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The shelterin component TIN2, encoded by the TINF2 gene, is essential for telomere maintenance and protection. Pathogenic heterozygous variants in TINF2 cause telomere shortening and manifest clinically as Hoyeraal-Hreidarsson syndrome, a severe variant of dyskeratosis congenita characterized by cerebellar hypoplasia, immunodeficiency, and bone marrow failure. HHS presents with neurodevelopmental delay, thrombocytopenia, anemia, and CNS imaging features including cerebellar hypoplasia, delayed myelination, hydrocephalus, and intracranial calcifications. TINF2-associated HHS follows an autosomal dominant inheritance pattern with de novo and familial truncating and missense variants. Clinical testing for TINF2 variants is available in bone marrow failure and telomere biology disorder panels. Early genetic diagnosis informs management including hematopoietic stem cell transplantation and surveillance for multi-system complications.
Genetic evidence for TINF2 in HHS includes multiple unrelated probands. In a multi-center cohort of patients with telomere biology disorders presenting with gastrointestinal hemorrhage, 8 harbored heterozygous TINF2 variants (8 probands PMID:32971146). In a separate imaging study, three children with clinically diagnosed HHS carried heterozygous TINF2 variants (3 probands PMID:33734615). The variant spectrum comprises truncating alleles (e.g., c.591del (p.Trp198GlyfsTer12)) and missense changes clustering in exon 6. One de novo missense variant, c.844C>T (p.Arg282Cys), was reported in a sporadic severe case (PMID:37070599). No consistent recessive inheritance or compound heterozygosity has been documented.
Segregation data are limited, and familial cosegregation studies in HHS pedigrees are lacking, resulting in no additional affected relatives meeting criteria for segregation analysis. The observed de novo occurrences support pathogenicity but multi-generation kindreds have not been reported. Thus, segregation contributes minimally to the current evidence base.
Functional assays corroborate the pathogenic impact of TINF2 HHS mutations. Telomere length measurements in patient lymphocytes demonstrate markedly shortened telomeres, distinguishing pathogenic variants from non-pathogenic polymorphisms (PMID:21199492). In vitro studies show that TIN2 mutations disrupt telomerase processivity through impaired interaction with TPP1/POT1, reducing telomere elongation (PMID:31383750). Gene-editing of TINF2 mutations in human embryonic and hematopoietic stem cells restores telomere length and replicative potential, demonstrating causality and a potential therapeutic avenue (PMID:35421215). These concordant data mirror the human HHS phenotype of telomere shortening and multi-system involvement.
Taken together, the genetic and functional evidence supports a moderate level of clinical validity for TINF2 in HHS. The predominance of de novo and heterozygous truncating and missense variants, their consistent impact on telomere maintenance, and the recapitulation of phenotype in cellular models establish a compelling etiological link. Further studies, including larger familial segregation and animal models, would strengthen the association toward a definitive classification.
Key take-home: TINF2 testing should be integrated into diagnostic evaluation of patients with Hoyeraal-Hreidarsson syndrome to guide prognosis, therapeutic decisions, and genetic counseling.
Gene–Disease AssociationModerate11 unrelated probands with heterozygous TINF2 variants across independent HHS cohorts (8 [PMID:32971146], 3 [PMID:33734615]); supportive functional concordance Genetic EvidenceModerate11 unrelated heterozygous truncating and missense TINF2 variants in HHS probands; de novo occurrences observed Functional EvidenceModerateTelomere length assays, telomerase processivity studies, and gene-editing rescue demonstrate telomere restoration |