Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a form of interstitial lung disease characterized by progressive lung scarring. It involves destruction of the alveolar architecture, thickening of the basement membrane, abnormal deposition of the extracellular matrix, inflammatory cell infiltration in the interstitial space, and formation of fibroblast foci. Mutations in telomerase reverse transcriptase (TERT) have been reported to be associated with IPF.

Aims: To explore the genetic cause of a family affected by IPF and chronic obstructive pulmonary disease.

Study Design: Cross-sectional study.

Methods: Whole-exome sequencing combined with IPF candidate gene filtering was used to identify the causative mutations. Sanger sequencing was applied to validate the mutation and perform c-segregation analysis. Real-time polymerase chain reaction (PCR) was conducted to analyze the telomere lengths of family members.

Results: We identified a rare mutation, c.2669G > A (p. Gly890Asp), in TERT (NM_198253.2) in the proband and another affected family member. Bioinformatics analysis predicted this mutation to be deleterious, and structural modeling suggested that it altered the structure and surface charge distribution of the TERT protein. Additionally, real-time PCR demonstrated that mutation carriers had significantly shorter telomere lengths compared with individuals of the same age. According to American College of Medical Genetics and Genomics guidelines, this rare mutation was classified as likely pathogenic.

Conclusions: This is the first reported case of IPF caused by the p. Gly890Asp mutation of TERT in the Chinese population. Our findings support the diagnosis of IPF in the patient and further highlight the role of TERT in the disease.