{
  "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. Author summary: Telomeres are protective structures at the ends of chromosomes that shorten with age and are extended by telomerase, encoded by TERT. Rare germline variants in TERT cause telomere biology disorders, a group of conditions associated with pulmonary fibrosis, liver disease, bone marrow failure, and elevated cancer risk. Because prior research has relied on cohorts referred for genetic testing based on clinical presentation, the true prevalence of deleterious TERT variants in the general population is unclear. We analyzed exome sequencing and linked clinical data from two large population-based biobanks (UK Biobank and Geisinger-Regeneron DiscovEHR) to answer this question. Variants were classified as deleterious using standardized criteria from the American College of Medical Genetics and Genomics. Deleterious TERT variants were present in approximately 1 in 1,200–1 in 2,300 individuals, a higher prevalence than previously estimated. Individuals with TERT variants were more likely to have pulmonary fibrosis than controls. Increased risks of liver disease and head and neck squamous cell carcinoma were also detected, though only in one cohort. These results underscore the utility of population-scale genomic data for characterizing disease risk associated with rare genetic variants.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany",
    "Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America",
    "Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America",
    "Department of Genomic Health, Weis Center for Research, Geisinger Medical Center, Danville, Pennsylvania, United States of America"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Marena R. Niewisch"
    },
    {
      "affs": [
        1
      ],
      "name": "Sherifa A. Akinniyi"
    },
    {
      "affs": [
        2
      ],
      "name": "Kelvin C. de Andrade"
    },
    {
      "affs": [
        3
      ],
      "name": "Jung Kim"
    },
    {
      "name": "Logan P. Zeigler"
    },
    {
      "name": "Jeremy S. Haley"
    },
    {
      "name": "Gretchen Urban"
    },
    {
      "name": "David J. Carey"
    },
    {
      "name": "Douglas R. Stewart"
    },
    {
      "name": "Sharon A. Savage"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bm7e99cz27fat.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pgen.1012352",
  "fulltext_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012352",
  "id": "bm7e99cz27fat",
  "issns": [
    "1553-7404"
  ],
  "landing_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012352",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "plos",
      "/Biology and life sciences/Cell biology/Chromosome biology/Chromosomes/Chromosome structure and function/Telomeres/Telomere length"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Genomics"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Genomics/Genomic medicine/Cancer genomics"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Heredity/Heterozygosity"
    ],
    [
      "plos",
      "/Medicine and health sciences/Diagnostic medicine/Cancer detection and diagnosis"
    ],
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      "plos",
      "/Medicine and health sciences/Epidemiology/Medical risk factors/Cancer risk factors"
    ],
    [
      "plos",
      "/Medicine and health sciences/Hematology/Hematologic cancers and related disorders"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Basic cancer research/Cancer genomics"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancer detection and diagnosis"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancer risk factors"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancers and neoplasms/Hematologic cancers and related disorders"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancers and neoplasms/Lung and intrathoracic tumors"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1012352&type=printable",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-05",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/bm7e99cz27fat.ris",
  "sources": [
    {
      "first_seen": "2026-11-06T12:20:42Z",
      "native_id": "10.1371/journal.pgen.1012352",
      "source": "plos",
      "url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012352"
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  "subjects": [
    {
      "field": "biology",
      "origin": "plos:genomics",
      "subfield": "genetics-genomics"
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    {
      "field": "medicine",
      "origin": "plos:oncology",
      "subfield": "oncology"
    }
  ],
  "title": "Genomic ascertainment refines the population prevalence and phenotype associations of germline TERT variants",
  "title_text": "Genomic ascertainment refines the population prevalence and phenotype associations of germline TERT variants",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:20:24Z",
  "url": "https://research.draconitic.com/paper/bm7e99cz27fat",
  "venue": "PLOS Genetics",
  "versions": []
}