Dyskeratosis congenita, autosomal recessive 1

Summary

Dyskeratosis congenita, autosomal recessive 1 (MONDO:0009136) is a disease caused by NOP10 (GenCC Strong), with 6 cohort genes. The dominant Reactome pathway is Telomere Extension By Telomerase (4 cohort genes).

At a glance

• Causal gene: NOP10 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 79

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dyskeratosis congenita, autosomal recessive 1
Mondo ID	MONDO:0009136
MeSH	C565611
OMIM	224230
DOID	DOID:0070015
NCIT	C176925
SNOMED CT	707272006
UMLS	C1857144
MedGen	341705
GARD	0006300
Is cancer (heuristic)	no

Also known as: autosomal recessive dyskeratosis congenita · DKCB · DKCB1 · dyskeratosis congenita autosomal recessive · dyskeratosis congenita, autosomal recessive 1 · dyskeratosis congenita, autosomal recessive type 1

Data availability: 79 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › dyskeratosis congenita › dyskeratosis congenita, autosomal recessive 1

Related subtypes (15): dyskeratosis congenita, autosomal dominant 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, DKC1-related disorder, dyskeratosis congenita, autosomal dominant 4, dyskeratosis congenita, autosomal recessive 7, dyskeratosis congenita and related telomere biology disorder, dyskeratosis congenita, autosomal recessive 8

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

79 retrieved; paginated sample, class counts are floors:

43 uncertain significance, 15 likely benign, 7 benign/likely benign, 6 conflicting classifications of pathogenicity, 4 benign, 3 pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
4280	NM_017838.4(NHP2):c.415T>C (p.Tyr139His)	NHP2	Pathogenic	no assertion criteria provided
4281	NM_017838.4(NHP2):c.376G>A (p.Val126Met)	NHP2	Pathogenic	no assertion criteria provided
4282	NM_017838.4(NHP2):c.460T>A (p.Ter154Arg)	NHP2	Pathogenic	criteria provided, single submitter
235529	NM_018648.4(NOP10):c.34G>C (p.Asp12His)	NOP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315637	NM_018648.4(NOP10):c.55-9C>T	NOP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315638	NM_018648.4(NOP10):c.51G>C (p.Leu17=)	NOP10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
858747	NM_001283009.2(RTEL1):c.1266+3_1266+80del	RTEL1-TNFRSF6B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
29900	NM_198253.3(TERT):c.2431C>T (p.Arg811Cys)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
29901	NM_198253.3(TERT):c.2701C>T (p.Arg901Trp)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
315640	NM_018648.4(NOP10):c.-38C>T	LOC130056750	Uncertain significance	criteria provided, single submitter
315642	NM_018648.4(NOP10):c.-57C>T	LOC130056750	Uncertain significance	criteria provided, single submitter
3577075	NM_018648.4(NOP10):c.-10A>G	LOC130056750	Uncertain significance	criteria provided, single submitter
885736	NM_018648.3(NOP10):c.-88A>G	LOC130056750	Uncertain significance	criteria provided, single submitter
1000345	NC_000015.9:g.(?34634149)(34635294_?)del	NOP10	Uncertain significance	criteria provided, single submitter
1018359	NM_018648.4(NOP10):c.89C>A (p.Ala30Asp)	NOP10	Uncertain significance	criteria provided, single submitter
1036993	NM_018648.4(NOP10):c.141dup (p.Ile48fs)	NOP10	Uncertain significance	criteria provided, single submitter
1047758	NM_018648.4(NOP10):c.127C>G (p.Arg43Gly)	NOP10	Uncertain significance	criteria provided, single submitter
1054213	NM_018648.4(NOP10):c.31G>A (p.Gly11Arg)	NOP10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1054241	NM_018648.4(NOP10):c.156C>G (p.Phe52Leu)	NOP10	Uncertain significance	criteria provided, single submitter
1059000	NM_018648.4(NOP10):c.92A>G (p.His31Arg)	NOP10	Uncertain significance	criteria provided, single submitter
1428113	NM_018648.4(NOP10):c.75A>T (p.Gln25His)	NOP10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1441454	NM_018648.4(NOP10):c.154T>C (p.Phe52Leu)	NOP10	Uncertain significance	criteria provided, single submitter
1449170	NC_000015.9:g.(?34634169)(34635274_?)dup	NOP10	Uncertain significance	criteria provided, single submitter
1519452	NM_018648.4(NOP10):c.36T>G (p.Asp12Glu)	NOP10	Uncertain significance	criteria provided, single submitter
1947972	NM_018648.4(NOP10):c.181C>T (p.Arg61Cys)	NOP10	Uncertain significance	criteria provided, single submitter
1965628	NM_018648.4(NOP10):c.128G>A (p.Arg43Gln)	NOP10	Uncertain significance	criteria provided, single submitter
1967479	NM_018648.4(NOP10):c.95C>G (p.Pro32Arg)	NOP10	Uncertain significance	criteria provided, single submitter
1968335	NM_018648.4(NOP10):c.91C>T (p.His31Tyr)	NOP10	Uncertain significance	criteria provided, single submitter
2049282	NM_018648.4(NOP10):c.76_77del (p.Gln26fs)	NOP10	Uncertain significance	criteria provided, single submitter
2150118	NM_018648.4(NOP10):c.185C>T (p.Pro62Leu)	NOP10	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 14 · 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
NOP10	Strong	Autosomal recessive	dyskeratosis congenita, autosomal recessive 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NOP10	Orphanet:1775	Dyskeratosis congenita
TERT	Orphanet:146	Differentiated thyroid carcinoma
TERT	Orphanet:1501	Adrenocortical carcinoma
TERT	Orphanet:1775	Dyskeratosis congenita
TERT	Orphanet:2032	Idiopathic pulmonary fibrosis
TERT	Orphanet:2495	Meningioma
TERT	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TERT	Orphanet:457246	Clear cell sarcoma of kidney
TERT	Orphanet:618	Familial melanoma
TERT	Orphanet:88	Idiopathic aplastic anemia
NHP2	Orphanet:1775	Dyskeratosis congenita
RTEL1	Orphanet:1775	Dyskeratosis congenita
RTEL1	Orphanet:2032	Idiopathic pulmonary fibrosis
RTEL1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NOP10	HGNC:14378	ENSG00000182117	Q9NPE3	H/ACA ribonucleoprotein complex subunit 3	gencc,clinvar
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	clinvar
NHP2	HGNC:14377	ENSG00000145912	Q9NX24	H/ACA ribonucleoprotein complex subunit 2	clinvar
RTEL1	HGNC:15888	ENSG00000258366	Q9NZ71	Regulator of telomere elongation helicase 1	clinvar
RMND5B	HGNC:26181	ENSG00000145916	Q96G75	E3 ubiquitin-protein transferase RMND5B	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)
NOP10	H/ACA ribonucleoprotein complex subunit 3	Required for ribosome biogenesis and telomere maintenance.
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
NHP2	H/ACA ribonucleoprotein complex subunit 2	Required for ribosome biogenesis and telomere maintenance.
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.
RMND5B	E3 ubiquitin-protein transferase RMND5B	Core component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 5 · 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	5	1.5×	0.348
Transcription factor	1	1.4×	0.539

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NOP10	Other/Unknown	no		H/ACA_rnp_Nop10, H/ACA_rnp_Nop10_sf
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
NHP2	Other/Unknown	no		H/ACA_rnp_Nhp2-like, Ribosomal_eL8/eL30/eS12/Gad45, Ribosomal_eL8/Nhp2
RTEL1	Other/Unknown	no		Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
RMND5B	Transcription factor	no		LisH, CTLH_C, CRA_dom
RTEL1-TNFRSF6B	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

4 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	2
right hemisphere of cerebellum	2
leukocyte	1
monocyte	1
rectum	1
olfactory bulb	1
stromal cell of endometrium	1
type B pancreatic cell	1
epithelium of esophagus	1
esophagus mucosa	1
esophagus squamous epithelium	1
sural nerve	1
left testis	1
lower esophagus mucosa	1
right testis	1
cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NOP10	286	ubiquitous	marker	monocyte, rectum, leukocyte
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
NHP2	292	ubiquitous	marker	esophagus squamous epithelium, esophagus mucosa, epithelium of esophagus
RTEL1	134	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
RMND5B	273	ubiquitous	marker	lower esophagus mucosa, left testis, right testis
RTEL1-TNFRSF6B	135		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellum

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TERT	5,717
NHP2	4,751
NOP10	2,488
RTEL1	2,324
RMND5B	655
RTEL1-TNFRSF6B	0

Intra-cohort edges

A	B	Sources
NHP2	NOP10	biogrid_interaction, intact, string_interaction
NHP2	RTEL1	string_interaction
NHP2	TERT	string_interaction
NOP10	RTEL1	string_interaction
NOP10	TERT	string_interaction
RTEL1	TERT	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TERT	O14746	23
NOP10	Q9NPE3	7
NHP2	Q9NX24	7
RTEL1	Q9NZ71	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RMND5B	Q96G75	90.58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 6 evidence-associated genes (5 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 5 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	4	365.4×	2e-09	NOP10, TERT, NHP2, RTEL1
Extension of Telomeres	2	240.4×	3e-04	TERT, RTEL1
Telomere Maintenance	2	147.3×	6e-04	TERT, RTEL1
Chromosome Maintenance	2	84.6×	0.001	TERT, RTEL1
rRNA modification in the nucleus and cytosol	2	74.9×	0.001	NOP10, NHP2
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	326.3×	0.013	TERT
Cytosolic iron-sulfur cluster assembly	1	152.3×	0.023	RTEL1
Resolution of D-Loop Structures	1	126.9×	0.023	RTEL1
Regulation of pyruvate metabolism	1	114.2×	0.023	RMND5B
Cell Cycle	2	14.4×	0.023	TERT, RTEL1
Pyruvate metabolism	1	81.6×	0.027	RMND5B
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	78.8×	0.027	RTEL1
Homology Directed Repair	1	61.7×	0.030	RTEL1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	61.7×	0.030	RTEL1
DNA Double-Strand Break Repair	1	49.6×	0.035	RTEL1
HDR through Homologous Recombination (HRR)	1	38.1×	0.042	RTEL1
MITF-M-dependent gene expression	1	36.2×	0.042	TERT
Formation of the beta-catenin:TCF transactivating complex	1	24.0×	0.054	TERT
TCF dependent signaling in response to WNT	1	23.6×	0.054	TERT
MITF-M-regulated melanocyte development	1	22.8×	0.054	TERT
Signaling by WNT	1	22.4×	0.054	TERT
DNA Repair	1	19.7×	0.059	RTEL1
Aerobic respiration and respiratory electron transport	1	17.7×	0.062	RMND5B
Metabolism	2	4.7×	0.067	RTEL1, RMND5B
Developmental Biology	1	2.9×	0.313	TERT
Signal Transduction	1	2.0×	0.404	TERT

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
telomere maintenance via telomerase	3	439.6×	1e-06	NOP10, TERT, NHP2
snRNA pseudouridine synthesis	2	2246.9×	5e-06	NOP10, NHP2
rRNA pseudouridine synthesis	2	1685.2×	7e-06	NOP10, NHP2
telomerase RNA localization to Cajal body	2	963.0×	2e-05	NOP10, NHP2
DNA strand displacement	1	3370.4×	0.001	RTEL1
RNA-templated transcription	1	3370.4×	0.001	TERT
DNA strand elongation	1	3370.4×	0.001	TERT
siRNA transcription	1	3370.4×	0.001	TERT
positive regulation of transdifferentiation	1	3370.4×	0.001	TERT
negative regulation of telomere maintenance in response to DNA damage	1	3370.4×	0.001	RTEL1
positive regulation of telomeric loop disassembly	1	3370.4×	0.001	RTEL1
telomere maintenance	2	107.0×	0.001	TERT, RTEL1
RNA-templated DNA biosynthetic process	1	1685.2×	0.002	TERT
positive regulation of hair cycle	1	1685.2×	0.002	TERT
telomeric loop disassembly	1	1685.2×	0.002	RTEL1
snoRNA guided rRNA pseudouridine synthesis	1	1123.5×	0.002	NHP2
pseudouridine synthesis	1	1123.5×	0.002	NOP10
mitotic telomere maintenance via semi-conservative replication	1	1123.5×	0.002	RTEL1
negative regulation of t-circle formation	1	1123.5×	0.002	RTEL1
positive regulation of telomere capping	1	674.1×	0.004	RTEL1
positive regulation of telomere maintenance via telomere lengthening	1	561.7×	0.004	RTEL1
positive regulation of protein localization to nucleolus	1	561.7×	0.004	TERT
establishment of protein localization to telomere	1	421.3×	0.005	TERT
siRNA processing	1	374.5×	0.006	TERT
telomere maintenance in response to DNA damage	1	374.5×	0.006	RTEL1
telomere maintenance via recombination	1	306.4×	0.007	TERT
negative regulation of DNA recombination	1	224.7×	0.009	RTEL1
regulation of double-strand break repair via homologous recombination	1	198.3×	0.009	RTEL1
replicative senescence	1	198.3×	0.009	TERT
positive regulation of vascular associated smooth muscle cell migration	1	198.3×	0.009	TERT

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 6 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TERT	BERBERINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TERT	10	4
NHP2	1	2
NOP10	0	0
RTEL1	0	0
RMND5B	0	0
RTEL1-TNFRSF6B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
RESVERATROL	3	TERT
EPIGALOCATECHIN GALLATE	3	TERT
PERIFOSINE	3	TERT
ISOMETAMIDIUM	2	TERT
HOMIDIUM BROMIDE	2	TERT
ALLICIN	2	TERT
OLEIC ACID	2	TERT
ETHACRIDINE	2	TERT
MOLIBRESIB	2	NHP2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TERT	391	Binding:389, Functional:2
NHP2	7	Binding:7
NOP10	1	Binding:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TERT	391

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

11 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)
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
RESVERATROL	3	TERT
EPIGALOCATECHIN GALLATE	3	TERT
PERIFOSINE	3	TERT
ISOMETAMIDIUM	2	TERT
HOMIDIUM BROMIDE	2	TERT
ALLICIN	2	TERT
OLEIC ACID	2	TERT
ETHACRIDINE	2	TERT
MOLIBRESIB	2	NHP2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TERT
B	Phased (≥1) drug, not yet approved	1	NHP2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	NOP10, RTEL1, RMND5B, RTEL1-TNFRSF6B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NOP10	1	NHP2, TERT
RTEL1	0	—
RMND5B	0	—
RTEL1-TNFRSF6B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.