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

Germline mutations in POT1 are linked to familial cancer predisposition, and somatic POT1 mutations occur recurrently in tumors. These mutations promote oncogenesis by enabling aberrant telomere elongation. For inherited POT1 mutations, a critical question is the extent to which elongated telomeres are transmitted to the next generation from the POT1 carrier parent and whether the inherited hyper-elongated telomeres elevate cancer risk. Using a nanopore sequencing approach that provides haplotype-specific telomere length measurements, we examined telomere inheritance in families harboring POT1 mutations. We found that individuals preferentially inherit their longest telomeres from the carrier parent, consistent with extensive telomere elongation in the carrier germline, whereas their comparatively short telomeres originate from the non-carrier parent. Analysis of carrier and non-carrier siblings showed that both sets of parental telomeres are longer in POT1 carriers, yet the shortest non-carrier-derived telomeres undergo disproportionately greater elongation than those inherited from the carrier parent. This identifies a mechanism of genetic anticipation in which the inheritance of long telomeres from one parent drives excessive extension of shorter telomeres. These findings demonstrate that telomere length inherited from both parents jointly defines the telomere-based tumor suppressor mechanism. Summary sentenceAllele specific nanopore sequencing reveals that POT1 mutations reshape germline and somatic telomere dynamics, uncovering a novel mechanism of generational anticipation driven by preferential elongation of short inherited telomeres.