dyskeratosis congenita, X-linked

Summary

dyskeratosis congenita, X-linked (MONDO:0010584) is a disease caused by DKC1 (GenCC Definitive), with 3 cohort genes and 2 clinical trials. Top therapeutic interventions include fludarabine phosphate and doxecitine.

At a glance

• Causal gene: DKC1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 80
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dyskeratosis congenita, X-linked
Mondo ID	MONDO:0010584
OMIM	305000
DOID	DOID:0070025
NCIT	C126352
SNOMED CT	708536001
UMLS	C1148551
MedGen	216941
GARD	0002007
Is cancer (heuristic)	no

Also known as: DKCX · dyskeratosis congenita X-linked · dyskeratosis congenita, X-linked · dyskeratosis congenita, X-linked, X-linked recessive · Hoyeraal Hreidarsson syndrome · X-linked dyskeratosis congenita · Zinsser-Cole-Engman syndrome

Data availability: 80 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › dyskeratosis congenita, X-linked

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

Subtypes (1): Hoyeraal-Hreidarsson syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

80 retrieved; paginated sample, class counts are floors:

22 uncertain significance, 19 not provided, 14 pathogenic, 10 likely pathogenic, 10 conflicting classifications of pathogenicity, 3 benign/likely benign, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
11582	NM_001363.5(DKC1):c.106T>G (p.Phe36Val)	DKC1	Pathogenic	no assertion criteria provided
11584	NM_001363.5(DKC1):c.119C>G (p.Pro40Arg)	DKC1	Pathogenic	no assertion criteria provided
11585	NM_001363.5(DKC1):c.214_215delinsTA (p.Leu72Tyr)	DKC1	Pathogenic	no assertion criteria provided
11586	NM_001363.5(DKC1):c.1205G>A (p.Gly402Glu)	DKC1	Pathogenic	no assertion criteria provided
11587	NM_001363.5(DKC1):c.1058C>T (p.Ala353Val)	DKC1	Pathogenic	criteria provided, multiple submitters, no conflicts
11588	NC_000023.11:g.(154776372_154776374)_(154778317_154778319)del	DKC1	Pathogenic	no assertion criteria provided
11590	NM_001363.5(DKC1):c.16+592C>G	DKC1	Pathogenic	no assertion criteria provided
11591	NM_001363.5(DKC1):c.146C>T (p.Thr49Met)	DKC1	Pathogenic	criteria provided, multiple submitters, no conflicts
11593	NM_001363.5(DKC1):c.113T>C (p.Ile38Thr)	DKC1	Pathogenic	no assertion criteria provided
11594	NM_001363.5(DKC1):c.91C>A (p.Gln31Lys)	DKC1	Pathogenic	no assertion criteria provided
11596	NM_001363.5(DKC1):c.1259+1G>A	DKC1	Pathogenic	no assertion criteria provided
38936	NM_001363.5(DKC1):c.1156G>A (p.Ala386Thr)	DKC1	Pathogenic	criteria provided, single submitter
38946	NM_001363.5(DKC1):c.196A>G (p.Thr66Ala)	DKC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446380	NM_001363.5(DKC1):c.203A>G (p.His68Arg)	DKC1	Pathogenic	criteria provided, single submitter
1802166	NM_001283009.2(RTEL1):c.1379C>T (p.Pro460Leu)	RTEL1	Pathogenic	no assertion criteria provided
11583	NM_001363.5(DKC1):c.109_111del (p.Leu37del)	DKC1	Likely pathogenic	criteria provided, single submitter
1343818	NM_001363.5(DKC1):c.204C>G (p.His68Gln)	DKC1	Likely pathogenic	criteria provided, single submitter
2664154	NM_001363.5(DKC1):c.114C>G (p.Ile38Met)	DKC1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674846	NM_001363.5(DKC1):c.964C>T (p.Arg322Ter)	DKC1	Likely pathogenic	criteria provided, single submitter
38942	NM_001363.5(DKC1):c.1226C>T (p.Pro409Leu)	DKC1	Likely pathogenic	criteria provided, single submitter
38957	NM_001363.5(DKC1):c.949C>T (p.Leu317Phe)	DKC1	Likely pathogenic	criteria provided, single submitter
427887	NM_001363.5(DKC1):c.1054A>G (p.Thr352Ala)	DKC1	Likely pathogenic	no assertion criteria provided
434943	NM_001363.5(DKC1):c.1255T>A (p.Tyr419Asn)	DKC1	Likely pathogenic	criteria provided, single submitter
916631	NM_001363.5(DKC1):c.1195G>C (p.Asp399His)	DKC1	Likely pathogenic	criteria provided, single submitter
930355	NM_001363.5(DKC1):c.133G>A (p.Ala45Thr)	DKC1	Likely pathogenic	criteria provided, single submitter
11592	NM_001363.5(DKC1):c.361A>G (p.Ser121Gly)	DKC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1434341	NM_001363.5(DKC1):c.253G>A (p.Asp85Asn)	DKC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
238951	NM_001363.5(DKC1):c.1494GAA[6] (p.Lys505del)	DKC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
379736	NM_001363.5(DKC1):c.1133G>A (p.Arg378Gln)	DKC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
38941	NM_001363.5(DKC1):c.1223C>T (p.Thr408Ile)	DKC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
DKC1	Definitive	X-linked	dyskeratosis congenita, X-linked	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DKC1	Orphanet:1775	Dyskeratosis congenita
DKC1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
RTEL1	Orphanet:1775	Dyskeratosis congenita
RTEL1	Orphanet:2032	Idiopathic pulmonary fibrosis
RTEL1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DKC1	HGNC:2890	ENSG00000130826	O60832	H/ACA ribonucleoprotein complex subunit DKC1	gencc,clinvar
RTEL1	HGNC:15888	ENSG00000258366	Q9NZ71	Regulator of telomere elongation helicase 1	clinvar
RTEL1-TNFRSF6B	HGNC:44095	ENSG00000026036		RTEL1-TNFRSF6B readthrough (NMD candidate)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DKC1	H/ACA ribonucleoprotein complex subunit DKC1	Catalytic subunit of H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA.
RTEL1	Regulator of telomere elongation helicase 1	A probable ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair and the maintenance of genomic stability.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DKC1	Other/Unknown	no		PUA, PsdUridine_synth_N, Uncharacterised_CHP00451
RTEL1	Other/Unknown	no		Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
RTEL1-TNFRSF6B	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
gingival epithelium	1
secondary oocyte	1
cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DKC1	287	ubiquitous	marker	secondary oocyte, sural nerve, gingival epithelium
RTEL1	134	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
RTEL1-TNFRSF6B	135		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellum

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DKC1	4,882
RTEL1	2,324
RTEL1-TNFRSF6B	0

Intra-cohort edges

A	B	Sources
DKC1	RTEL1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DKC1	O60832	7
RTEL1	Q9NZ71	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Telomere Extension By Telomerase	2	456.8×	7e-05	DKC1, RTEL1
Cytosolic iron-sulfur cluster assembly	1	380.7×	0.012	RTEL1
Resolution of D-Loop Structures	1	317.2×	0.012	RTEL1
Extension of Telomeres	1	300.5×	0.012	RTEL1
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	196.9×	0.012	RTEL1
Telomere Maintenance	1	184.2×	0.012	RTEL1
Homology Directed Repair	1	154.3×	0.012	RTEL1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	154.3×	0.012	RTEL1
DNA Double-Strand Break Repair	1	124.1×	0.013	RTEL1
Chromosome Maintenance	1	105.7×	0.013	RTEL1
HDR through Homologous Recombination (HRR)	1	95.2×	0.013	RTEL1
rRNA modification in the nucleus and cytosol	1	93.6×	0.013	DKC1
DNA Repair	1	49.2×	0.023	RTEL1
Cell Cycle	1	18.0×	0.059	RTEL1
Metabolism	1	5.8×	0.165	RTEL1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA strand displacement	1	8426.0×	0.001	RTEL1
negative regulation of telomere maintenance in response to DNA damage	1	8426.0×	0.001	RTEL1
positive regulation of telomeric loop disassembly	1	8426.0×	0.001	RTEL1
box H/ACA sno(s)RNA 3’-end processing	1	4213.0×	0.001	DKC1
telomeric loop disassembly	1	4213.0×	0.001	RTEL1
protein localization to Cajal body	1	4213.0×	0.001	DKC1
snRNA pseudouridine synthesis	1	2808.7×	0.001	DKC1
mitotic telomere maintenance via semi-conservative replication	1	2808.7×	0.001	RTEL1
negative regulation of t-circle formation	1	2808.7×	0.001	RTEL1
enzyme-directed rRNA pseudouridine synthesis	1	2106.5×	0.001	DKC1
rRNA pseudouridine synthesis	1	2106.5×	0.001	DKC1
telomerase RNA stabilization	1	2106.5×	0.001	DKC1
regulation of telomerase RNA localization to Cajal body	1	2106.5×	0.001	DKC1
scaRNA localization to Cajal body	1	1685.2×	0.001	DKC1
positive regulation of telomere capping	1	1685.2×	0.001	RTEL1
positive regulation of telomere maintenance via telomere lengthening	1	1404.3×	0.001	RTEL1
telomerase holoenzyme complex assembly	1	1404.3×	0.001	DKC1
telomere maintenance in response to DNA damage	1	936.2×	0.002	RTEL1
positive regulation of telomerase RNA localization to Cajal body	1	936.2×	0.002	DKC1
mRNA pseudouridine synthesis	1	842.6×	0.002	DKC1
negative regulation of DNA recombination	1	561.7×	0.003	RTEL1
regulation of double-strand break repair via homologous recombination	1	495.6×	0.003	RTEL1
telomere maintenance via telomerase	1	366.4×	0.003	DKC1
positive regulation of telomere maintenance via telomerase	1	366.4×	0.003	DKC1
positive regulation of telomere maintenance	1	255.3×	0.005	RTEL1
replication fork processing	1	210.7×	0.005	RTEL1
telomere maintenance	1	133.8×	0.008	RTEL1
RNA processing	1	109.4×	0.010	DKC1
rRNA processing	1	70.8×	0.015	DKC1
DNA repair	1	31.9×	0.031	RTEL1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DKC1	1	2
RTEL1	0	0
RTEL1-TNFRSF6B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	DKC1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DKC1	8	Binding:8

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	DKC1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	DKC1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	RTEL1, RTEL1-TNFRSF6B

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RTEL1	0	—
RTEL1-TNFRSF6B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01659606	PHASE2	ACTIVE_NOT_RECRUITING	Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
NCT06817590	PHASE1	RECRUITING	Nucleoside Therapy in Patients With Telomere Biology Disorders

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLUDARABINE PHOSPHATE	4	1
DOXECITINE	2	1