Genomic ascertainment refines prevalence and disease associations of germline TERT variants
A PLOS Genetics study using population-scale genomic data finds that germline TERT variants are more common than clinically ascertained cohorts suggest, with phenotype associations that differ from those observed in specialist referral populations.
A study published on 5 November 2026 in PLOS Genetics, led by Marena R. Niewisch, Sherifa A. Akinniyi, Kelvin C. de Andrade, and colleagues at the National Cancer Institute and Geisinger Health System, used genomic ascertainment to revisit the population prevalence and phenotype associations of deleterious germline variants in TERT, the gene encoding the catalytic subunit of telomerase.
TERT encodes telomerase reverse transcriptase, and loss-of-function variants in TERT — along with other genes encoding components of the telomerase complex — underlie a spectrum of conditions collectively termed telomere biology disorders (TBDs). Clinically recognised manifestations include pulmonary fibrosis, liver disease, bone marrow failure, and head and neck squamous cell carcinoma. Prior knowledge of penetrance and phenotype in TERT variant carriers has been shaped largely by clinically ascertained cohorts, which are inherently biassed toward individuals with severe or early-onset disease and families with multiple affected members.
By analysing TERT variants in a broader, genomically ascertained population — drawn from biobank-linked data at Geisinger — the authors found that deleterious TERT variants are more prevalent in the general population than clinical series imply, and that many carriers do not present with the severe multi-system phenotypes seen in specialist referral settings. The findings have implications for how published penetrance estimates for TERT variants are interpreted in unselected genomic testing contexts, including population-scale sequencing programmes and research biobanks.
The study was published in PLOS Genetics (DOI: 10.1371/journal.pgen.1012352) under open access.
Plain-language version
For patients, families, and general readers. Educational only — not medical advice.
Telomerase is a protein that helps maintain the protective caps at the ends of chromosomes, known as telomeres. Some people are born with inherited changes (called variants) in the TERT gene, which provides instructions for making telomerase. These variants can be linked to conditions such as scarring of the lungs, liver disease, and bone marrow problems. Until now, most of what researchers knew about TERT variants came from families where the condition was already severe enough to prompt specialist referral — which can make the conditions appear worse on average than they really are across the broader population. This new study, published in the journal PLOS Genetics, used a much wider dataset of people whose genomes were sequenced without any pre-selection for illness. It found that TERT variants are more common than previously thought, and that many people who carry them do not develop serious disease. This is an educational summary, not medical advice. If anything here raises questions for you, please speak with your GP or a clinical professional.
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Primary source Public Library of Science · 2026-11-05Genomic ascertainment refines the population prevalence and phenotype associations of germline TERT variants