Genomic ascertainment refines the population prevalence and phenotype associations of germline TERT variants
In brief
Telomerase variants affect up to 1 in 1,235; pulmonary fibrosis risk rose sixfold
In two large genomic cohorts, deleterious variants in one copy of the telomerase gene occurred in about 1 in 1,200 to 1 in 2,300 people. Pulmonary fibrosis was six to eleven times more common in carriers in both cohorts, while liver disease and head and neck cancer associations appeared in only one; cohort differences may explain the uneven findings.
- Journal
- PLoS genetics (Q1)
- Published
- 5 November 2026
- Study design
- Case-control study
- Evidence level
- Level 3, Low (CEBM 3b)
- Authors
- Marena R Niewisch, Sherifa A Akinniyi, Kelvin C de Andrade, Jung Kim, Logan P Zeigler, Jeremy S Haley, et al.
- PMID
- 42986891
- DOI
- 10.1371/journal.pgen.1012352
Why clinicians should know about it
- Picked for Genetics (clinical) (paper of the day, 6 November 2026): Quantifies TERT-associated disease risks relevant to family counseling
Abstract
BACKGROUND: Individuals with deleterious germline variants in telomerase (encoded by TERT) are at high risk of pulmonary fibrosis (PF), liver disease (LD), bone marrow failure, head/neck squamous cell carcinoma (HNSCC), and other complications. Clinically ascertained cohorts are subject to biased ascertainment of affected individuals and families with early onset, complex disease. This study used genomic ascertainment to determine prevalence of deleterious TERT variants and the associated risks of telomere biology disorder (TBD) phenotypes. METHODS: TERT variants were extracted from exome sequencing data in UK Biobank (UKB, 469,377 exomes) and Geisinger-Regeneron DiscovEHR collaboration (DiscovEHR, 170,503 exomes). Cases were individuals with heterozygous deleterious TERT variants classified per modified ACMG/AMP criteria. Controls excluded rare, exonic, and splice site TERT variants. Electronic health records were assessed for TBD-related ICD10 codes. Case-control comparisons were done separately for UKB and DiscovEHR, accounting for smoking, alcohol, BMI, sex, genetic ancestry, and birthyear. RESULTS: There were 64 deleterious TERT variants in 203 UKB participants and 32 in 138 DiscovEHR participants. Prevalence estimates were 1:2,312 in UKB and 1:1,235 in DiscovEHR. Risk of PF was significantly increased for TERT heterozygotes compared with controls (UKB: odds ratio [OR] 10.9 95% confidence interval [CI]: 6.11-19.45, p < 0.001; DiscovEHR: OR 6.64, 95% CI: 3.31-13.3, p < 0.001). Deleterious TERT variants were also associated with higher risk of LD (OR 2.4, 95% CI:1.25-4.59, p = 0.038) and HNSCC (OR 5.75, 95% CI: 2.36-14.02, p = 0.001) in UKB but not in DiscovEHR. CONCLUSIONS: Rare deleterious TERT variants were present in 0.04 to 0.08% of the populations studied. Genomic ascertainment shows a predominance of pulmonary phenotypes, with PF associated with deleterious TERT variants in both cohorts. Associations with LD and HNSCC were observed only in UKB, possibly reflecting cohort differences including healthy volunteer bias. These findings illustrate the clinical importance of genetic diagnosis, and need for TBD-specific clinical trials.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.