Wieacker-Wolff syndrome

Summary

Wieacker-Wolff syndrome (MONDO:0010758) is a disease caused by ZC4H2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ZC4H2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 44
• Phenotypes (HPO): 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000496	Abnormality of eye movement	Very frequent (80-99%)
HP:0000657	Oculomotor apraxia	Very frequent (80-99%)
HP:0001256	Intellectual disability, mild	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001376	Limitation of joint mobility	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0003693	Distal amyotrophy	Very frequent (80-99%)
HP:0004209	Clinodactyly of the 5th finger	Very frequent (80-99%)
HP:0005745	Congenital foot contractures	Very frequent (80-99%)
HP:0100022	Abnormality of movement	Very frequent (80-99%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Wieacker-Wolff syndrome
Mondo ID	MONDO:0010758
MeSH	C536703, C537472
OMIM	314580
Orphanet	3454, 85283
DOID	DOID:0060815
SNOMED CT	719012009, 722456001
UMLS	C0796200
MedGen	163227
GARD	0007890
NORD	91159
Is cancer (heuristic)	no

Also known as: apraxia, oculomotor, with congenital contractures and muscle atrophy · contractures of feet, muscle atrophy, and oculomotor apraxia · foot contractures-muscle atrophy-oculomotor apraxia syndrome · intellectual disability-developmental delay-contractures syndrome · MCS · mental retardation, X-linked, syndromic 4 · mental retardation, X-linked, with congenital contractures and Low fingertip arches · mental retardation, X-linked, with congenital contractures and low fingertip arches · Miles-Carpenter syndrome · Miles-CARPENTER X-linked mental retardation syndrome · MRXS4 · Wieacker syndrome · Wieacker Wolff syndrome · Wieacker-Wolff syndrome · Wieacker-Wolff syndrome, X-linked · Wieacker-Wolff syndrome, X-linked recessive · WRWF · WRWFXLR · X-linked intellectual disability, Miles-Carpenter type · ZC4H2-Associated Rare Disorders (ZARD)

Data availability: 44 ClinVar variants · 4 GenCC gene-disease records · 5 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › Wieacker-Wolff syndrome

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

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

44 retrieved; paginated sample, class counts are floors:

13 likely pathogenic, 13 pathogenic, 10 uncertain significance, 6 pathogenic/likely pathogenic, 1 not provided, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
378042	NM_018684.4(ZC4H2):c.197T>A (p.Leu66His)	ZC4H2	Pathogenic	no assertion criteria provided
378044	NM_018684.4(ZC4H2):c.225+5G>A	ZC4H2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
378045	NM_018684.4(ZC4H2):c.53G>A (p.Arg18Lys)	ZC4H2	Pathogenic	no assertion criteria provided
3781335	NM_018684.4(ZC4H2):c.196C>T (p.Leu66Phe)	ZC4H2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3899329	NM_018684.4(ZC4H2):c.442G>T (p.Glu148Ter)	ZC4H2	Pathogenic	criteria provided, single submitter
4056437	NM_018684.4(ZC4H2):c.225+1G>T	ZC4H2	Pathogenic	criteria provided, single submitter
429826	NM_018684.4(ZC4H2):c.199C>T (p.Arg67Ter)	ZC4H2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
432364	NM_018684.4(ZC4H2):c.592C>T (p.Arg198Trp)	ZC4H2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488641	NM_018684.4(ZC4H2):c.22_23del (p.Met8fs)	ZC4H2	Pathogenic	criteria provided, multiple submitters, no conflicts
50980	NM_018684.4(ZC4H2):c.187G>C (p.Val63Leu)	ZC4H2	Pathogenic	no assertion criteria provided
50981	NM_018684.4(ZC4H2):c.593G>A (p.Arg198Gln)	ZC4H2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
50983	NM_018684.4(ZC4H2):c.637C>T (p.Arg213Trp)	ZC4H2	Pathogenic	criteria provided, multiple submitters, no conflicts
548020	NM_018684.4(ZC4H2):c.427C>T (p.Gln143Ter)	ZC4H2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
598761	Single allele	ZC4H2	Pathogenic	criteria provided, single submitter
689619	NM_018684.4(ZC4H2):c.412C>T (p.Gln138Ter)	ZC4H2	Pathogenic	criteria provided, multiple submitters, no conflicts
834097	NM_018684.4(ZC4H2):c.650A>G (p.Lys217Arg)	ZC4H2	Pathogenic	no assertion criteria provided
930303	NM_018684.4(ZC4H2):c.576del (p.His193fs)	ZC4H2	Pathogenic	criteria provided, single submitter
930963	NM_018684.4(ZC4H2):c.598G>A (p.Ala200Thr)	ZC4H2	Pathogenic	criteria provided, single submitter
977161	NM_018684.4(ZC4H2):c.243_246del (p.Lys81fs)	ZC4H2	Pathogenic	criteria provided, multiple submitters, no conflicts
3897699	NM_002890.3(RASA1):c.829-2A>G	CCNH	Likely pathogenic	criteria provided, single submitter
1334010	NM_018684.4(ZC4H2):c.174_178del (p.Glu58fs)	ZC4H2	Likely pathogenic	criteria provided, single submitter
3340477	NM_018684.4(ZC4H2):c.208C>T (p.His70Tyr)	ZC4H2	Likely pathogenic	criteria provided, single submitter
3773845	NM_018684.4(ZC4H2):c.226-1G>C	ZC4H2	Likely pathogenic	criteria provided, single submitter
3899336	NM_018684.4(ZC4H2):c.561+2T>C	ZC4H2	Likely pathogenic	criteria provided, single submitter
4280635	NM_018684.4(ZC4H2):c.83del (p.Lys28fs)	ZC4H2	Likely pathogenic	criteria provided, single submitter
4292667	NM_018684.4(ZC4H2):c.637del (p.Arg213fs)	ZC4H2	Likely pathogenic	criteria provided, single submitter
451159	NM_018684.4(ZC4H2):c.631C>T (p.Arg211Trp)	ZC4H2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4813347	Single allele	ZC4H2	Likely pathogenic	criteria provided, single submitter
50982	NM_018684.4(ZC4H2):c.601C>T (p.Pro201Ser)	ZC4H2	Likely pathogenic	criteria provided, single submitter
522752	NM_018684.4(ZC4H2):c.375AGA[1] (p.Glu128del)	ZC4H2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
ZC4H2	Definitive	X-linked	Wieacker-Wolff syndrome, female-restricted	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZC4H2	Orphanet:3454	Wieacker-Wolff syndrome

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
ZC4H2	HGNC:24931	ENSG00000126970	Q9NQZ6	Zinc finger C4H2 domain-containing protein	gencc,clinvar
CCNH	HGNC:1594	ENSG00000134480	P51946	Cyclin-H	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZC4H2	Zinc finger C4H2 domain-containing protein	Plays a role in interneurons differentiation.
CCNH	Cyclin-H	Regulates CDK7, the catalytic subunit of the CDK-activating kinase (CAK) enzymatic complex.

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)
ZC4H2	Transcription factor	no		Znf-C4H2, ZF_C4H2
CCNH	Other/Unknown	no		Cyclin_N, Cyclin-like_dom, CyclinH/Ccl1

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
embryo	1
ganglionic eminence	1
calcaneal tendon	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZC4H2	196	ubiquitous	yes	ganglionic eminence, cortical plate, embryo
CCNH	297	ubiquitous	marker	calcaneal tendon, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCNH	2,116
ZC4H2	954

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CCNH	P51946	47
ZC4H2	Q9NQZ6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 61. Enrichment computed across 2 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
Global Genome Nucleotide Excision Repair (GG-NER)	1	456.8×	0.009	CCNH
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	1	407.9×	0.009	CCNH
RNA Pol II CTD phosphorylation and interaction with CE	1	407.9×	0.009	CCNH
G1 Phase	1	393.8×	0.009	CCNH
mRNA Capping	1	380.7×	0.009	CCNH
Formation of the Early Elongation Complex	1	335.9×	0.009	CCNH
Formation of the HIV-1 Early Elongation Complex	1	335.9×	0.009	CCNH
HIV Transcription Elongation	1	335.9×	0.009	CCNH
RNA Polymerase I Transcription Termination	1	326.3×	0.009	CCNH
Cyclin A/B1/B2 associated events during G2/M transition	1	308.6×	0.009	CCNH
RNA Polymerase I Promoter Clearance	1	292.8×	0.009	CCNH
Nucleotide Excision Repair	1	285.5×	0.009	CCNH
Cyclin E associated events during G1/S transition	1	285.5×	0.009	CCNH
RNA Polymerase I Transcription	1	285.5×	0.009	CCNH
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1	265.6×	0.009	CCNH
Cyclin A:Cdk2-associated events at S phase entry	1	265.6×	0.009	CCNH
Formation of HIV-1 elongation complex containing HIV-1 Tat	1	259.6×	0.009	CCNH
Tat-mediated elongation of the HIV-1 transcript	1	259.6×	0.009	CCNH
Negative epigenetic regulation of rRNA expression	1	259.6×	0.009	CCNH
Formation of Incision Complex in GG-NER	1	253.8×	0.009	CCNH
Formation of HIV elongation complex in the absence of HIV Tat	1	248.3×	0.009	CCNH
HIV Transcription Initiation	1	233.1×	0.009	CCNH
RNA Polymerase II HIV Promoter Escape	1	233.1×	0.009	CCNH
G1/S Transition	1	233.1×	0.009	CCNH
Cyclin D associated events in G1	1	233.1×	0.009	CCNH
RNA Polymerase II Promoter Escape	1	233.1×	0.009	CCNH
RNA Polymerase II Transcription Pre-Initiation And Promoter Opening	1	233.1×	0.009	CCNH
RNA Polymerase II Transcription Initiation	1	233.1×	0.009	CCNH
RNA Polymerase II Transcription Initiation And Promoter Clearance	1	233.1×	0.009	CCNH
RNA Polymerase I Transcription Initiation	1	223.9×	0.009	CCNH

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
regulation of transcription regulatory region DNA binding	1	2106.5×	0.004	ZC4H2
noradrenergic neuron development	1	1685.2×	0.004	ZC4H2
spinal cord motor neuron differentiation	1	468.1×	0.009	ZC4H2
obsolete positive regulation of DNA-binding transcription factor activity	1	300.9×	0.009	ZC4H2
neuromuscular junction development	1	263.3×	0.009	ZC4H2
transcription initiation at RNA polymerase II promoter	1	187.2×	0.010	CCNH
protein monoubiquitination	1	172.0×	0.010	ZC4H2
regulation of G1/S transition of mitotic cell cycle	1	153.2×	0.010	CCNH
positive regulation of neuron differentiation	1	99.1×	0.013	ZC4H2
protein stabilization	1	33.4×	0.036	CCNH
nervous system development	1	23.0×	0.047	ZC4H2
regulation of transcription by RNA polymerase II	1	5.8×	0.164	CCNH

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

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
CCNH	ABEMACICLIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CCNH	28	4
ZC4H2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ABEMACICLIB	4	CCNH
QUIZARTINIB	4	CCNH
ADAGRASIB	4	CCNH
ALVOCIDIB	3	CCNH
DINACICLIB	3	CCNH
LEROCICLIB	3	CCNH
SELICICLIB	2	CCNH
ASNUCICLIB	2	CCNH
CYC-065	2	CCNH
ULECACICLIB	2	CCNH
RONICICLIB	2	CCNH
AT-7519	2	CCNH
INIXACICLIB	2	CCNH
ISTISOCICLIB	2	CCNH
MILCICLIB	2	CCNH
ZOTIRACICLIB	2	CCNH
NARAZACICLIB	2	CCNH
CT-7001	2	CCNH
ZEMIRCICLIB	2	CCNH
PHA-793887	1	CCNH
BMS-387032	1	CCNH
RGB-286638	1	CCNH
BTX-A51	1	CCNH
AZD-5438	1	CCNH
SY-5609	1	CCNH
SU-9516	1	CCNH
PF-03758309	1	CCNH
SEL-120 FREE BASE	1	CCNH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CCNH	348	Binding:346, Functional:2

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CCNH	348

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

28 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)
ABEMACICLIB	4	CCNH
QUIZARTINIB	4	CCNH
ADAGRASIB	4	CCNH
ALVOCIDIB	3	CCNH
DINACICLIB	3	CCNH
LEROCICLIB	3	CCNH
SELICICLIB	2	CCNH
ASNUCICLIB	2	CCNH
CYC-065	2	CCNH
ULECACICLIB	2	CCNH
RONICICLIB	2	CCNH
AT-7519	2	CCNH
INIXACICLIB	2	CCNH
ISTISOCICLIB	2	CCNH
MILCICLIB	2	CCNH
ZOTIRACICLIB	2	CCNH
NARAZACICLIB	2	CCNH
CT-7001	2	CCNH
ZEMIRCICLIB	2	CCNH
PHA-793887	1	CCNH
BMS-387032	1	CCNH
RGB-286638	1	CCNH
BTX-A51	1	CCNH
AZD-5438	1	CCNH
SY-5609	1	CCNH
SU-9516	1	CCNH
PF-03758309	1	CCNH
SEL-120 FREE BASE	1	CCNH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CCNH
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ZC4H2

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)
ZC4H2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.