WRAP53 was first reported in relation to semidominant telomere syndrome in 2011 (Zhong et al., PMID: 21205863). Individuals with WRAP53 variants presented with features of the classic dyskeratosis congenita triad (oral leukoplakia, nail dystrophy, abnormal skin pigmentation), bone marrow failure, short telomeres, and a variable age of onset, some with other features reported in addition to these findings (PMID: 21205863). Importantly, interstitial lung disease was not reported to be a feature found in any of the cases, but one case did have hepatopulmonary syndrome and respiratory insufficiency (PMID: 37149759).
Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: Dyskeratosis congenita, autosomal recessive 3 (OMIM:613988), Hoyeraal-Hreidarsson syndrome, early-onset epileptic encephalopathy, myelodysplastic syndrome, and aplastic anemia. Other assertions have been made for Ewing sarcoma (PMID: 28125078), pediatric acute myeloid leukemia (PMID: 31470354), primary immunodeficiency (PMID: 32888943), craniometadiaphyseal dysplasia (PMID: 34484289), gastric cancer (PMID: 28875981), and breast cancer (PMID: 17683073); however, these additional assertions were split for various reasons including sequencing errors (PMID:36116037), presence of variants in other genes, and high allele frequencies.
Eleven missense variants that have been reported in 8 probands across 7 publications (PMIDs: 21205863, 29514627, 32303682, 34599657, 30552426, 37149759, 30523342) are included in this curation. The mechanism of pathogenicity is reported to be a loss of function that results in shortened telomeres (PMID: 21205863).
This gene-disease relationship is also supported by experimental evidence including biochemical function data that is consistent with the phenotype (PMID: 19179534), protein interactions with other genes known to cause dyskeratosis congenita (PMID: 32303682), functional alteration in iPSCs that demonstrate the human disease process (PMID: 21602826), and a cell culture model that displayed telomere shortening (PMID: 19179534).
In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Interstitial Lung Disease GCEP on the meeting date June 17, 2025 (SOP Version 11).
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