Long-telomeropathy is associated with tumor predisposition syndrome

Summary Telomeres protect chromosomal integrity, and telomere length (TL) is influenced by environmental and genetic factors. While short-telomeres are linked to rare telomeropathies, this study explored the hypothesis that a “long-telomeropathy” is associated with a cancer-predisposing syndrome. Using genomic and health data from 113,861 individuals, a trans-ancestry polygenic risk score for TL (PRS TL ) was developed. A phenome-wide association study (PheWAS) identified 65 tumor traits linked to elevated PRS TL . Using this result, a trans-ancestry phenotype risk score for a long-TL (PheRS LTL ) was develop and validated. Rare variant analyses revealed 13 genes associated with PheRS LTL . Individuals who were carriers of these rare variants had a predisposition for long-TL validating original hypothesis. Most of these genes were new to both cancer and telomere biology. In conclusion, this study identified a novel tumor-predisposing syndrome shaped by both common and rare genetic variants, broadening the understanding of telomeropathies to those with a predisposition for long telomeres.