X-linked cerebral-cerebellar-coloboma syndrome syndrome

Summary

X-linked cerebral-cerebellar-coloboma syndrome syndrome (MONDO:0010464) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 3
• Phenotypes (HPO): 31

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0000238	Hydrocephalus	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000567	Chorioretinal coloboma	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001320	Cerebellar vermis hypoplasia	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002363	Abnormal brainstem morphology	Frequent (30-79%)
HP:0002538	Abnormality of the cerebral cortex	Frequent (30-79%)
HP:0002876	Episodic tachypnea	Frequent (30-79%)
HP:0005949	Apneic episodes in infancy	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0040288	Nasogastric tube feeding	Frequent (30-79%)
HP:0000278	Retrognathia	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000358	Posteriorly rotated ears	Occasional (5-29%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0001305	Dandy-Walker malformation	Occasional (5-29%)
HP:0002007	Frontal bossing	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002033	Poor suck	Occasional (5-29%)
HP:0002245	Meckel diverticulum	Occasional (5-29%)
HP:0002335	Agenesis of cerebellar vermis	Occasional (5-29%)
HP:0003196	Short nose	Occasional (5-29%)
HP:0005815	Supernumerary ribs	Occasional (5-29%)
HP:0007738	Uncontrolled eye movements	Occasional (5-29%)
HP:0007965	Undetectable visual evoked potentials	Occasional (5-29%)
HP:0009928	Thick nasal alae	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked cerebral-cerebellar-coloboma syndrome syndrome
Mondo ID	MONDO:0010464
OMIM	300864
Orphanet	163961
UMLS	C3275487
MedGen	477118
GARD	0017006
Is cancer (heuristic)	no

Also known as: cerebral-cerebellar-coloboma syndrome, X-linked, X-linked recessive · X-linked intellectual disability, Kroes type

Data availability: 3 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › X-linked cerebral-cerebellar-coloboma syndrome syndrome

Related subtypes (53): craniosynostosis-Dandy-Walker malformation-hydrocephalus syndrome, Aase-Smith syndrome, arachnoid cyst, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, Dandy-Walker malformation-postaxial polydactyly syndrome, cervical hypertrichosis-peripheral neuropathy syndrome, Joubert syndrome with oculorenal defect, NPHP3-related Meckel-like syndrome, orofaciodigital syndrome type 6, X-linked intellectual disability-cerebellar hypoplasia syndrome, syndromic X-linked intellectual disability Najm type, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, aprosencephaly cerebellar dysgenesis, Gomez-Lopez-Hernandez syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, pontine tegmental cap dysplasia, ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome, cerebellar-facial-dental syndrome, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal recessive spinocerebellar ataxia 20, SLC39A8-CDG, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, isolated cerebellar vermis hypoplasia, cerebral gigantism-jaw cysts syndrome, holoprosencephaly-caudal dysgenesis syndrome, Joubert syndrome with ocular defect, macrocephaly-short stature-paraplegia syndrome, glioependymal/ependymal cyst, isolated cerebellar vermis agenesis, isolated unilateral hemispheric cerebellar hypoplasia, isolated bilateral hemispheric cerebellar hypoplasia, Hoyeraal-Hreidarsson syndrome, neural tube defect, partial corpus callosum agenesis-cerebellar vermis hypoplasia with posterior fossa cysts syndrome, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, tubulinopathy-associated dysgyria, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, rhombencephalosynapsis, Lhermitte-Duclos disease, Ritscher-Schinzel syndrome, spinal muscular atrophy-Dandy-Walker malformation-cataracts syndrome, cystic malformation of the posterior fossa, pontocerebellar hypoplasia, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, hereditary cerebral malformation, isolated arhinencephaly

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

3 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
560932	NM_001029896.2(WDR45):c.131-11_145del	LOC126863256	Pathogenic	criteria provided, single submitter
212592	NM_001029896.2(WDR45):c.397C>T (p.Arg133Ter)	WDR45	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218903	NM_001029896.2(WDR45):c.158TGG[1] (p.Val54del)	LOC126863256	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WDR45	Orphanet:329284	Beta-propeller protein-associated neurodegeneration
WDR45	Orphanet:697160	Infantile epileptic spasms syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WDR45	HGNC:28912	ENSG00000196998	Q9Y484	WD repeat domain phosphoinositide-interacting protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WDR45	WD repeat domain phosphoinositide-interacting protein 4	Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WDR45	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
granulocyte	1
mucosa of stomach	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WDR45	293	ubiquitous	marker	apex of heart, mucosa of stomach, granulocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WDR45	1,233

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WDR45	Q9Y484	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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
Macroautophagy	1	115.3×	0.009	WDR45

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nucleophagy	1	3370.4×	0.002	WDR45
glycophagy	1	1404.3×	0.002	WDR45
pexophagy	1	1053.2×	0.002	WDR45
protein localization to phagophore assembly site	1	991.3×	0.002	WDR45
positive regulation of autophagosome assembly	1	802.5×	0.002	WDR45
autophagy of mitochondrion	1	732.7×	0.002	WDR45
autophagosome assembly	1	224.7×	0.006	WDR45
cellular response to starvation	1	193.7×	0.006	WDR45
autophagy	1	110.1×	0.009	WDR45

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
WDR45	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	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	WDR45

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)
WDR45	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.