Genomic ascertainment refines the population prevalence and phenotype associations of germline TERT variants.

Genomic ascertainment in UK Biobank and DiscovEHR estimates deleterious germline TERT variant prevalence at 1:2,312 and 1:1,235, with pulmonary fibrosis risk elevated.

• Why it matters: Clinically recruited cohorts can overrepresent early-onset, complex cases, obscuring true population prevalence and phenotype links for telomere biology disorder.
• What they did: Exome data from UK Biobank (469,377) and DiscovEHR (170,503) were used to define heterozygous deleterious TERT variants and compare them with controls lacking rare exonic/splice-site variants, using ICD10 TBD codes and adjusted case-control models.
• The result: Pulmonary fibrosis odds were higher in both cohorts (UKB OR 10.9, 95% CI 6.11–19.45; DiscovEHR OR 6.64, 95% CI 3.31–13.3), while liver disease (OR 2.4) and HNSCC (OR 5.75) were linked only in UKB, implying cohort differences.

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