Abstract Background Telomere maintenance and surfactant-related genetic mutations are increasingly recognized as contributing factors in familial pulmonary fibrosis (PF). Pathogenic variants in the SFTPA2 gene have been associated with early-onset pulmonary fibrosis and an elevated risk of developing lung cancer. Currently, PF lacks a definitive cure beyond lung transplantation, and treatment options remain limited. Understanding the prevalence and clinical implications of pathogenic SFTPA2 variants is critical. This study aims to assess the prevalence of PF, lung cancer, and other co-morbidities among individuals carrying pathogenic SFTPA2 variants. Ultimately, this study seeks a comprehensive understanding of the natural history and potential screening needs for SFTPA2 variants. Methods Individuals with pathogenic SFTPA2 variants were identified in the Tapestry genomic database at our academic medical center. Electronic medical records (EMR) were reviewed for personal or family histories of PF, lung cancer, and other significant comorbidities. Imaging reports were evaluated for radiographic evidence of PF or lung cancer. Studies were approved by the local IRB. Results Out of 98, 109 participants in the Tapestry database, 18 individuals were identified as carriers of SFTPA2 variants. The variants (NM₀01098668. 4) included c. 460GC - p. (Ala154Pro) in 13 individuals, c. 557AG - p. (Tyr186Cys) in 1 individual, and c. 532GA - p. (Val178Met) in 4 individuals. The mean age was 60. 5 years, and 67% were female. No participants had a formal diagnosis of PF; however, five (28%) had prior chest CTs showing ground-glass opacities, fibrosis, or irregular nodularity. EMR review did not confirm clinically significant PF. Notably, 44% reported a family history of primary lung cancer, though no familial PF was documented. Comorbidities included inflammatory bowel disease (22%, with a tapestry cohort prevalence of 9%) and a personal history of cancer in 44%, encompassing nine distinct malignancies such as metastatic colon adenocarcinoma (1), prostate cancer (1), basal cell carcinoma of the skin (1), endometrial cancer (1), breast cancer (2), melanoma (1), and squamous cell carcinoma of the skin (1). Conclusions In this cohort of individuals with SFTPA2 variants, no cases of clinically confirmed PF or lung cancer were identified. However, there was a notable prevalence of abnormal parenchymal chest CT findings, inflammatory bowel disease, personal cancer history, and family history of lung cancer. These findings underscore the variable penetrance of SFTPA2 variants and highlight the need for longitudinal studies to elucidate the genetic, environmental, and immunologic factors that modulate disease expression. Improved understanding may inform screening strategies and therapeutic interventions for at-risk individuals. This abstract is funded by: None
Harris et al. (Fri,) studied this question.