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

TERT

Heterozygous deleterious germline variants in TERT, the catalytic subunit of telomerase

Clinically ascertained telomere biology disorder cohorts are biased toward early-onset, complex disease. The authors extracted TERT variants from exomes in UK Biobank (469,377 exomes) and the Geisinger-Regeneron DiscovEHR collaboration (170,503 exomes), classified them under modified ACMG/AMP criteria, and compared heterozygous carriers with controls using ICD-10 codes from electronic health records. Sixty-four deleterious variants were found in 203 UK Biobank participants and 32 in 138 DiscovEHR participants, giving prevalences of one in 2,312 and one in 1,235. Pulmonary fibrosis risk was significantly increased in both cohorts (OR 10.9; 95% CI 6.11-19.45 and OR 6.64; 95% CI 3.31-13.3), whereas associations with liver disease (OR 2.4) and head and neck squamous cell carcinoma (OR 5.75) were found only in UK Biobank.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The counseling message is clear: a deleterious TERT variant found outside a clinical context mainly carries pulmonary risk, the liver and head and neck excess being inconsistent across cohorts. Phenotypes rely on ICD-10 codes, without clinical adjudication or telomere length measurement, and UK Biobank's healthy volunteer bias may cut both ways. Carriers identified by genomic ascertainment probably have a more favorable prognosis than those seen in specialist clinics.

Analysis by Dr Thibaut Benquey