X-linked intellectual disability, Cabezas type

Summary

X-linked intellectual disability, Cabezas type (MONDO:0010306) is a disease caused by CUL4B (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CUL4B (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 226
• Phenotypes (HPO): 49

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		24	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

49 HPO clinical features (Orphanet curated; top 49 by frequency):

HPO ID	Term	Frequency
HP:0000023	Inguinal hernia	Very frequent (80-99%)
HP:0000154	Wide mouth	Very frequent (80-99%)
HP:0000322	Short philtrum	Very frequent (80-99%)
HP:0000363	Abnormality of earlobe	Very frequent (80-99%)
HP:0000448	Prominent nose	Very frequent (80-99%)
HP:0000470	Short neck	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0000664	Synophrys	Very frequent (80-99%)
HP:0000752	Hyperactivity	Very frequent (80-99%)
HP:0001344	Absent speech	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0002342	Intellectual disability, moderate	Very frequent (80-99%)
HP:0004209	Clinodactyly of the 5th finger	Very frequent (80-99%)
HP:0004279	Short palm	Very frequent (80-99%)
HP:0008736	Hypoplasia of penis	Very frequent (80-99%)
HP:0010720	Abnormal hair pattern	Very frequent (80-99%)
HP:0010807	Open bite	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0200021	Down-sloping shoulders	Very frequent (80-99%)
HP:0200055	Small hand	Very frequent (80-99%)
HP:0000179	Thick lower lip vermilion	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000581	Blepharophimosis	Frequent (30-79%)
HP:0000718	Aggressive behavior	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0001513	Obesity	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0001773	Short foot	Frequent (30-79%)
HP:0001852	Sandal gap	Frequent (30-79%)
HP:0002136	Broad-based gait	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004326	Cachexia	Frequent (30-79%)
HP:0008734	Decreased testicular size	Frequent (30-79%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0000135	Hypogonadism	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000956	Acanthosis nigricans	Occasional (5-29%)
HP:0000975	Hyperhidrosis	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001770	Toe syndactyly	Occasional (5-29%)
HP:0002353	EEG abnormality	Occasional (5-29%)
HP:0002721	Immunodeficiency	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0002967	Cubitus valgus	Occasional (5-29%)
HP:0004422	Biparietal narrowing	Occasional (5-29%)
HP:0100490	Camptodactyly of finger	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked intellectual disability, Cabezas type
Mondo ID	MONDO:0010306
OMIM	300354
Orphanet	85293
DOID	DOID:0060822
SNOMED CT	719811001
UMLS	C1845861
MedGen	337334
GARD	0013244
Is cancer (heuristic)	no

Also known as: Cabezas syndrome · Cabezas syndrome; syndromic X-linked intellectual disability 15 · Cabezas type of X-linked syndromic intellectual disability · Cul4B-related X-linked intellectual disability · intellectual disability, X-linked, syndromic 15 · intellectual disability, X-linked, syndromic 15 (Cabezas type) · intellectual disability, X-linked, syndromic, Cabezas type · intellectual disability, X-linked, with short stature · mental retardation, X-linked, syndromic 15 · mental retardation, X-linked, syndromic 15 (Cabezas type), X-linked recessive · mental retardation, X-linked, syndromic, Cabezas type · mental retardation, X-linked, with short stature · mental retardation, X-linked, with short stature, hypogonadism, and abnormal Gait · MRSS · MRXS15 · MRXSC · syndromic X-linked intellectual disability Cabezas type · X-linked intellectual disability with short stature · X-linked intellectual disability with short stature, hypogonadism, and abnormal gait · X-linked intellectual disability, Cabezas type

Data availability: 226 ClinVar variants · 3 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › X-linked intellectual disability, Cabezas type

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-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, Wieacker-Wolff syndrome, 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

226 retrieved; paginated sample, class counts are floors:

83 uncertain significance, 59 likely benign, 27 benign, 20 pathogenic, 17 likely pathogenic, 11 benign/likely benign, 9 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
11338	NM_001079872.2(CUL4B):c.1660C>T (p.Arg554Cys)	CUL4B	Pathogenic	criteria provided, single submitter
11339	NM_001079872.2(CUL4B):c.1108C>T (p.Arg370Ter)	CUL4B	Pathogenic	criteria provided, multiple submitters, no conflicts
11340	NM_001079872.2(CUL4B):c.847-2A>G	CUL4B	Pathogenic	no assertion criteria provided
1174539	NM_001079872.2(CUL4B):c.784T>A (p.Leu262Met)	CUL4B	Pathogenic	no assertion criteria provided
1803957	NM_001079872.2(CUL4B):c.2264_2265dup (p.Glu756Ter)	CUL4B	Pathogenic	criteria provided, single submitter
208796	NM_001079872.2(CUL4B):c.1852+1G>T	CUL4B	Pathogenic	criteria provided, single submitter
3629995	NC_000023.10:g.(119681095_119691778)_(119694481_119708405)del	CUL4B	Pathogenic	criteria provided, single submitter
375587	NM_001079872.2(CUL4B):c.1682_1683del (p.Thr561fs)	CUL4B	Pathogenic	no assertion criteria provided
3773643	NM_001079872.2(CUL4B):c.1742-2A>G	CUL4B	Pathogenic	criteria provided, single submitter
3895538	NM_001079872.2(CUL4B):c.1201_1204del (p.Lys401fs)	CUL4B	Pathogenic	criteria provided, single submitter
4056404	NM_001079872.2(CUL4B):c.2069dup (p.Lys691fs)	CUL4B	Pathogenic	criteria provided, single submitter
426723	NM_001079872.2(CUL4B):c.953_957del (p.Ile318fs)	CUL4B	Pathogenic	criteria provided, multiple submitters, no conflicts
4530606	NM_001079872.2(CUL4B):c.1741_1741+8del	CUL4B	Pathogenic	criteria provided, single submitter
4721795	NM_001079872.2(CUL4B):c.1079T>A (p.Leu360Ter)	CUL4B	Pathogenic	criteria provided, single submitter
520903	NM_001079872.2(CUL4B):c.721C>T (p.Gln241Ter)	CUL4B	Pathogenic	criteria provided, multiple submitters, no conflicts
523617	NM_001079872.2(CUL4B):c.1404_1405del (p.Val469fs)	CUL4B	Pathogenic	criteria provided, single submitter
804080	NM_001079872.2(CUL4B):c.1386del (p.Phe462fs)	CUL4B	Pathogenic	criteria provided, single submitter
2702101	NM_001079872.2(CUL4B):c.355G>T (p.Glu119Ter)	LOC113845788	Pathogenic	criteria provided, single submitter
3024245	NM_001079872.2(CUL4B):c.516del (p.Lys172fs)	LOC113845788	Pathogenic	criteria provided, single submitter
2424705	NC_000023.10:g.(?117629935)(119761021_?)del	RHOXF2	Pathogenic	criteria provided, single submitter
1676570	NM_001079872.2(CUL4B):c.2439G>A (p.Thr813=)	CUL4B	Likely pathogenic	criteria provided, single submitter
1709716	NM_001079872.2(CUL4B):c.1423del (p.Gln475fs)	CUL4B	Likely pathogenic	criteria provided, single submitter
2506462	NM_001079872.2(CUL4B):c.2576_2588del (p.Gln858_Leu859insTer)	CUL4B	Likely pathogenic	criteria provided, single submitter
2683923	NM_001079872.2(CUL4B):c.1444-1G>A	CUL4B	Likely pathogenic	criteria provided, single submitter
3028897	NM_001079872.2(CUL4B):c.695dup (p.Tyr232Ter)	CUL4B	Likely pathogenic	criteria provided, single submitter
3256535	NM_001079872.2(CUL4B):c.2403del (p.Phe801fs)	CUL4B	Likely pathogenic	criteria provided, single submitter
3338087	NM_001079872.2(CUL4B):c.1007_1011del (p.Ile336fs)	CUL4B	Likely pathogenic	no assertion criteria provided
3377348	NM_001079872.2(CUL4B):c.1637-3T>A	CUL4B	Likely pathogenic	criteria provided, single submitter
3775208	NM_001079872.2(CUL4B):c.723_748del (p.Gln241fs)	CUL4B	Likely pathogenic	criteria provided, single submitter
3895515	NM_001079872.2(CUL4B):c.2394_2395del (p.His798fs)	CUL4B	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
CUL4B	Definitive	X-linked	X-linked intellectual disability, Cabezas type	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CUL4B	Orphanet:85293	X-linked intellectual disability, Cabezas type

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
CUL4B	HGNC:2555	ENSG00000158290	Q13620	Cullin-4B	gencc,clinvar
RHOXF2	HGNC:30011	ENSG00000131721	Q9BQY4	Rhox homeobox family member 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CUL4B	Cullin-4B	Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins.
RHOXF2	Rhox homeobox family member 2	Transcription factor maybe involved in reproductive processes.

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)
CUL4B	Other/Unknown	no		Cullin_N, Cullin_CS, Cullin_homology
RHOXF2	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

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
corpus epididymis	1
male germ cell	1
sperm	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CUL4B	291	ubiquitous	marker	sperm, male germ cell, corpus epididymis
RHOXF2	22	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CUL4B	4,342
RHOXF2	948

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CUL4B	Q13620	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RHOXF2	Q9BQY4	64.38

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Recognition of DNA damage by PCNA-containing replication complex	1	380.7×	0.007	CUL4B
DNA Damage Recognition in GG-NER	1	285.5×	0.007	CUL4B
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1	265.6×	0.007	CUL4B
Dual Incision in GG-NER	1	259.6×	0.007	CUL4B
Formation of Incision Complex in GG-NER	1	253.8×	0.007	CUL4B
Formation of TC-NER Pre-Incision Complex	1	211.5×	0.007	CUL4B
Gap-filling DNA repair synthesis and ligation in TC-NER	1	178.4×	0.007	CUL4B
Dual incision in TC-NER	1	173.0×	0.007	CUL4B
Neddylation	1	47.4×	0.021	CUL4B

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
UV-damage excision repair	1	648.1×	0.013	CUL4B
proteasomal protein catabolic process	1	383.0×	0.013	CUL4B
astrocyte differentiation	1	383.0×	0.013	CUL4B
ribosome biogenesis	1	312.1×	0.013	CUL4B
positive regulation of G1/S transition of mitotic cell cycle	1	200.6×	0.016	CUL4B
cellular response to UV	1	147.8×	0.018	CUL4B
neuron development	1	127.7×	0.018	RHOXF2
positive regulation of protein catabolic process	1	101.5×	0.018	CUL4B
G1/S transition of mitotic cell cycle	1	100.3×	0.018	CUL4B
protein polyubiquitination	1	57.7×	0.028	CUL4B
gene expression	1	39.9×	0.036	CUL4B
ubiquitin-dependent protein catabolic process	1	37.1×	0.036	CUL4B
DNA damage response	1	26.8×	0.046	CUL4B
protein ubiquitination	1	20.7×	0.054	CUL4B
positive regulation of gene expression	1	19.4×	0.054	RHOXF2
regulation of transcription by RNA polymerase II	1	5.8×	0.164	RHOXF2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
RHOXF2	1	2
CUL4B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	RHOXF2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RHOXF2	6	Binding:6
CUL4B	5	Binding:5

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	RHOXF2

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	RHOXF2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CUL4B

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)
CUL4B	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.