Familial Pulmonary Fibrosis: Genetic Features and Clinical Implications

Abstract

Pulmonary fibrosis comprises a wide range of fibrotic lung diseases with unknown pathogenesis and poor prognosis. Familial pulmonary fibrosis (FPF) represents a unique subgroup of patients in which at least one other relative is also affected. Patients with FPF exhibit a wide range of pulmonary fibrosis phenotypes, although idiopathic pulmonary fibrosis is the most common subtype. Despite variable disease manifestations, patients with FPF experience worse survival compared with their counterparts with the sporadic disease form. Therefore, ascertaining a positive family history not only provides prognostic value but should also raise suspicion for the inheritance of an underlying causative genetic variant within kindreds. By focusing on FPF kindreds, rare variants within surfactant metabolism and telomere maintenance genes have been discovered. However, such genetic variation is not solely restricted to FPF, as similar rare variants are found in patients with seemingly sporadic pulmonary fibrosis, further supporting the idea of genetic susceptibility underlying pulmonary fibrosis as a whole. Researchers are beginning to show how the presence of rare variants may inform clinical management, such as informing predisposition risk for yet unaffected relatives as well as informing prognosis and therapeutic strategy for those already affected. Despite these advances, rare variants in surfactant and telomere-related genes only explain the genetic basis in about one-quarter of FPF kindreds. Therefore, research is needed to identify the missing genetic contributors of pulmonary fibrosis, which would not only improve our understanding of disease pathobiology but may offer additional opportunities to improve the health of patients.

Keywords: familial pulmonary fibrosis; genetics; surfactant; telomere.

Figure 1

Estimated makeup of clinical diagnoses of patients with familial pulmonary fibrosis. CHP = chronic hypersensitivity pneumonitis; CTD = connective tissue disease; IPF = idiopathic pulmonary fibrosis; U-ILD = unclassifiable interstitial lung disease.

Figure 2

Decreased survival in familial forms of pulmonary fibrosis. ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis. (Reprinted from Cutting et al.²¹)