Genomic Ascertainment Clarifies Prevalence and Clinical Risks of Deleterious TERT Variants

Rare deleterious germline variants in telomerase, encoded by the TERT gene, are present in 0.04 to 0.08 percent of studied populations and are strongly associated with pulmonary fibrosis. While prior clinical cohorts were subject to ascertainment bias by focusing on individuals and families with early-onset, complex disease, this genomic ascertainment study evaluated the true population prevalence of deleterious TERT variants alongside risks for telomere biology disorder phenotypes.

The study analyzed exome sequencing data from two large resources: 469,377 exomes from the UK Biobank and 170,503 exomes from the Geisinger-Regeneron DiscovEHR collaboration. Individuals carrying heterozygous deleterious TERT variants classified under modified ACMG and AMP criteria served as cases, while controls explicitly excluded individuals with rare, exonic, or splice-site TERT variants.

Researchers assessed electronic health records for ICD-10 diagnostic codes related to telomere biology disorders. Case-control comparisons were conducted independently within the UK Biobank and DiscovEHR cohorts, incorporating adjustments for key covariates including smoking, alcohol consumption, body mass index, sex, genetic ancestry, and birth year.

The genomic analysis identified 64 deleterious TERT variants across 203 UK Biobank participants and 32 variants across 138 DiscovEHR participants, corresponding to prevalence estimates of 1 in 2,312 and 1 in 1,235, respectively. The risk of pulmonary fibrosis was significantly elevated among TERT heterozygotes in both cohorts, showing an odds ratio of 10.9 (95 percent confidence interval: 6.11 to 19.45, p < 0.001) in the UK Biobank and an odds ratio of 6.64 (95 percent confidence interval: 3.31 to 13.3, p < 0.001) in DiscovEHR.

Deleterious TERT variants were also associated with significantly increased risks of liver disease (odds ratio 2.4, 95 percent confidence interval: 1.25 to 4.59, p = 0.038) and head and neck squamous cell carcinoma (odds ratio 5.75, 95 percent confidence interval: 2.36 to 14.02, p = 0.001) in the UK Biobank, though these associations were not observed in DiscovEHR. The investigators noted that discrepancies between cohorts could reflect factors such as healthy volunteer bias, emphasizing the clinical value of genetic diagnosis and the need for dedicated telomere biology disorder clinical trials.

Subject of Research: Population prevalence and clinical phenotype associations of deleterious germline TERT variants

Article Title: Genomic ascertainment refines the population prevalence and phenotype associations of germline TERT variants

Article References: Niewisch, M. R., Akinniyi, S. A., de Andrade, K. C., Kim, J., Zeigler, L. P., Haley, J. S., Urban, G., Carey, D. J., Stewart, D. R., & Savage, S. A. (2026). Genomic ascertainment refines the population prevalence and phenotype associations of germline TERT variants. PLOS Genetics, 22(11), e1012352. https://doi.org/10.1371/journal.pgen.1012352

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DOI: 10.1371/journal.pgen.1012352

Keywords: TERT variants, telomerase, pulmonary fibrosis, genomic ascertainment, UK Biobank, DiscovEHR, telomere biology disorders, liver disease, Genomic, ascertainment, refines, population