Submission Details

Variants in DKC1 were first reported in 1998 (Heiss NS et al., PMID: 9590285) in relation to X-linked Dyskeratosis congenita [MIM:305000], a telomere biogenesis disorder that is characterized by a triad of abnormal skin pigmentation, nail dystrophy, leukoplakia of the oral mucosa, and increased risk for bone marrow failure and associated hematologic malignancies and solid tumors. ‘Hoyeraal-Hreidarsson syndrome’ consists of profound neurodevelopmental delay and cerebellar hypoplasia in addition to classical Dyskeratosis congenita findings. Interstitial lung disease has been repeatedly identified in patients with X-linked Dyskeratosis Congenita carrying DKC1 variants (PMIDs: 11641517, 23946118, 21415081, 24504062, 32710892).Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern between dyskeratosis congenita, -X linked (OMIM:305000), Hoyeraal-Hreidarsson syndrome (ORPHA:3322), and pulmonary fibrosis (OMIM:178500), suggesting that these may constitute a disease spectrum associated with variants in DKC1. Therefore, these conditions have been lumped into one disease entity– DKC1-related short telomere syndrome, dyskeratosis congenita, X-linked.

The vast majority (~95%) of the reported predicted and/or proven pathogenic variants are missense. Six recurrent missense variants, including the most common p.Ala353Val variant, and one non-frameshift deletion variant that have been reported in ~20 probands in at least seven publications (PMIDs: 10700698, 21931702, 10583221, 10364516, 29483670, 24914498, 9590285) are included in this curation. More evidence is available in the literature, but the maximum score (7 pts.) for genetic evidence of missense variants has been reached. This gene-disease association is also supported by protein interaction studies, in vitro functional assays on patient cells, and non-human model organism studies that demonstrated the protein’s (dyskerin) interaction/co-localization with other telomerase assembly proteins (TERT and TERC) that have also been associated with Dyskeratosis congenita in an autosomal dominant and autosomal recessive inheritances, decrease in telomere lengths in the cells of affected individuals, and recapitulation of functional and biochemical defects in non-human model organisms (PMIDs: 10591218, 15240872, 17395830, 18057229).

Interstitial lung disease has been repeatedly identified in patients with X-linked Dyskeratosis Congenita carrying DKC1 variants (PMIDs: 11641517, 23946118, 21415081, 24504062, 32710892).The patients showed features of pulmonary fibrosis, in addition to decreased dyskerin levels, compromised telomerase RNA levels, very short telomeres and the classic features of DC. In cases where pulmonary fibrosis was biopsied, there was evidence of usual interstitial pneumonia and bronchiolitis obliterans organizing pneumonia (PMIDs: 11641517 and 21415081). As observed in patients with X-linked DC, the variants reported are primarily missense, although one synonymous variant (c.942G>A p.K314K ) was reported in a patient with bone marrow failure, non-melanoma skin cancer, familial pulmonary fibrosis and dyskerin deficiency. The mutation was shown to create a competing de novo exonic splicing enhancer, resulting in degradation of the mis-spliced product (PMID: 32710892). In females with heterozygous DKC1 mutations, there is evidence of skewed X-inactivation, compromised telomerase RNA levels, short telomeres and mild DC features (PMIDs : 21415081 and 23946118). Hypomorphic Dkc1 mutant (Dkc1m ) mice showed the clinical features of DC in the first and second generations accompanied with a decrease in telomerase activity in Dkc1m cells, as compared with WT controls, and a reduction in mouse telomerase RNA (mTR) levels. Disruption of the normal architecture of the lung parenchyma, mainly produced by the fusion of alveolar spaces and the thickening of the alveolar walls was also observed in Dkc1m lung (PMID: 12522253).

Secondary contributor evidence was provided by the ILD GCEP and ID-Autism GCEP. In summary, there is Definitive evidence to support this gene-disease relationship. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.