TERT / TERC variants

TERT (telomerase reverse transcriptase) and TERC (telomerase RNA component) together constitute the catalytic core of telomerase; TERT provides reverse-transcriptase activity while TERC is the RNA template used to extend telomeric TTAGGG repeats. Common single-nucleotide variants in both loci are among the strongest GWAS hits for leukocyte telomere length and modestly influence disease risk for cancer, cardiovascular disease, and pulmonary fibrosis in proportion to their effect on telomere length. Rare heterozygous loss-of-function mutations in TERT or TERC cause autosomal dominant telomere biology disorders (TBDs) — a spectrum including dyskeratosis congenita, familial idiopathic pulmonary fibrosis, aplastic anemia, and hepatic cirrhosis — via telomere-mediated replicative failure in high-turnover tissues and anticipation across generations. The contrast between the modest effects of common variants and the severe phenotypes of rare pathogenic mutations illustrates the quantitative sensitivity of telomere homeostasis.