Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2

Summary

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2 (MONDO:0012430) is a disease caused by WDR81 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: WDR81 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 70

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2
Mondo ID	MONDO:0012430
MeSH	C567656
OMIM	610185
DOID	DOID:0070557
UMLS	C2750234
MedGen	412914
GARD	0015473
Is cancer (heuristic)	no

Also known as: CAMRQ2 · cerebellar ataxia and mental retardation with or without quadrupedal locomotion 2 · cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2 · cerebellar ataxia, intellectual disability, and dysequilibrium syndrome type 2 · cerebellar ataxia, mental retardation, and dysequilibrium syndrome 2 · cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 2 · dysequilibrium syndrome caused by mutation in WDR81 · WDR81 dysequilibrium syndrome

Data availability: 70 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › cerebellar ataxia, intellectual disability, and dysequilibrium › cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2

Related subtypes (3): cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3, cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4, cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1

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

70 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 11 likely pathogenic, 9 likely benign, 8 benign, 4 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity, 3 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1252003	NM_001163809.2(WDR81):c.3771T>G (p.Tyr1257Ter)	WDR81	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698908	NM_001163809.2(WDR81):c.3843C>A (p.Tyr1281Ter)	WDR81	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191291	NM_001163809.2(WDR81):c.3286C>T (p.Gln1096Ter)	WDR81	Pathogenic	criteria provided, multiple submitters, no conflicts
224836	NM_001163809.2(WDR81):c.3997C>T (p.Arg1333Ter)	WDR81	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31611	NM_001163809.2(WDR81):c.2567C>T (p.Pro856Leu)	WDR81	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3233622	NM_001163809.2(WDR81):c.2698G>T (p.Glu900Ter)	WDR81	Pathogenic	criteria provided, single submitter
984714	NM_001163809.2(WDR81):c.5335C>T (p.Arg1779Ter)	WDR81	Pathogenic	criteria provided, multiple submitters, no conflicts
1696176	NM_001163809.2(WDR81):c.1358dup (p.Tyr453Ter)	WDR81	Likely pathogenic	criteria provided, single submitter
183290	NM_001163809.2(WDR81):c.845G>A (p.Gly282Glu)	WDR81	Likely pathogenic	criteria provided, single submitter
2500760	NM_001163809.2(WDR81):c.5411G>T (p.Gly1804Val)	WDR81	Likely pathogenic	criteria provided, single submitter
2627973	NM_001163809.2(WDR81):c.2410C>T (p.Arg804Ter)	WDR81	Likely pathogenic	criteria provided, single submitter
3255116	NM_001163809.2(WDR81):c.5672T>C (p.Ile1891Thr)	WDR81	Likely pathogenic	criteria provided, single submitter
3362491	NM_001163809.2(WDR81):c.1285dup (p.Ala429fs)	WDR81	Likely pathogenic	criteria provided, single submitter
3362717	NM_001163809.2(WDR81):c.850_851del (p.Leu284fs)	WDR81	Likely pathogenic	criteria provided, single submitter
3780802	NM_001163809.2(WDR81):c.1213del (p.Arg405fs)	WDR81	Likely pathogenic	criteria provided, single submitter
3780803	NM_001163809.2(WDR81):c.1521del (p.Asp508fs)	WDR81	Likely pathogenic	criteria provided, single submitter
3780804	NM_001163809.2(WDR81):c.4489+1G>A	WDR81	Likely pathogenic	criteria provided, single submitter
4849337	NM_001163809.2(WDR81):c.1297G>T (p.Glu433Ter)	WDR81	Likely pathogenic	criteria provided, single submitter
1701671	NM_001163809.2(WDR81):c.2494G>A (p.Glu832Lys)	WDR81	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
235691	NM_001163809.2(WDR81):c.3532G>A (p.Ala1178Thr)	WDR81	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
377255	NM_001163809.2(WDR81):c.3115G>A (p.Ala1039Thr)	WDR81	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
808186	NM_001163809.2(WDR81):c.2051A>C (p.Gln684Pro)	WDR81	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029177	NM_001163809.2(WDR81):c.1072A>G (p.Ser358Gly)	WDR81	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029178	NM_001163809.2(WDR81):c.1157T>C (p.Val386Ala)	WDR81	Uncertain significance	criteria provided, single submitter
1030235	NM_001163809.2(WDR81):c.1474A>C (p.Ile492Leu)	WDR81	Uncertain significance	criteria provided, single submitter
1030237	NM_001163809.2(WDR81):c.5027C>T (p.Pro1676Leu)	WDR81	Uncertain significance	criteria provided, single submitter
1031890	NM_001163809.2(WDR81):c.2051A>G (p.Gln684Arg)	WDR81	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031891	NM_001163809.2(WDR81):c.3854C>T (p.Pro1285Leu)	WDR81	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031893	NM_001163809.2(WDR81):c.5248G>C (p.Ala1750Pro)	WDR81	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031894	NM_001163809.2(WDR81):c.5659G>A (p.Val1887Met)	WDR81	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · 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
WDR81	Strong	Autosomal recessive	cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WDR81	Orphanet:1766	Dysequilibrium syndrome
WDR81	Orphanet:269505	Congenital communicating hydrocephalus
WDR81	Orphanet:269510	Congenital non-communicating hydrocephalus

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
WDR81	HGNC:26600	ENSG00000167716	Q562E7	WD repeat-containing protein 81	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WDR81	WD repeat-containing protein 81	Functions as a negative regulator of the PI3 kinase/PI3K activity associated with endosomal membranes via BECN1, a core subunit of the PI3K complex.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WDR81	Kinase	yes		BEACH_dom, WD40_rpt, Kinase-like_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
granulocyte	1
left ovary	1
right ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WDR81	138	ubiquitous	marker	granulocyte, left ovary, right ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WDR81	1,404

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WDR81	Q562E7	69.23

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
CDC42 GTPase cycle	1	72.3×	0.014	WDR81

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
aggrephagy	1	1685.2×	0.003	WDR81
early endosome to late endosome transport	1	648.1×	0.004	WDR81
mitochondrion organization	1	151.8×	0.011	WDR81
ubiquitin-dependent protein catabolic process	1	74.2×	0.015	WDR81
protein stabilization	1	66.9×	0.015	WDR81

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
WDR81	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	1	WDR81
E	Difficult family or no structure, no drug	0

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)
WDR81	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.