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. 2018 Sep 20;131(18):2205-2209.
doi: 10.4103/0366-6999.240802.

A Rare Missense Variant in Telomerase Reverse Transcriptase is Associated with Idiopathic Pulmonary Fibrosis in a Chinese Han Family

Chun-Ming Zheng  1 , Xi Zhan  2 , Yuan-Hua Yang  3 , Tao Jiang  4 , Qiao Ye  5 , Yong Lu  3
Affiliations

A Rare Missense Variant in Telomerase Reverse Transcriptase is Associated with Idiopathic Pulmonary Fibrosis in a Chinese Han Family

Chun-Ming Zheng et al. Chin Med J (Engl). .

Abstract
in English, Chinese

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.

TERT基因的罕见错义突变与中国汉族家族特发性肺纤维化相关摘要背景：特发性肺纤维化（IPF）是一种和年龄相关的进展性间质性肺疾病。多达20%的IPF患者呈现家族聚集性，遗传因素在IPF发病过程中起到重要作用。本研究的目的是探寻罕见遗传变异与中国汉族家族特发性肺纤维化的相关性。 方法：收集了一个中国汉族IPF家系，包含3例IPF患者和5名非患病一级亲属。同时收集了100名与上述IPF患者性别、年龄相匹配的非患病的中国北方汉族人作为对照。所有受试者采集外周血提取DNA。为了研究罕见遗传变异是否与家族性IPF相关，我们对该家系的IPF患者进行了全外显子组测序。候选罕见变异位点采用Sanger测序证实。 结果：我们在该家系发现了一个可能致病的罕见变异位点，该杂合变异c.2146G>A位于端粒逆转录酶基因（TERT）的第6外显子区，导致p.Ala716Thr错义突变。Sanger测序在家系中证实了该变异，在100名对照受试者中未检测到该变异。携带该突变的IPF患者表现为频繁急性加重表型，预后差，诊断后平均生存时间为2.8年。 结论：通过对家族性IPF进行新一代测序技术分析，我们发现了与疾病相关的TERT基因的罕见变异，在中国IPF患者中进一步证实了遗传变异在端粒相关致病机制中的重要作用。.

Keywords: Genetics; Idiopathic Pulmonary Fibrosis; Telomerase Reverse Transcriptase; Telomere.

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Conflict of interest statement

There are no conflicts of interest

Figures

Figure 1
Figure 1
Pedigree of the Chinese family with IPF. Squares and circles indicate males and females, respectively; open symbols indicate unaffected individuals, filled symbols indicate affected individuals; diagonal indicates deceased individuals; arrow indicates the proband. IPF: Idiopathic pulmonary fibrosis.
Figure 2
Figure 2
HRCT scans of three affected members in the FPF pedigree. (a and b) The CT scan of the proband, II2. (c and d) The CT scans of his younger sisters, II4 and II5, respectively. Reticular patter, honeycombing, and traction bronchiectasis were identified throughout both lungs in the CT sections, with subpleural and lower lobe predominance. HRCT: High-resolution computed tomography; FPF: Familial pulmonary fibrosis; CT: Computed tomography.
Figure 3
Figure 3
Sanger sequencing confirms TERT mutation. (a) The missense mutation c.2146G>A in exon 6 of the TERT gene (arrow) was found in the proband. (b) Wild-type sequence was from an unaffected member II7. TERT: Telomerase reverse transcriptase.
Figure 4
Figure 4
The sequence conservation and functional domain analysis of A716T substitution of TERT protein. (a) Partial sequence alignment of vertebrate TERT proteins. The shaded yellow region identifies the conserved alanine (A) mutated in the proband. Sequence numbering refers to the human TERT. (b) Location of the A716T substitution in TERT (arrow). Dark gray indicates the RT domain. RT: Reverse transcriptase; TERT: Telomerase reverse transcriptase.
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