A Rare Missense Variant in Telomerase Reverse Transcriptase is Associated with Idiopathic Pulmonary Fibrosis in a Chinese Han Family
Chun-Ming Zheng1, Xi Zhan2, Yuan-Hua Yang3, Tao Jiang4, Qiao Ye5, Yong Lu3
1 Medical Research Center, Beijing Institute of Respiratory Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
2 Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital; Clinical Center for Interstitial Lung Diseases, Capital Medical University, Beijing 100020, China
3 Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
4 Department of Radiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
5 Clinical Center for Interstitial Lung Diseases; Department of Occupational Medicine and Toxicology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
Dr. Xi Zhan
Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020
Source of Support: None, Conflict of Interest: None
Background: Idiopathic pulmonary fibrosis (IPF) is an age-related and progressive interstitial lung disease. Up to 20% of cases of IPF cluster in families, genetic factors contribute significantly to the pathogenesis of the disease. This study aimed to explore the association between rare genetic variants and IPF in Chinese Han families.
Methods: A Han family, comprising three IPF patients and five unaffected their first-degree relatives, and 100 ethnically matched control individuals from North China were enrolled in this study. Peripheral blood was collected, and genomic DNA was extracted. To elucidate if rare genetic variants are associated with the familial IPF, we performed whole-exome sequencing of affected members from a Chinese Han IPF family. Candidate rare variants were then confirmed by Sanger sequencing.
Results: We identified a potentially damaging rare variant-a heterozygous mutation c.2146G>A in exon 6 of the gene encoding for telomerase reverse transcriptase (TERT), which results in an amino acid substitution (p.Ala716Thr). We confirmed the missense mutation by Sanger sequencing in all the affected family members but did not detect this mutation in 100 ethnically matched healthy controls. Patients carried this mutation were characterized by the frequently acute exacerbation of IPF phenotype, with poor prognosis. The mean time to death was 2.8 years after diagnosis.
Conclusion: Using next-generation sequencing technology in familial IPF patients, we identified the heterozygous rare variant in TERT gene, and strengthened the importance of genetic variants in telomere-related pathogenesis in Chinese IPF patients.