Immunodeficiency-centromeric instability-facial anomalies syndrome

Summary

Immunodeficiency-centromeric instability-facial anomalies syndrome (MONDO:0000133) is a disease with 5 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 5
• ClinVar variants: 816
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		66	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0002721	Immunodeficiency	Very frequent (80-99%)
HP:0003220	Abnormality of chromosome stability	Very frequent (80-99%)
HP:0004313	Decreased circulating antibody level	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001334	Communicating hydrocephalus	Frequent (30-79%)
HP:0001874	Abnormality of neutrophils	Frequent (30-79%)
HP:0001888	Lymphopenia	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0002024	Malabsorption	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0005374	Cellular immunodeficiency	Frequent (30-79%)
HP:0000158	Macroglossia	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0001537	Umbilical hernia	Occasional (5-29%)
HP:0010808	Protruding tongue	Occasional (5-29%)
HP:0012368	Flat face	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency-centromeric instability-facial anomalies syndrome
Mondo ID	MONDO:0000133
MeSH	C537362
OMIM	242860
Orphanet	2268
DOID	DOID:0090007
SNOMED CT	234633000
UMLS	C0398788
MedGen	140770
GARD	0002945
Is cancer (heuristic)	no

Also known as: CIID · immunodeficiency-centromeric instability-facial anomalies · immunodeficiency-centromeric instability-facial anomalies syndrome

Data availability: 816 ClinVar variants · 5 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › immunodeficiency-centromeric instability-facial anomalies syndrome

Related subtypes (218): 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 2, 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

Subtypes (4): immunodeficiency-centromeric instability-facial anomalies syndrome 1, immunodeficiency-centromeric instability-facial anomalies syndrome 2, immunodeficiency-centromeric instability-facial anomalies syndrome 3, immunodeficiency-centromeric instability-facial anomalies syndrome 4

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

600 retrieved; paginated sample, class counts are floors:

400 likely benign, 135 uncertain significance, 21 conflicting classifications of pathogenicity, 19 benign, 12 pathogenic, 8 likely pathogenic, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069118	NM_006892.4(DNMT3B):c.691G>T (p.Gly231Ter)	DNMT3B	Pathogenic	criteria provided, single submitter
1070976	NM_006892.4(DNMT3B):c.996del (p.Met332fs)	DNMT3B	Pathogenic	criteria provided, single submitter
1453417	NM_006892.4(DNMT3B):c.2246C>A (p.Ser749Ter)	DNMT3B	Pathogenic	criteria provided, single submitter
2138340	NM_006892.4(DNMT3B):c.1817T>C (p.Val606Ala)	DNMT3B	Pathogenic	criteria provided, single submitter
2736958	NM_006892.4(DNMT3B):c.160C>T (p.Arg54Ter)	DNMT3B	Pathogenic	criteria provided, single submitter
2737775	NM_006892.4(DNMT3B):c.1466_1488del (p.Leu489fs)	DNMT3B	Pathogenic	criteria provided, single submitter
2760966	NM_006892.4(DNMT3B):c.2197C>T (p.Arg733Ter)	DNMT3B	Pathogenic	criteria provided, single submitter
2828402	NM_006892.4(DNMT3B):c.2044_2047del (p.Ser682fs)	DNMT3B	Pathogenic	criteria provided, single submitter
2874786	NM_006892.4(DNMT3B):c.1453C>T (p.Arg485Ter)	DNMT3B	Pathogenic	criteria provided, single submitter
2967369	NM_006892.4(DNMT3B):c.754C>T (p.Arg252Ter)	DNMT3B	Pathogenic	criteria provided, single submitter
3248262	NC_000020.10:g.(?31368130)(31592146_?)del	DNMT3B	Pathogenic	criteria provided, single submitter
2840497	NM_006892.4(DNMT3B):c.1711C>T (p.Arg571Ter)	LOC126863014	Pathogenic	criteria provided, single submitter
1705256	NM_006892.4(DNMT3B):c.2441A>G (p.His814Arg)	DNMT3B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2708351	NM_006892.4(DNMT3B):c.654+1G>C	DNMT3B	Likely pathogenic	criteria provided, single submitter
2736959	NM_006892.4(DNMT3B):c.2296G>C (p.Ala766Pro)	DNMT3B	Likely pathogenic	criteria provided, single submitter
2741913	NM_006892.4(DNMT3B):c.2009G>A (p.Arg670Gln)	DNMT3B	Likely pathogenic	criteria provided, single submitter
2765379	NM_006892.4(DNMT3B):c.1996+2T>A	DNMT3B	Likely pathogenic	criteria provided, single submitter
2841543	NM_006892.4(DNMT3B):c.2146-1G>C	DNMT3B	Likely pathogenic	criteria provided, single submitter
2996502	NM_006892.4(DNMT3B):c.433-2A>G	DNMT3B	Likely pathogenic	criteria provided, single submitter
3248263	NC_000020.10:g.(?31380412)(31383520_?)dup	DNMT3B	Likely pathogenic	criteria provided, single submitter
1001135	NM_006892.4(DNMT3B):c.379C>T (p.Arg127Trp)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1017462	NM_006892.4(DNMT3B):c.43G>A (p.Gly15Ser)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1026466	NM_006892.4(DNMT3B):c.2477G>A (p.Arg826His)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1423002	NM_006892.4(DNMT3B):c.1091G>A (p.Arg364His)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1424153	NM_006892.4(DNMT3B):c.1309T>C (p.Ser437Pro)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2081505	NM_006892.4(DNMT3B):c.593G>A (p.Gly198Glu)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2197303	NM_006892.4(DNMT3B):c.1754C>T (p.Ala585Val)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338151	NM_006892.4(DNMT3B):c.115G>C (p.Glu39Gln)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338152	NM_006892.4(DNMT3B):c.143-9C>G	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338153	NM_006892.4(DNMT3B):c.143-8C>T	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 6 · 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
DNMT3B	Definitive	Autosomal recessive	immunodeficiency-centromeric instability-facial anomalies syndrome 1	6
ZBTB24	Definitive	Autosomal recessive	immunodeficiency-centromeric instability-facial anomalies syndrome 2	4
CDCA7	Strong	Autosomal recessive	immunodeficiency-centromeric instability-facial anomalies syndrome 3	2
HELLS	Strong	Autosomal recessive	immunodeficiency-centromeric instability-facial anomalies syndrome 4	3
UHRF1	Limited	Autosomal recessive	immunodeficiency-centromeric instability-facial anomalies syndrome	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNMT3B	Orphanet:2268	ICF syndrome
DNMT3B	Orphanet:269	Facioscapulohumeral dystrophy
UHRF1	Orphanet:2268	ICF syndrome
CDCA7	Orphanet:2268	ICF syndrome
ZBTB24	Orphanet:2268	ICF syndrome
HELLS	Orphanet:2268	ICF syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DNMT3B	HGNC:2979	ENSG00000088305	Q9UBC3	DNA (cytosine-5)-methyltransferase 3B	gencc,clinvar
UHRF1	HGNC:12556	ENSG00000276043	Q96T88	E3 ubiquitin-protein ligase UHRF1	gencc
CDCA7	HGNC:14628	ENSG00000144354	Q9BWT1	Cell division cycle-associated protein 7	gencc
ZBTB24	HGNC:21143	ENSG00000112365	O43167	Zinc finger and BTB domain-containing protein 24	gencc
HELLS	HGNC:4861	ENSG00000119969	Q9NRZ9	Lymphoid-specific helicase	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNMT3B	DNA (cytosine-5)-methyltransferase 3B	Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development.
UHRF1	E3 ubiquitin-protein ligase UHRF1	E3 ubiquitin-protein ligase that acts as a key epigenetic regulator by bridging DNA methylation and chromatin modification.
CDCA7	Cell division cycle-associated protein 7	Participates in MYC-mediated cell transformation and apoptosis; induces anchorage-independent growth and clonogenicity in lymphoblastoid cells.
ZBTB24	Zinc finger and BTB domain-containing protein 24	May be involved in BMP2-induced transcription.
HELLS	Lymphoid-specific helicase	ATP-dependent chromatin remodeler that regulates chromatin accessibility, DNA methylation, and histone modifications.

Protein-family classification

Druggable: 0 · Difficult: 4 · 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	4	6.6×	0.002
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNMT3B	Transcription factor	no	2.1.1.37	PWWP_dom, C5_MeTfrase, Znf_FYVE_PHD
UHRF1	Transcription factor	no		Ubiquitin-like_dom, Znf_RING, Znf_PHD
CDCA7	Transcription factor	no		Znf-4CXXC_R1, CDCA7/CDA7L
ZBTB24	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type
HELLS	Other/Unknown	no		SNF2_N, Helicase_C-like, Helicase_ATP-bd

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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	2
secondary oocyte	2
ventricular zone	2
hair follicle	1
thymus	1
embryo	1
ileal mucosa	1
Brodmann (1909) area 23	1
endothelial cell	1
tendon of biceps brachii	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNMT3B	184	ubiquitous	marker	secondary oocyte, oocyte, hair follicle
UHRF1	198	ubiquitous	marker	oocyte, secondary oocyte, thymus
CDCA7	215	ubiquitous	marker	ileal mucosa, ventricular zone, embryo
ZBTB24	256	ubiquitous	yes	endothelial cell, Brodmann (1909) area 23, tendon of biceps brachii
HELLS	221	ubiquitous	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 7.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNMT3B	4,378
HELLS	4,165
UHRF1	3,009
CDCA7	1,875
ZBTB24	1,685

Intra-cohort edges

A	B	Sources
CDCA7	HELLS	string_interaction
CDCA7	ZBTB24	string_interaction
DNMT3B	HELLS	string_interaction
DNMT3B	UHRF1	intact, string_interaction
DNMT3B	ZBTB24	string_interaction
HELLS	UHRF1	string_interaction
HELLS	ZBTB24	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNMT3B	Q9UBC3	47
UHRF1	Q96T88	45
HELLS	Q9NRZ9	4
CDCA7	Q9BWT1	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZBTB24	O43167	56.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
DNA methylation	2	119.0×	6e-04	DNMT3B, UHRF1
SUMOylation of DNA methylation proteins	1	223.9×	0.015	DNMT3B
TGFBR3 expression	1	152.3×	0.015	HELLS
Chromatin modifications during the maternal to zygotic transition (MZT)	1	54.4×	0.023	UHRF1
Defective pyroptosis	1	52.1×	0.023	DNMT3B
PRC2 methylates histones and DNA	1	50.8×	0.023	DNMT3B
NoRC negatively regulates rRNA expression	1	34.9×	0.028	DNMT3B

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
chromosomal DNA methylation maintenance following DNA replication	2	1685.2×	1e-05	UHRF1, HELLS
negative regulation of gene expression via chromosomal CpG island methylation	2	421.3×	1e-04	UHRF1, HELLS
double-strand break repair via homologous recombination	2	62.4×	0.004	UHRF1, HELLS
pericentric heterochromatin formation	1	674.1×	0.012	HELLS
lymphocyte proliferation	1	481.5×	0.013	HELLS
homologous recombination	1	280.9×	0.019	UHRF1
urogenital system development	1	198.3×	0.019	HELLS
positive regulation of protein metabolic process	1	198.3×	0.019	UHRF1
regulation of epithelial cell proliferation	1	187.2×	0.019	UHRF1
negative regulation of intrinsic apoptotic signaling pathway	1	153.2×	0.021	HELLS
protein localization to chromatin	1	116.2×	0.024	UHRF1
DNA methylation-dependent constitutive heterochromatin formation	1	108.7×	0.024	HELLS
apoptotic process	2	11.5×	0.028	CDCA7, HELLS
epigenetic regulation of gene expression	1	76.6×	0.030	UHRF1
mitotic spindle assembly	1	68.8×	0.031	UHRF1
heterochromatin formation	1	51.1×	0.038	UHRF1
hematopoietic progenitor cell differentiation	1	47.5×	0.038	ZBTB24
protein autoubiquitination	1	46.8×	0.038	UHRF1
double-strand break repair	1	40.6×	0.041	HELLS
methylation	1	34.0×	0.044	DNMT3B
negative regulation of transcription by RNA polymerase II	2	7.1×	0.044	DNMT3B, UHRF1
cellular response to leukemia inhibitory factor	1	31.8×	0.045	HELLS
kidney development	1	28.1×	0.049	HELLS
regulation of cell population proliferation	1	23.1×	0.057	CDCA7
ubiquitin-dependent protein catabolic process	1	14.8×	0.084	UHRF1
DNA damage response	1	10.7×	0.111	UHRF1
cell division	1	9.2×	0.123	HELLS
protein ubiquitination	1	8.3×	0.132	UHRF1
positive regulation of gene expression	1	7.8×	0.135	DNMT3B
regulation of DNA-templated transcription	1	6.3×	0.159	CDCA7

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 5 evidence-associated genes (80%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DNMT3B	1	2
UHRF1	0	0
CDCA7	0	0
ZBTB24	0	0
HELLS	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NANAFROCIN	2	DNMT3B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DNMT3B	76	Binding:75, Functional:1
UHRF1	36	Binding:36
HELLS	6	Binding:6
ZBTB24	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DNMT3B	2.1.1.37	DNA (cytosine-5-)-methyltransferase

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

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)
NANAFROCIN	2	DNMT3B

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	DNMT3B
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	UHRF1, CDCA7, ZBTB24, HELLS

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)
UHRF1	36	DNMT3B
ZBTB24	3	DNMT3B
HELLS	6	DNMT3B
CDCA7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.