Submission Details

SFTPB was first reported in relation to autosomal recessive surfactant metabolism dysfunction, pulmonary, 1, also known as SFTPB-related interstitial lung disease, in 1993 (Nogee et al., PMID:8421459) in an index family with three full term neonates that passed away due to respiratory failure. All three siblings were found to be homozygous for the SFTPB mutation ‘121ins2’ (NM_000542.5:c.361delinsGAA) that is reported to be found in up to two thirds of mutant alleles of SFTPB. SFTPB encodes the pulmonary-associated surfactant B protein, known as SP-B, and was the first reported genetic cause of respiratory distress syndrome in infants. SP-B is expressed both in alveolar type II cells and in non-ciliated bronchial epithelial cells, although only alveolar type II cells fully process the proprotein to its mature form that is secreted into the airspaces, and is essential for lung function after birth (Nogee et al., PMID:8421459; Hartl et al., PMID:15819986). Patients typically present at term, often after an uneventful pregnancy, with respiratory distress, tachypnea, dyspnea, and apnea. Lung biopsy of patients shows alveolar proteinosis and interstitial fibrosis. Without lung transplant, the disease progression typically leads to fatal respiratory failure within months (Hartl et al., PMID:15819986; Desroziers et al., PMID:37380697). Rare cases have been reported of prolonged survival without lung transplant (Khalsi et al., PMID:37455866; López-Andreu et al., PMID:28888561, Ballard et al., PMID: 7491219, Dunbar et al., PMID 10960490) and one study reports adult onset in a proband confirmed to have biallelic SFTPB variants (Desroziers et al., PMID:37380697).

More than 700 unique variants (e.g. synonymous, missense, in-frame indel, nonsense, frameshift) have been reported in humans by ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Seven variants of different types that have been reported in seven probands in seven publications (PMIDs: 8163685, 26199800, 37455866, 28888561, 10365365, 37380697, 10960490) are included in this curation. We report four probands with typical disease presentation and three probands with an atypical disease presentation. More evidence is available in the literature, but the maximum score for genetic evidence has been reached.

The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is supported by tissue specific expression, patient expression, protein interaction, model, and rescue experimental evidence (Fagerberg et al., PMID:24309898; Martínez-Calle et al., PMID:31357031; Axelsson et al., PMID:35438610; Nesslein et al., PMID:15722377; Melton et al., PMID:12639841; Munis et al., PMID:33426150). Transcriptomics and antibody-based proteomics have shown SFTPB expression to be exclusive to lung tissue (Fagerberg et al., PMID:24309898). A proteomics assay showed a high level of association between SFTPB and interstitial lung abnormalities in a large cohort (N = 5,259) study (Axelsson et al., 2022, PMID:35438610). The Melton et al. doxycycline-regulated compound transgenic mouse model shows that SP-B is required for postnatal lung function and that levels of SP-B at or below 25% of normal expression leads to surfactant dysfunction, respiratory failure, and death (Melton et al., PMID:12639841). This experiment also showed the rescue of the respiratory failure phenotype in the model. The Munis et al. cell culture rescue experiment treated an SP-B deficient surfactant air-liquid interface cell culture model with simian immunodeficiency virus (SIV)-based lentiviral vector (LV) pseudotyped with Sendai virus glycoproteins F and HN expressing SP-B protein. The rSIV.F/HN*-expressing SPB corrected the disease phenotype in the model culture (Munis et al., PMID:33426150). Additional cell model and rescue experiments (not included in this curation) are present in the literature (Lin et al., PMID:10383422; Akinbi et al., PMID:9092492, Jacob et al., PMID:28965766). The maximum score for experimental evidence was exceeded in this curation.

In summary, there is definitive evidence supporting the relationship between SFTPB and autosomal recessive surfactant metabolism dysfunction, pulmonary, 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Interstitial Lung Disease GCEP on the meeting date November 21, 2023 (SOP Version 9).