TINF2 – Revesz syndrome

Revesz syndrome is a severe telomere biology disorder within the dyskeratosis congenita spectrum, characterized by exudative retinopathy, bone marrow failure, cerebellar hypoplasia and skin abnormalities. Patients typically present in early childhood with proliferative vitreoretinopathy, thrombocytopenia progressing to pancytopenia, neurodevelopmental delay and cutaneous pigmentary changes.

Autosomal dominant pathogenic variants in TINF2 have been identified in four unrelated probands with Revesz syndrome: a mosaic c.865C>T (p.Pro289Ser) variant in a two-year-old male presenting with total retinal detachment ([PMID:29749240]), identical twins harboring a T284P missense change with bilateral avascularity and exudation ([PMID:28095086]), and a truncating c.811C>T (p.Gln271Ter) allele found in one child with the severe Revesz subtype of dyskeratosis congenita ([PMID:21477109]).

Segregation analysis in the twin kindred demonstrated one additional affected relative carrying the same TIN2 mutation ([PMID:28095086]). No unaffected carriers have been reported, supporting full penetrance of Revesz-associated alleles.

Variant spectrum in Revesz syndrome includes missense changes (p.Pro289Ser, p.Thr284Pro) and early truncating mutations (p.Gln271Ter) clustered in exon 6 of TINF2, a hotspot for telomere-shortening alleles.

Functional studies show that truncating TIN2 variants result in markedly shortened telomeres by flow-FISH, impaired interaction with shelterin component TRF1 in co-immunoprecipitation assays ([PMID:21477109]), and deficient telomerase processivity when assayed with TPP1/POT1 in vitro ([PMID:31383750]). These data support a haploinsufficiency mechanism.

Integration of genetic and experimental findings yields a Moderate clinical validity classification: four probands with consistent phenotypes, one segregation event, and concordant functional defects. Key take-home: autosomal dominant TINF2 variants should be sought in early-onset exudative retinopathy with marrow failure to enable timely diagnosis and management.

References

• Bratislavske lekarske listy • 2018 • Why is it necessary to examine retina when the patient suffers from aplastic anemia? PMID:29749240
• Ophthalmic genetics • 2017 • Retinal findings and a novel TINF2 mutation in Revesz syndrome: Clinical and molecular correlations with pediatric retinal vasculopathies. PMID:28095086
• Clinical genetics • 2012 • Three novel truncating TINF2 mutations causing severe dyskeratosis congenita in early childhood. PMID:21477109
• Molecular and cellular biology • 2019 • TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity. PMID:31383750

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