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TINF2 encodes the shelterin component TIN2, a critical regulator of telomere maintenance. While germline TINF2 mutations are well established in short‐telomere syndromes, emerging data implicate TINF2 in familial non‐medullary thyroid cancer (FNMTC), specifically papillary thyroid carcinoma (PTC) (TINF2; Papillary Thyroid Carcinoma).
Genetic screening in a multigenerational family revealed a heterozygous frameshift TINF2 variant, c.591del (p.Trp198GlyfsTer12), completely co‐segregating with PTC and melanoma across multiple affected members (PMID:31928178). A separate FNMTC cohort identified a novel splice‐affecting variant c.507G>T (p.Gln169His) co‐segregating in all five affected relatives (PMID:39103207). Both variants were absent from large control datasets and other screened families.
Inheritance is autosomal dominant with complete penetrance in studied pedigrees, with five affected relatives showing segregation of the splice variant in one kindred (PMID:39103207). No unaffected carriers were reported. Rare missense and synonymous variants in TINF2 and other shelterin genes were identified but lacked disease segregation.
Functional assays demonstrate that p.Trp198GlyfsTer12 TIN2 fails to bind TERF1 in co‐immunoprecipitation studies and that mutation carriers exhibit significantly longer telomeres compared with unaffected relatives and 62 healthy controls, suggesting a gain‐of‐function telomere elongation mechanism ([PMID:31928178]). The splice variant c.507G>T likely disrupts normal TIN2 structure and telomere regulation in a similar manner.
Mechanistically, dysregulated telomere elongation may lower the oncogenic threshold, allowing acquisition and persistence of driver mutations such as BRAF p.Val600Glu without additional telomere maintenance mechanisms. This aligns with observations in other long‐telomere syndromes predisposing to familial cancers.
Collectively, the evidence supports a strong gene–disease association between TINF2 truncating/splice variants and papillary thyroid carcinoma, justifying inclusion of TINF2 in genetic testing panels for FNMTC. Ongoing studies should refine penetrance estimates and explore targeted surveillance in variant carriers.
Gene–Disease AssociationStrongComplete co‐segregation of truncating/splice TINF2 variants in multiple affected family members (PMID:31928178; PMID:39103207) and absent in controls Genetic EvidenceModerateHeterozygous truncating (c.591del) and splice‐affecting (c.507G>T) variants in two pedigrees; co‐segregation in 5 probands; absent from population databases Functional EvidenceModerateTruncated TIN2 loses TERF1 binding and carriers display significantly elongated telomeres, consistent with a pathogenic telomere‐lengthening mechanism |