Submission Details

Telomerase RNA component (TERC) variants were first reported in relation to autosomal dominant dyskeratosis congenita in 2001 (Vulliamy et al., PMID 11574891). TERC is a nearly ubiquitously expressed, long non-coding RNA (lncRNA) that complexes with telomerase reverse transcriptase (TERT) and is the template used by TERT to add TTAGGG nucleotide repeats to the ends of telomeres. Variants in telomere related genes have been reported to lead to a group of diseases referred to as telomere biology disorders (TBD’s) (PMID 39371255). Features of TBD’s like dyskeratosis congenita (DC) can include but are not limited to shortened telomeres with or without the classic DC mucocutaneous features (reticular pigmentation of the skin, oral leukoplakia, and nail dystrophy), pulmonary fibrosis, hepatic fibrosis, or bone marrow failure. At least one variant has been reported in a family with only pulmonary fibrosis as a diagnosis in a 64 year old proband with no reported cytopenias or other phenotypes related to dyskeratosis congenita (PMID 17460043). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, dyskeratosis congenita AD 1 (OMIM:127550), pulmonary fibrosis and/or bone marrow failure, telomere related 2 (OMIM:614743). Twenty-five variants (17 SNV’s and 9 indels) that have been reported in twenty-five probands in eleven publications (PMIDs 11574891, 26024875, 21436073, 19760749, 17640862, 19936245, 16990594, 34267850, 21931702, 17460043, 17392301) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity is known to be loss of function leading to shortened telomeres and early cell death. This gene-disease relationship is also supported by mouse models, pull-down assay, and in vitro functional modification assays performed in non-patient cells (PMIDs 26518879, 27587879, 32150348, 11520856, 9335332). In summary, there is definitive evidence supporting the relationship between TERC and autosomal dominant TERC-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 ILD GCEP on the meeting date November 12, 2024 (SOP11).