SFTPA1

Inheritance Pattern: SD

Disease ID:MONDO:0030608

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0030608

Submitter: ClinGen

*SFTPA1* encodes Surfactant Protein A1, which is a lung surfactant protein associated with a subfamily of C-type lectins called collectins. Surfactant protein A (SP-A) forms a bouquet-like structure containing 6 trimeric subunits, or a total of 18 SFTPA1 and SFTPA2 monomers (PMID: 23069847). Further, SP-A binds specific carbohydrate moieties found on lipids and on the surface of microorganisms, playing an essential role in the defense against respiratory pathogens (PMID: 15630429). *SFTPA1* was first reported in relation to autosomal dominant interstitial lung disease (ILD) in 2016 (Nathan et al, PMID: 26792177). Lung disease associated with *SFTPA1* variants is characterized by pulmonary fibrosis, interstitial pneumonia, and/or lung adenocarcinoma, with variability in presentation. Environmental exposures increase the risk and/or severity of these clinical features. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no differences in the phenotypic presentations or molecular mechanism associated with ILD inherited in the autosomal dominant manner (MIM:619611, MONDO:0015925). At this time, the data asserting an autosomal recessive inheritance pattern are limited, and sufficient evidence has not been provided in published reports regarding the monogenic nature of the lung disease found in the probands (PMID 31601679). Due to these reasons the ILD disease entity is curated in the autosomal dominant mode of inheritance only. Variants reported in this gene are all missense variants in exon 6 encoding the carbohydrate-binding domain, which do not affect the expression of the protein but interfere with its secretion. The genetic evidence for this curation includes 12 probands from 7 publications reporting heterozygous variants, one report of a family with homozygous *SFTPA1* variants and segregation data from a multigenerational French family (PMIDs 26792177, 28869238, 30854216, 32855221, 31601679, 26792177, 38575158). The mechanism of disease is not clear but is expected to involve loss of secretion and intracellular accumulation of SFTPA1 which is similar to the mechanism described for SFTPA2 related disease, which is currently curated as definitive for ILD. This gene-disease association is supported by functional and expression assays. Immunoprecipitation in A594 cells co-transfected with wildtype *SFTPA2* and variant *SFTPA1* (p.Tyr208His) showed that variant SFTPA1 could still form complexes with SFTPA2 but was not secreted out of the cell (PMID: 31601679). The same report found that SFTPA1 and SFTPA2 interacted closely evidenced by co-immunoprecipitation data. Immunohistochemistry of variant carrying patient lung tissue shows a significant alteration in expression pattern for SFTPA1 where lung biopsy tissue showed a discontinuous and largely intracellular SP-A staining which differed from control tissue (PMID: 26792177). A knockdown mouse model generated by CRISPR/Cas9 technology shows development of lung fibrosis induced by low-dose bleomycin injection, while wild-type mice do not (PMID: 35628104). However, the knockdown mouse model is not scored as it is inconsistent with the suspected disease mechanism. A second knock-in mouse model showed increases in spontaneous lung fibrosis and decreased SFTPA1 in bronchoalveolar lavage fluid (PMID 31601679). This second model was not scored as the introduced variant was found in a biallelic variant carrier with conflicting evidence of monogenic SFTPA1 related disease. In summary, there is moderate evidence supporting the gene-disease relationship of *SFTPA1* and autosomal dominant ILD. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Interstitial Lung Disease GCEP on January, 28 2025 (SOP Version 11).