative variants have been reported in the ABCA3 gene. Missense changes occurring throughout the gene account for greater than 75% of the reported causative variants (Shulenin et al. 2004. PubMed ID: 15044640; Garmany et al. 2008. PubMed ID: 18317237). Nonsense, splice site, insertions/deletions, and gross deletions have also been reported in a minority of cases (Shulenin et al. 2004. PubMed ID: 15044640; Garmany et al. 2008. PubMed ID: 18317237). The ABCA3 gene encodes an ATP-binding cassette transporter which is expressed in alveolar type II cells and is involved in pulmonary surfactant metabolism and lamellar biogenesis. Failure of ABCA3 function results in reduced surface tension at air-liquid interfaces leading to respiratory distress (Ban et al. 2007. PubMed ID: 17267394).

In a study of 21 individuals with a history of severe respiratory disease where both SFTPB and SFTPC surfactant deficiencies as well as other forms of lung disease were ruled out initially, pathogenic variants in the ABCA3 gene were identified in 16 of 21 patients. In two patients, only one pathogenic variant was identified in the ABCA3 gene (Shulenin et al. 2004. PubMed ID: 15044640). Analytical sensitivity is >95% for detection of causative variants in the ABCA3 gene by sequencing.

Clinical sensitivity for Copy Number Variants is less than 5% as gross deletions involving one or more exons have only been reported in a few cases (Garmany et al. 2008. PubMed ID: 18317237).

This test provides full coverage of all coding exons of the ABCA3 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).