Dyskeratosis congenita, autosomal recessive 2

Summary

Dyskeratosis congenita, autosomal recessive 2 (MONDO:0013519) is a disease caused by NHP2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: NHP2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 23

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dyskeratosis congenita, autosomal recessive 2
Mondo ID	MONDO:0013519
OMIM	613987
DOID	DOID:0070017
NCIT	C176926
UMLS	C3151441
MedGen	462791
GARD	0015739
Is cancer (heuristic)	no

Also known as: DKCB2 · dyskeratosis congenita, autosomal recessive 2 · dyskeratosis congenita, autosomal recessive type 2

Data availability: 23 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 › autosomal genetic disease › autosomal recessive disease › dyskeratosis congenita, autosomal recessive 2

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

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

23 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 4 benign/likely benign, 3 pathogenic, 2 benign, 1 conflicting classifications of pathogenicity, 1 likely benign

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
353027	NM_017838.4(NHP2):c.160+10A>T	NHP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1484639	NM_017838.4(NHP2):c.434A>T (p.Glu145Val)	NHP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
353025	NM_017838.4(NHP2):c.190G>A (p.Val64Met)	NHP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3592169	NM_017838.4(NHP2):c.445C>G (p.Leu149Val)	NHP2	Uncertain significance	criteria provided, single submitter
3592170	NM_017838.4(NHP2):c.413C>G (p.Ala138Gly)	NHP2	Uncertain significance	criteria provided, single submitter
3592171	NM_017838.4(NHP2):c.301C>G (p.Arg101Gly)	NHP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3592172	NM_017838.4(NHP2):c.199G>A (p.Val67Ile)	NHP2	Uncertain significance	criteria provided, single submitter
643775	NM_017838.4(NHP2):c.289A>G (p.Met97Val)	NHP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
838056	NM_017838.4(NHP2):c.70T>A (p.Tyr24Asn)	NHP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
840508	NM_017838.4(NHP2):c.335C>T (p.Thr112Met)	NHP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
934247	NM_017838.4(NHP2):c.394C>T (p.His132Tyr)	NHP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
965425	NM_017838.4(NHP2):c.289_290del (p.Met97fs)	NHP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
973656	NM_017838.4(NHP2):c.50C>T (p.Ala17Val)	NHP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1165686	NM_017838.4(NHP2):c.336+20del	NHP2	Benign	criteria provided, multiple submitters, no conflicts
1606761	NM_017838.4(NHP2):c.337-14T>C	NHP2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
241213	NM_017838.4(NHP2):c.302G>A (p.Arg101Gln)	NHP2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
260941	NM_017838.4(NHP2):c.160+16G>C	NHP2	Benign	criteria provided, multiple submitters, no conflicts
353024	NM_017838.4(NHP2):c.231-17_231-16del	NHP2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
3766465	NM_017838.4(NHP2):c.337-6C>T	NHP2	Likely benign	criteria provided, single submitter
241214	NM_017838.4(NHP2):c.351C>T (p.Ala117=)	RMND5B	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
NHP2	Strong	Autosomal recessive	dyskeratosis congenita, autosomal recessive 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NHP2	Orphanet:1775	Dyskeratosis congenita

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NHP2	HGNC:14377	ENSG00000145912	Q9NX24	H/ACA ribonucleoprotein complex subunit 2	gencc,clinvar
RMND5B	HGNC:26181	ENSG00000145916	Q96G75	E3 ubiquitin-protein transferase RMND5B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NHP2	H/ACA ribonucleoprotein complex subunit 2	Required for ribosome biogenesis and telomere maintenance.
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: 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NHP2	Other/Unknown	no		H/ACA_rnp_Nhp2-like, Ribosomal_eL8/eL30/eS12/Gad45, Ribosomal_eL8/Nhp2
RMND5B	Transcription factor	no		LisH, CTLH_C, CRA_dom

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelium of esophagus	1
esophagus mucosa	1
esophagus squamous epithelium	1
left testis	1
lower esophagus mucosa	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NHP2	292	ubiquitous	marker	esophagus squamous epithelium, esophagus mucosa, epithelium of esophagus
RMND5B	273	ubiquitous	marker	lower esophagus mucosa, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NHP2	4,751
RMND5B	655

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NHP2	Q9NX24	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RMND5B	Q96G75	90.58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 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
Regulation of pyruvate metabolism	1	285.5×	0.010	RMND5B
Telomere Extension By Telomerase	1	228.4×	0.010	NHP2
Pyruvate metabolism	1	203.9×	0.010	RMND5B
rRNA modification in the nucleus and cytosol	1	93.6×	0.016	NHP2
Aerobic respiration and respiratory electron transport	1	44.3×	0.027	RMND5B
Metabolism	1	5.8×	0.165	RMND5B

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
snoRNA guided rRNA pseudouridine synthesis	1	2808.7×	9e-04	NHP2
snRNA pseudouridine synthesis	1	2808.7×	9e-04	NHP2
rRNA pseudouridine synthesis	1	2106.5×	9e-04	NHP2
telomerase RNA localization to Cajal body	1	1203.7×	0.001	NHP2
telomere maintenance via telomerase	1	366.4×	0.003	NHP2
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.038	RMND5B

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NHP2	1	2
RMND5B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
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
NHP2	7	Binding:7

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	NHP2

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	NHP2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RMND5B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RMND5B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.