Novel lamp3 gene mutation associated with variable clinical presentation of interstitial lung disease

<bold>Introduction:</bold> Genetic testing has become instrumental in diagnosing rare interstitial lung diseases (ILD), shedding light on novel genes implicated in lung development and function <bold>Aims and objectives:</bold> We aimed to perform a comprehensive clinical and genetic evaluation of multiple individuals within a consanguineous family presenting with ILD of undefined etiology <bold>Methods:</bold> Multiple individuals from a highly consanguineous family underwent thorough clinical investigations and genetic studies including whole exome sequencing (WES). To identify a novel genetic cause, we conducted WES using an unbiased semi-automated internal gene-matching algorithm. <bold>Results:</bold> A rare homozygous missense variant NM_014398.4:c.862G>A; p.(Gly288Arg) in lysosome-associated membrane protein 3 (<italic>LAMP3</italic>) was identified in four affected males. Segregation analysis led to the diagnosis of an additional adult male and two asymptomatic females. The affected males exhibited a variable age of symptoms onset and clinical presentation, ranging from neonatal to adulthood onset and symptoms varying from exertional dyspnea to severe shortness of breath and hypoxemia. Pulmonary function tests (PFTs) displayed elevated specific airway resistance and chest computed tomography (CT) scans revealed diffuse ground glass opacities in all affected males. <bold>Conclusion:</bold> We propose <italic>LAMP3</italic> gene as a novel cause of ILD with variable phenotypic presentation. Prior animal models have shown that loss of <italic>LAMP3</italic> function disrupts lamellar body maturation, leading to fatal neonatal ILD in dogs and elevated airway resistance and disturbances in surfactant homeostasis in mice. Further research is warranted to elucidate its function in humans.