Biallelic LAMP3 variants in 5 families with interstitial lung disease: Evidence of a disease-gene association.

PURPOSE: Genetic causes of surfactant dysfunction are associated with childhood interstitial lung disease. Lysosome-associated membrane glycoprotein 3 (LAMP3) is highly expressed within lamellar bodies of alveolar epithelial type II cells, and variants in LAMP3 have recently been suggested as a novel cause of childhood interstitial lung disease. This study describes the phenotypes of participants with biallelic variants in LAMP3 and presents functional studies evaluating the role of specific LAMP3 variants. METHODS: Phenotypic data were collected through chart review and clinical evaluation. In vitro effects of LAMP3 variants were evaluated through immunohistochemistry, western blot, and flow cytometry. RESULTS: Thirteen participants were identified with biallelic variants in LAMP3. They presented with variable phenotypes ranging from neonatal respiratory distress to asymptomatic in adulthood. All symptomatic participants demonstrated ground glass opacities early in life and lung fibrosis later in life. For 1 participant, BAL analysis showed abnormal surfactant protein composition and lung biopsy revealed irregular lamellar bodies. In vitro studies in lung epithelial cells with induced expression of specific LAMP3 variants demonstrated reduced protein expression and abnormal glycosylation. CONCLUSION: Biallelic LAMP3 variants are associated with an interstitial lung disease phenotype with variable expressivity. Evaluation for LAMP3 variants should be considered in individuals with unexplained interstitial lung disease.