Submission Details

TINF2 was first reported in relation to dyskeratosis congenita, autosomal dominant 3 (MONDO: 0013522) in 2008 (Savage et al., 2008 PMID: 18252230). It is caused by mutations in the TINF2 gene, which encodes a component of shelterin, a six-protein complex that coats the telomere and is essential for suppressing the DNA damage response at telomeres (Kirwan et al., 2009; PMID:19419704). This disorder is related to telomere biology disorders (DC/TBD) which are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic Dyskeratosis congenita (DC) as well as those with a clinical picture that is dominated by dysfunction of a single organ, such as pulmonary fibrosis. Two forms of DC/TBD with more severe manifestations have been identified, Hoyeraal Hreidarsson syndrome, and Revesz syndrome, which were previously thought to be distinct disorders, but are now recognized to be part of the phenotypic spectrum of DC (Savage SA et al., 2023. Dyskeratosis Congenita and Related Telomere Biology Disorders. GeneReviews). While pulmonary fibrosis is part of the phenotypic spectrum of DC, cases of isolated fibrotic interstitial lung disease have been observed without other characteristic features of DC. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern between these conditions suggesting that these may constitute a disease spectrum associated with variants in TINF2. Therefore, the four conditions– dyskeratosis congenita, autosomal dominant 3 (OMIM:613990), Revesz syndrome (OMIM:268130), Hoyeraal-Hreidarsson syndrome (ORPHA:3322), and pulmonary fibrosis (OMIM:178500), have been lumped into one disease entity– TINF2-related short telomere syndrome.

Eight variants that have been reported in 12 probands in 7 publications (Tsangaris E, et al., 2008, PMID:18979121; Sasa GS, et al., 2012, PMID:21477109; Savage SA, et al., 2008, PMID:18252230; v Walne AJ, et al., 2008, PMID:18669893; Touzot F, et al., 2012, PMID:22078571; Geng J, et al., 2022, PMID:36073719; Vulliamy T, et al., 2012, PMID:21199492), are included in this curation. This gene-disease relationship is also supported by protein interactions, functional alteration studies, a cell-culture model, a mouse model (Liu D, et al., 2004, PMID:15181449; Touzot F, et al., 2012, PMID:22078571; Yang D, et al., 2011, PMID:21536674; Choo S et al., 2022, PMID:35421215; Frescas D et al., 2014, PMID:24449270; Frank AK et al., 2015, PMID:26230315 ). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. In summary, there is definitive evidence to support the relationship between TINF2 and TINF2-related short telomere syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Interstitial Lung Disease GCEP on the meeting date November 19, 2024 (SOP Version 11).