Telomere length of both parents contributes to heritable POT1 cancer-predisposition syndrome

Abstract Germline and somatic mutations in POT1 promote oncogenesis by enabling aberrant telomere elongation. For inherited POT1 mutations, it remains unclear whether elongated telomeres are transmitted to the next generation and whether the inherited long telomeres elevate cancer risk. Using a nanopore sequencing approach that provides haplotype-specific telomere length resolution, we examined telomere inheritance in families carrying POT1 mutations. We found that offspring preferentially inherit their longest telomeres from the carrier parent, consistent with extensive germline telomere elongation, whereas comparatively short telomeres predominantly derive from the non-carrier parent. Analysis of carrier and non-carrier siblings demonstrated that telomeres from both parents are elongated in POT1 carriers, with preferential elongation of the shortest telomeres. These findings support a potential mechanism of genetic anticipation in which POT1 mutations progressively deplete short telomeres capable of enforcing telomere-based tumor suppression from the carrier germline. Therefore, telomeres inherited from both parents jointly shape telomere-based tumor suppressive barriers.