Details of Disease

General Information of Disease (ID: DISSXV0K)

• Disease Name: Dyskeratosis congenita
• Synonyms: Zinsser Cole Engman syndrome; Hoyeraal-Hreidarsson syndrome; DKC; Zinsser-Engman-Cole syndrome; MONDO:DC; dyskeratosis congenita
• Definition: Dyskeratosis congenita (DC) is a rare ectodermal dysplasia that often presents with the classic triad of nail dysplasia, skin pigmentary changes, and oral leukoplakia associated with a high risk of bone marrow failure (BMF) and cancer.|Editor note: in ORDO this is X-linked but this is the inheritance-neutral form and non-X-linked forms exist
• Disease Hierarchy:
  DISGXLG5: Hereditary neoplastic syndrome
  DISLRS4M: Ectodermal dysplasia
  DISSXV0K: Dyskeratosis congenita
• Disease Identifiers:
  MONDO ID: MONDO_0015780
  MESH ID: D019871
  UMLS CUI: C0265965
  MedGen ID: 78580
  Orphanet ID: 1775
  SNOMED CT ID: 74911008

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 30 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
USB1	OTENP2YQ	Supportive	Autosomal dominant	[1]
WRAP53	OTYJQQSG	Moderate	Autosomal recessive	[2]
RPS19	OTBKGP48	Limited	Genetic Variation	[10]
CTC1	OTRJY7QD	Supportive	Autosomal dominant	[4]
DKC1	OTX7DJR6	Supportive	Autosomal dominant	[4]
NHP2	OTZK4FU5	Supportive	Autosomal dominant	[4]
NOP10	OT1MVO2F	Supportive	Autosomal dominant	[4]
NPM1	OTTBYYT0	Supportive	Autosomal dominant	[3]
PARN	OTTG4PE3	Supportive	Autosomal dominant	[11]
RTEL1	OTI3PJCT	Supportive	Autosomal dominant	[12]
TERT	OT085VVA	Supportive	Autosomal dominant	[4]
TINF2	OT861N2N	Supportive	Autosomal dominant	[4]
ACD	OTC54EPO	Strong	Biomarker	[13]
AK6	OT84OHHP	Strong	Biomarker	[14]
CBX3	OTOP9RLD	Strong	Biomarker	[15]
DDX11	OT1WR3MD	Strong	Genetic Variation	[5]
DNAJC21	OT8C14QA	Strong	Biomarker	[16]
HBG2	OT4J48JJ	Strong	Genetic Variation	[17]
HPSE2	OTGEPP8V	Strong	Posttranslational Modification	[18]
MLIP	OTMT7AII	Strong	Biomarker	[14]
NAF1	OTMJKJAK	Strong	Genetic Variation	[6]
PRDM8	OTRA3265	Strong	Posttranslational Modification	[19]
PUS7	OTE5AQHJ	Strong	Altered Expression	[20]
RNPC3	OTW5MKC1	Strong	Biomarker	[21]
SBDS	OTHDCCIB	Strong	Biomarker	[22]
SHQ1	OTFBXX2H	Strong	Genetic Variation	[23]
STN1	OT8UWRA3	Strong	Biomarker	[13]
TECR	OT2NT4MV	Strong	Altered Expression	[24]
TRUB1	OT15EP5B	Strong	Biomarker	[25]
GAR1	OTA580RX	Definitive	Biomarker	[26]

This Disease Is Related to 8 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
NPM1	TTHBS98	Supportive	Autosomal dominant	[3]
TERT	TTQY2EJ	Supportive	Autosomal dominant	[4]
NPM1	TTHBS98	moderate	Genetic Variation	[3]
BRIP1	TTZV7LJ	Strong	Biomarker	[5]
TENT4B	TTB5R6M	Strong	Biomarker	[6]
TERF1	TT1Y6J2	Strong	Genetic Variation	[7]
TERT	TTQY2EJ	Strong	Genetic Variation	[8]
TPP1	TTOVYPT	Definitive	Genetic Variation	[9]

References

• [1] Mutations in C16orf57 and normal-length telomeres unify a subset of patients with dyskeratosis congenita, poikiloderma with neutropenia and Rothmund-Thomson syndrome. Hum Mol Genet. 2010 Nov 15;19(22):4453-61. doi: 10.1093/hmg/ddq371. Epub 2010 Sep 3.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Germline NPM1 mutations lead to altered rRNA 2'-O-methylation and cause dyskeratosis congenita. Nat Genet. 2019 Oct;51(10):1518-1529. doi: 10.1038/s41588-019-0502-z. Epub 2019 Sep 30.
• [4] Dyskeratosis Congenita and Related Telomere Biology Disorders. 2009 Nov 12 [updated 2023 Jan 19]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [5] Specialization among iron-sulfur cluster helicases to resolve G-quadruplex DNA structures that threaten genomic stability.J Biol Chem. 2013 Sep 27;288(39):28217-29. doi: 10.1074/jbc.M113.496463. Epub 2013 Aug 9.
• [6] Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita.Blood. 2019 Mar 21;133(12):1308-1312. doi: 10.1182/blood-2018-11-885368. Epub 2019 Feb 6.
• [7] The C-Terminal Extension Unique to the Long Isoform of the Shelterin Component TIN2 Enhances Its Interaction with TRF2 in a Phosphorylation- and Dyskeratosis Congenita Cluster-Dependent Fashion.Mol Cell Biol. 2018 May 29;38(12):e00025-18. doi: 10.1128/MCB.00025-18. Print 2018 Jun 15.
• [8] Telomerase insufficiency induced telomere erosion accumulation in successive generations in dyskeratosis congenita family.Mol Genet Genomic Med. 2019 Jul;7(7):e00709. doi: 10.1002/mgg3.709. Epub 2019 May 22.
• [9] The role of telomere binding molecules for normal and abnormal hematopoiesis.Int J Hematol. 2018 Jun;107(6):646-655. doi: 10.1007/s12185-018-2432-4. Epub 2018 Mar 17.
• [10] Pregnancy outcomes in mothers of offspring with inherited bone marrow failure syndromes.Pediatr Blood Cancer. 2018 Jan;65(1):10.1002/pbc.26757. doi: 10.1002/pbc.26757. Epub 2017 Aug 12.
• [11] Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita. J Clin Invest. 2015 May;125(5):2151-60. doi: 10.1172/JCI78963. Epub 2015 Apr 20.
• [12] Constitutional mutations in RTEL1 cause severe dyskeratosis congenita. Am J Hum Genet. 2013 Mar 7;92(3):448-53. doi: 10.1016/j.ajhg.2013.02.001. Epub 2013 Feb 28.
• [13] Germline Genetic Predisposition to Hematologic Malignancy.J Clin Oncol. 2017 Mar 20;35(9):1018-1028. doi: 10.1200/JCO.2016.70.8644. Epub 2017 Feb 13.
• [14] The p53/p21(WAF/CIP) pathway mediates oxidative stress and senescence in dyskeratosis congenita cells with telomerase insufficiency.Antioxid Redox Signal. 2011 Mar 15;14(6):985-97. doi: 10.1089/ars.2010.3444. Epub 2011 Jan 17.
• [15] A role for heterochromatin protein 1 at human telomeres.Genes Dev. 2011 Sep 1;25(17):1807-19. doi: 10.1101/gad.17325211. Epub 2011 Aug 24.
• [16] Refining the phenotype associated with biallelic DNAJC21 mutations.Clin Genet. 2018 Aug;94(2):252-258. doi: 10.1111/cge.13370. Epub 2018 Jun 7.
• [17] Genetic regulation of fetal haemoglobin in inherited bone marrow failure syndromes.Br J Haematol. 2013 Aug;162(4):542-6. doi: 10.1111/bjh.12399. Epub 2013 May 29.
• [18] Skewed X-inactivation in carriers of X-linked dyskeratosis congenita.Blood. 1997 Sep 15;90(6):2213-6.
• [19] DNA methylation in PRDM8 is indicative for dyskeratosis congenita.Oncotarget. 2016 Mar 8;7(10):10765-72. doi: 10.18632/oncotarget.7458.
• [20] Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA.Cell. 2014 Sep 25;159(1):148-162. doi: 10.1016/j.cell.2014.08.028. Epub 2014 Sep 11.
• [21] Very short telomeres in the peripheral blood of patients with X-linked and autosomal dyskeratosis congenita.Blood Cells Mol Dis. 2001 Mar-Apr;27(2):353-7. doi: 10.1006/bcmd.2001.0389.
• [22] Phylogeny, sequence conservation, and functional complementation of the SBDS protein family.Genomics. 2006 Jun;87(6):758-71. doi: 10.1016/j.ygeno.2006.01.010. Epub 2006 Mar 10.
• [23] Inherited SHQ1 mutations impair interaction with NAP57/dyskerin, a major target in dyskeratosis congenita. Mol Genet Genomic Med. 2017 Nov;5(6):805-808. doi: 10.1002/mgg3.314. Epub 2017 Aug 15.
• [24] Telomere restoration and extension of proliferative lifespan in dyskeratosis congenita fibroblasts.Aging Cell. 2007 Jun;6(3):383-94. doi: 10.1111/j.1474-9726.2007.00288.x. Epub 2007 Mar 23.
• [25] The human TruB family of pseudouridine synthase genes, including the Dyskeratosis Congenita 1 gene and the novel member TRUB1.Int J Mol Med. 2003 Jun;11(6):697-704.
• [26] Zebrafish models for dyskeratosis congenita reveal critical roles of p53 activation contributing to hematopoietic defects through RNA processing.PLoS One. 2012;7(1):e30188. doi: 10.1371/journal.pone.0030188. Epub 2012 Jan 27.