DKC1-related disorder

Summary

DKC1-related disorder (MONDO:0100152) is a disease caused by DKC1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: DKC1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 24

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	DKC1-related disorder
Mondo ID	MONDO:0100152
GARD	0026065
Is cancer (heuristic)	no

Also known as: DKC1-related disorder

Data availability: 24 ClinVar variants · 1 GenCC gene-disease record.

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 › hereditary neoplastic syndrome › dyskeratosis congenita › DKC1-related disorder

Related subtypes (15): dyskeratosis congenita, autosomal dominant 1, dyskeratosis congenita, autosomal recessive 1, Revesz syndrome, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, dyskeratosis congenita, autosomal recessive 6, dyskeratosis congenita, autosomal dominant 6, autosomal recessive dyskeratosis congenita 4, dyskeratosis congenita, digenic, dyskeratosis congenita, autosomal dominant 4, dyskeratosis congenita, autosomal recessive 7, dyskeratosis congenita and related telomere biology disorder, dyskeratosis congenita, autosomal recessive 8

Subtypes (1): dyskeratosis congenita, X-linked

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

24 retrieved; paginated sample, class counts are floors:

9 likely benign, 6 uncertain significance, 5 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11590	NM_001363.5(DKC1):c.16+592C>G	DKC1	Pathogenic	no assertion criteria provided
1010558	NM_001363.5(DKC1):c.1471G>A (p.Asp491Asn)	DKC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1026304	NM_001363.5(DKC1):c.84C>T (p.Ala28=)	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
38944	NM_001363.5(DKC1):c.-142C>G	DKC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
590231	NM_001363.5(DKC1):c.1456G>A (p.Gly486Arg)	DKC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1047250	NM_001363.5(DKC1):c.484G>A (p.Ala162Thr)	DKC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2628809	NM_001363.5(DKC1):c.199A>G (p.Thr67Ala)	DKC1	Uncertain significance	criteria provided, single submitter
2630979	NM_001363.5(DKC1):c.1141G>A (p.Gly381Ser)	DKC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2632874	NM_001363.5(DKC1):c.329G>A (p.Arg110Gln)	DKC1	Uncertain significance	criteria provided, single submitter
952260	NM_001363.5(DKC1):c.1036+6_1036+7del	DKC1	Uncertain significance	criteria provided, single submitter
967191	NM_001363.5(DKC1):c.1210C>G (p.Pro404Ala)	DKC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1084743	NM_001363.5(DKC1):c.267A>C (p.Thr89=)	DKC1	Likely benign	criteria provided, single submitter
1097268	NM_001363.5(DKC1):c.262A>C (p.Arg88=)	DKC1	Likely benign	criteria provided, single submitter
1169272	NM_001363.5(DKC1):c.915+8C>T	DKC1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
3036414	NM_001363.5(DKC1):c.641-18TG[4]	DKC1	Likely benign	no assertion criteria provided
3054252	NM_001363.5(DKC1):c.16+7G>A	DKC1	Likely benign	no assertion criteria provided
38952	NM_001363.5(DKC1):c.838A>C (p.Ser280Arg)	DKC1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
412223	NM_001363.5(DKC1):c.1494GAA[9] (p.Lys504_Lys505dup)	DKC1	Likely benign	criteria provided, single submitter
529200	NM_001363.5(DKC1):c.84+10A>T	DKC1	Likely benign	criteria provided, single submitter
696852	NM_001363.5(DKC1):c.1431G>A (p.Lys477=)	DKC1	Benign	criteria provided, multiple submitters, no conflicts
697360	NM_001363.5(DKC1):c.1293G>A (p.Val431=)	DKC1	Likely benign	criteria provided, multiple submitters, no conflicts
698478	NM_001363.5(DKC1):c.85-4G>A	DKC1	Likely benign	criteria provided, single submitter
701791	NM_001363.5(DKC1):c.1155+8G>A	DKC1	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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	Strong	X-linked	DKC1-related disorder	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DKC1	Orphanet:1775	Dyskeratosis congenita
DKC1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DKC1	HGNC:2890	ENSG00000130826	O60832	H/ACA ribonucleoprotein complex subunit DKC1	gencc,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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DKC1	Other/Unknown	no		PUA, PsdUridine_synth_N, Uncharacterised_CHP00451

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingival epithelium	1
secondary oocyte	1
sural nerve	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DKC1	4,882

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DKC1	O60832	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 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 1 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	1	456.8×	0.004	DKC1
rRNA modification in the nucleus and cytosol	1	187.2×	0.005	DKC1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
box H/ACA sno(s)RNA 3’-end processing	1	8426.0×	5e-04	DKC1
protein localization to Cajal body	1	8426.0×	5e-04	DKC1
snRNA pseudouridine synthesis	1	5617.3×	5e-04	DKC1
enzyme-directed rRNA pseudouridine synthesis	1	4213.0×	5e-04	DKC1
rRNA pseudouridine synthesis	1	4213.0×	5e-04	DKC1
telomerase RNA stabilization	1	4213.0×	5e-04	DKC1
regulation of telomerase RNA localization to Cajal body	1	4213.0×	5e-04	DKC1
scaRNA localization to Cajal body	1	3370.4×	6e-04	DKC1
telomerase holoenzyme complex assembly	1	2808.7×	6e-04	DKC1
positive regulation of telomerase RNA localization to Cajal body	1	1872.4×	8e-04	DKC1
mRNA pseudouridine synthesis	1	1685.2×	8e-04	DKC1
telomere maintenance via telomerase	1	732.7×	0.002	DKC1
positive regulation of telomere maintenance via telomerase	1	732.7×	0.002	DKC1
RNA processing	1	218.9×	0.005	DKC1
rRNA processing	1	141.6×	0.007	DKC1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

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: 1; 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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.