Submission Details

Dyskeratosis congenita (DC) is a multisystem disorder caused by defective telomere maintenance. Features are variable and include bone marrow failure, pulmonary and liver fibrosis, and premature graying of the hair (PMID: 16247010). TERT is one of the eleven genes encoding critical components of the telomere and telomerase complex that have been found to be mutated in individuals with DC. There is abundant evidence published associating the TERT gene with Dyskeratosis Congenita, since the gene-disease relationship was first proposed by Yamaguchi et al. (2005) (PMID: 15814878). Variants in TERT are considered to convey semi-dominant inheritance since both heterozygous and homozygous or compound heterozygous variants were reported in DC patients with different severity and age of onset. This is a lumped curation for Dyskeratosis congenita, autosomal dominant 2 (MIM: 613989), Dyskeratosis congenita, autosomal recessive 4 (MIM: 613989), Leukemia, acute myeloid (MIM: 601626) and Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1 (MIM: 614742). The MONDO entry of dyskeratosis congenita, autosomal dominant 2 is used in this curation, but a new disease entry is needed in the future for the telomere-mediated syndrome (PMID: 19405848). Multiple case level studies have been performed with DC patients that have variants in the TERT gene. A significant amount of case-level data is available, but the maximum points for genetic evidence has been reached (12 points). Multiple mouse models with TERT-specific deficiency or short telomeres have been established to show consistent phenotypes with DC patients, and TERT reactivation reverses tissue degeneration in aged mice. In summary, TERT is definitively associated with semi-dominant Dyskeratosis Congenita, the telomere-mediated syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.