Dyskeratosis congenita: genes and variants

Genes linked to Dyskeratosis congenita

• TERT: Telomerase reverse transcriptase

  It extends telomeric DNA using an internal RNA template and helps counter progressive chromosome-end shortening in stem and proliferative cells. Loss-of-function variants cause telomere-biology disorders, while promoter activation and increased activity support unlimited proliferation in many cancers.

  23 disease-causing and 1,378 uncertain variants in TERT are linked to Dyskeratosis congenita.

• POT1: Protection of telomeres protein 1

  It binds the single-stranded ends of telomeres and helps control telomerase access while preventing chromosome ends from being mistaken for DNA breaks. Germline loss-of-function variants predispose to several cancers, including melanoma, glioma, and chronic lymphocytic leukemia, and can produce unusually long telomeres.

  1 disease-causing and 2 uncertain variants in POT1 are linked to Dyskeratosis congenita.

• NPM1: Nucleophosmin

  It coordinates ribosome biogenesis, nucleolar stress responses, centrosome regulation, and nucleocytoplasmic transport. Recurrent frameshift variants that mislocalize the protein to cytoplasm define one of the most common molecular subtypes of acute myeloid leukemia.

  0 disease-causing and 0 uncertain variants in NPM1 are linked to Dyskeratosis congenita.

Where Dyskeratosis congenita variants cluster

• TERT Reverse transcriptase (positions 605–935): 14 of 23 disease-causing changes, 2.1× more than its size predicts.

Known disease-causing variants in Dyskeratosis congenita

Uncertain variants in Dyskeratosis congenita that look disease-causing

Which prediction tools work for Dyskeratosis congenita

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 100 out of 100
• REVEL: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 97 out of 100
• PolyPhen-2: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 96 out of 100
• MetaLR: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 91 out of 100
• SIFT: 90 out of 100

Same protein, different disease

• Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 is also caused by TERT variants; they fall mostly in different places as the Dyskeratosis congenita variants (13 disease-causing).
• Tumor predisposition syndrome 3 is also caused by POT1 variants; they fall mostly in different places as the Dyskeratosis congenita variants (8 disease-causing).

Diseases related to Dyskeratosis congenita

• Acute myeloid leukemia, also linked to NPM1 and TERT
• Familial melanoma, also linked to POT1 and TERT
• Non-small cell lung carcinoma, also linked to NPM1
• Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1, also linked to TERT
• Idiopathic pulmonary fibrosis, also linked to TERT
• Melanoma, cutaneous malignant, susceptibility to, 8, also linked to TERT
• Lung adenocarcinoma, also linked to TERT
• Tumor predisposition syndrome 3, also linked to POT1
• Hepatocellular carcinoma, also linked to TERT
• Prostate cancer, also linked to TERT
• Myelodysplastic syndrome, also linked to TERT
• Lung carcinoma, also linked to TERT

Frequently asked questions

Which genes are linked to Dyskeratosis congenita?

In CATVariant, Dyskeratosis congenita is linked to 3 analyzed proteins: TERT (Telomerase reverse transcriptase), POT1 (Protection of telomeres protein 1) and NPM1 (Nucleophosmin).

How many genetic variants are linked to Dyskeratosis congenita?

1,458 variants: 24 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,380 are of uncertain significance or have conflicting reports.

Which uncertain variants in Dyskeratosis congenita look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example TERT R865C. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Dyskeratosis congenita?

Among tools not trained on clinical labels, EVE separates this disease's known disease-causing variants from harmless ones best (AUROC 1.00, based on 10 disease-causing and 8 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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