Genetics of Pulmonary Fibrosis

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Genetic sequence variants have been linked to familial pulmonary fibrosis (FPF). Many of the same genetic mechanisms implicated in FPF are relevant to sporadic interstitial lung disease (ILD) and, especially, idiopathic pulmonary fibrosis (IPF). Thus, these genetic insights have begun to reveal the molecular basis of a disease that was previously thought to be unknown. A common variant within the promoter of the MUC5B gene is the most replicated single nucleotide polymorphism linked to familial and sporadic forms of IPF as well as early radiographic findings of IPF. Pathogenic rare variants in multiple different genes have been described; in one FPF cohort, these explain about one-third of the kindreds. Pathogenic rare variants are found in genes encoding surfactant- and telomere-related proteins. More mutations have been found in the TERT gene, which encodes the protein component of telomerase, than any other gene. The clinical manifestations and survival characteristics of patients with pathogenic rare variants in telomere-related genes mirror those observed for certain sporadic ILD patients with short telomere lengths. Since there are so many rare variants in the human genome, determining which of these are pathogenic remains a major challenge. We discuss the evidence to support the pathogenicity of variants discovered in ILD patients, highlighting the data supporting individual TERT variants. Current practices regarding clinical and genetic testing for FPF are suggested. Because the field of pulmonary fibrosis genetics is rapidly evolving, future research may better illuminate how genetic information can be best utilized to improve the care of patients with ILD.