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Dyskeratosis congenita (DC) is a heterogeneous disorder, both genetically and phenotypically (1). Clinical presentation is classically defined by a triad of mucocutaneous features: abnormal reticulate skin pigmentation, nail dystrophy and leukoplakia. Bone marrow failure and a spectrum of other somatic abnormalities are also commonly observed (2). In its severe form, DC overlaps with the Hoyeraal–Hreidarsson (HH) syndrome, characterized by immunodeficiency, cerebellar hypoplasia, microcephaly and growth retardation as well as aplastic anaemia (AA). Because of this wide range of phenotypes, a clinical diagnosis of DC can often be quite difficult, although we would usually define a DC patient as having at least two of the three mucocutaneous features with either evidence of bone marrow failure or two or more other somatic abnormalities (3). In some cases a genetic diagnosis can be made, based on the identification of a mutation in one of the seven genes (DKC1, TERC, TERT, NOP10, NHP2, TINF2 and C16orf57). Through genome-wide linkage analysis and candidate gene sequencing, the TINF2 gene was initially identified as the cause of DC in one family showing autosomal dominant inheritance of the disease (4). It has subsequently become clear that mutations in this gene usually arise de novo in sporadic cases, causing a relatively severe form of DC (4, 5). The gene encodes a core component of the shelterin complex – a group of proteins that interact to protect telomeres. This protein is called TIN2, the telomeric repeat binding factor 1 (TRF1)-interacting nuclear factor 2; it is an essential mediator of TRF1 function and acts as an important regulator of telomere length (6, 7). TIN2 acts as the central component of the shelterin complex, binding not only TRF1 but also TRF2, a second telomere DNA-binding protein (8) and TPP1, the TIN2-interacting protein (9). TIN2-anchored TPP1 plays a major role in the recruitment of telomerase to telomeres in human cells (10). TPP1 is also important for recruiting POT1 (protection of telomeres), which is the third DNA-binding protein of the shelterin complex. POT1 binds to telomeric single-stranded DNA, protecting chromosome ends from the DNA-damage response (11). A second larger isoform of TIN2 has recently been identified, and this appears to have a role in tethering telomeres to the nuclear matrix (12). Since our previous report in 2008 (5), we have been screening for TINF2 mutations in all patients referred to our DC registry with various forms of bone marrow failure. This has led to the identification of 16 new families with eight previously unreported variants. They show that the phenotype associated with TINF2 mutation is broader than previously thought, but also raise the question as to whether all of these novel variants are pathogenic.

Dyskeratosis congenita (DC) is an inherited syndrome exhibiting marked clinical and genetic heterogeneity. It is characterized by multiple features including mucocutaneous abnormalities, bone marrow failure and an increased predisposition to cancer. Three genetic subtypes are recognized: X-linked recessive DC bears mutations in DKC1, the gene encoding dyskerin, a component of H/ACA small nucleolar ribonucleoprotein particles; autosomal dominant (AD) DC has heterozygous mutations in either TERC or TERT, the RNA and enzymatic components of telomerase, respectively, and autosomal recessive DC in which the genes involved remain largely elusive. Disease pathology is believed to be a consequence of chromosome instability because of telomerase deficiency due to mutations in DKC1, TERC and TERT; in patients with DKC1 mutations, defects in ribosomal RNA modification, ribosome biogenesis, translation control or mRNA splicing may also contribute to disease pathogenesis. The involvement of telomerase complex components in X-linked and AD forms and the presence of short telomeres in DC patients suggest that DC is primarily a disease of defective telomere maintenance. Treatment is variable and complicated by the development of secondary cancers but, being a monogenic disorder, it could potentially be treated by gene therapy. DC overlaps both clinically and genetically with several other diseases including Hoyeraal-Hreidarsson syndrome, aplastic anaemia and myelodysplasia, among others and its underlying telomeric defect has implications for a broader range of biological processes including ageing and many forms of cancer.