Autosomal recessive spinocerebellar ataxia 12

Summary

Autosomal recessive spinocerebellar ataxia 12 (MONDO:0013687) is a disease caused by WWOX (GenCC Strong), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: WWOX (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 880
• Phenotypes (HPO): 8
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0001265	Hyporeflexia	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0002066	Gait ataxia	Very frequent (80-99%)
HP:0002070	Limb ataxia	Very frequent (80-99%)
HP:0002839	Urinary bladder sphincter dysfunction	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive spinocerebellar ataxia 12
Mondo ID	MONDO:0013687
OMIM	614322
Orphanet	284282
DOID	DOID:0080060
UMLS	C3280452
MedGen	482082
GARD	0017313
Is cancer (heuristic)	no

Also known as: autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome caused by mutation in WWOX · autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome caused by mutation in WWOX · autosomal recessive spinocerebellar ataxia 12 · autosomal recessive spinocerebellar ataxia type 12 · SCAR12 · spinocerebellar ataxia with mental retardation and epilepsy · spinocerebellar ataxia, autosomal recessive 12 · spinocerebellar ataxia, autosomal recessive type 12 · WWOX autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome · WWOX autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome

Data availability: 880 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive cerebellar ataxia › autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome › autosomal recessive spinocerebellar ataxia 12

Related subtypes (2): autosomal recessive spinocerebellar ataxia 15, spinocerebellar ataxia, autosomal recessive 23

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:

269 likely benign, 215 uncertain significance, 39 pathogenic, 22 benign, 21 conflicting classifications of pathogenicity, 17 benign/likely benign, 11 likely pathogenic, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3243515	NC_000016.9:g.(?78420737)(81991603_?)del	DYNLRB2	Pathogenic	criteria provided, single submitter
100648	NM_016373.4(WWOX):c.1114G>C (p.Gly372Arg)	MAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1381570	NM_016373.4(WWOX):c.1057C>T (p.Gln353Ter)	MAF	Pathogenic	criteria provided, single submitter
2426299	NC_000016.9:g.(?78133676)(79633799_?)del	MAF	Pathogenic	criteria provided, single submitter
100649	NM_016373.4(WWOX):c.139C>A (p.Pro47Thr)	WWOX	Pathogenic	no assertion criteria provided
1068501	NM_016373.4(WWOX):c.127C>T (p.Gln43Ter)	WWOX	Pathogenic	criteria provided, multiple submitters, no conflicts
1072064	NM_016373.4(WWOX):c.321C>G (p.Tyr107Ter)	WWOX	Pathogenic	criteria provided, multiple submitters, no conflicts
1076468	NC_000016.9:g.(?78133671)(78149061_?)del	WWOX	Pathogenic	criteria provided, single submitter
1076469	NC_000016.9:g.(?78420747)(78458962_?)del	WWOX	Pathogenic	criteria provided, single submitter
1076470	NC_000016.9:g.(?78420747)(78466659_?)del	WWOX	Pathogenic	criteria provided, single submitter
120325	NM_016373.4(WWOX):c.160C>T (p.Arg54Ter)	WWOX	Pathogenic	criteria provided, multiple submitters, no conflicts
1452002	NM_016373.4(WWOX):c.333del (p.Thr112fs)	WWOX	Pathogenic	criteria provided, single submitter
1456547	NC_000016.9:g.(?78142310)(78142394_?)del	WWOX	Pathogenic	criteria provided, single submitter
1459088	NM_016373.4(WWOX):c.517-1G>T	WWOX	Pathogenic	criteria provided, single submitter
1676782	NM_016373.4(WWOX):c.172+1G>C	WWOX	Pathogenic	criteria provided, single submitter
1712484	NC_000016.9:g.78179358_78219143delins[78185355_78199419inv]	WWOX	Pathogenic	criteria provided, single submitter
180250	NM_016373.4(WWOX):c.46_49del (p.Asp16fs)	WWOX	Pathogenic	criteria provided, single submitter
183303	NM_016373.4(WWOX):c.606-1G>A	WWOX	Pathogenic	criteria provided, multiple submitters, no conflicts
1898392	NM_016373.4(WWOX):c.2T>C (p.Met1Thr)	WWOX	Pathogenic	criteria provided, single submitter
1938931	NM_016373.4(WWOX):c.108_112dup (p.Thr38fs)	WWOX	Pathogenic	criteria provided, single submitter
1979930	NM_016373.4(WWOX):c.1A>C (p.Met1Leu)	WWOX	Pathogenic	criteria provided, single submitter
2025591	NM_016373.4(WWOX):c.1035del (p.Arg346fs)	WWOX	Pathogenic	criteria provided, single submitter
2099038	NM_016373.4(WWOX):c.552dup (p.Ala185fs)	WWOX	Pathogenic	criteria provided, multiple submitters, no conflicts
2114515	NM_016373.4(WWOX):c.173-1G>C	WWOX	Pathogenic	criteria provided, multiple submitters, no conflicts
2137848	NM_016373.4(WWOX):c.173-1G>T	WWOX	Pathogenic	criteria provided, multiple submitters, no conflicts
241104	NM_016373.4(WWOX):c.779C>G (p.Ser260Ter)	WWOX	Pathogenic	criteria provided, single submitter
241105	NM_016373.4(WWOX):c.790C>T (p.Arg264Ter)	WWOX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2426300	NC_000016.9:g.(?78148853)(78149071_?)del	WWOX	Pathogenic	criteria provided, single submitter
2426301	NC_000016.9:g.(?78148853)(78198206_?)del	WWOX	Pathogenic	criteria provided, single submitter
2426303	NC_000016.9:g.(?78420737)(78458972_?)del	WWOX	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 8 · 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
WWOX	Strong	Autosomal recessive	autosomal recessive spinocerebellar ataxia 12	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WWOX	Orphanet:251510	46,XY partial gonadal dysgenesis
WWOX	Orphanet:284282	Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to WWOX deficiency
WWOX	Orphanet:708171	Facial dysmorphism-corpus callosum hypoplasia-infantile epileptic encephalopathy
WWOX	Orphanet:99977	Squamous cell carcinoma of the esophagus
MAF	Orphanet:1272	Aymé-Gripp syndrome
MAF	Orphanet:1377	Cataract-microcornea syndrome
MAF	Orphanet:98984	Pulverulent cataract
MAF	Orphanet:98989	Cerulean cataract

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WWOX	HGNC:12799	ENSG00000186153	Q9NZC7	WW domain-containing oxidoreductase	gencc,clinvar
DYNLRB2	HGNC:15467	ENSG00000168589	Q8TF09	Dynein light chain roadblock-type 2	clinvar
MAF	HGNC:6776	ENSG00000178573	O75444	Transcription factor Maf	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WWOX	WW domain-containing oxidoreductase	Putative oxidoreductase.
DYNLRB2	Dynein light chain roadblock-type 2	Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function.
MAF	Transcription factor Maf	Acts as a transcriptional activator or repressor.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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
Scaffold/PPI	1	5.8×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WWOX	Scaffold/PPI	no		WW_dom, SDR_fam, WW_dom_sf
DYNLRB2	Other/Unknown	no		Roadblock/LAMTOR2_dom, DYNLRB1/2
MAF	Transcription factor	no		bZIP_Maf, bZIP, TF_DNA-bd_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cervix squamous epithelium	1
cranial nerve II	1
parotid gland	1
bronchial epithelial cell	1
bronchus	1
right uterine tube	1
germinal epithelium of ovary	1
gingiva	1
jejunal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WWOX	286	ubiquitous	marker	parotid gland, cervix squamous epithelium, cranial nerve II
DYNLRB2	182	broad	marker	bronchial epithelial cell, right uterine tube, bronchus
MAF	290	ubiquitous	marker	jejunal mucosa, germinal epithelium of ovary, gingiva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WWOX	5,892
MAF	4,111
DYNLRB2	1,444

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WWOX	Q9NZC7	1
DYNLRB2	Q8TF09	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAF	O75444	62.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 3 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
Negative regulation of activity of TFAP2 (AP-2) family transcription factors	1	380.7×	0.013	WWOX
Activation of the TFAP2 (AP-2) family of transcription factors	1	317.2×	0.013	WWOX
RUNX2 regulates bone development	1	271.9×	0.013	MAF
RUNX2 regulates osteoblast differentiation	1	152.3×	0.018	MAF
Nuclear signaling by ERBB4	1	115.3×	0.019	WWOX
Transcriptional regulation by RUNX2	1	84.6×	0.022	MAF
Intraflagellar transport	1	66.8×	0.023	DYNLRB2
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	48.8×	0.028	MAF
RNA Polymerase II Transcription	1	7.5×	0.156	MAF
Gene expression (Transcription)	1	6.0×	0.175	MAF
Generic Transcription Pathway	1	5.0×	0.186	MAF

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	510.7×	0.016	WWOX
regulation of chondrocyte differentiation	1	468.1×	0.016	MAF
megakaryocyte differentiation	1	401.2×	0.016	MAF
lens fiber cell differentiation	1	351.1×	0.016	MAF
integrated stress response signaling	1	234.1×	0.017	MAF
intrinsic apoptotic signaling pathway by p53 class mediator	1	193.7×	0.017	WWOX
skeletal system morphogenesis	1	165.2×	0.017	WWOX
positive regulation of extrinsic apoptotic signaling pathway	1	151.8×	0.017	WWOX
inner ear development	1	124.8×	0.017	MAF
negative regulation of Wnt signaling pathway	1	114.6×	0.017	WWOX
extrinsic apoptotic signaling pathway	1	102.1×	0.017	WWOX
microtubule-based movement	1	98.5×	0.017	DYNLRB2
response to nutrient	1	98.5×	0.017	MAF
cellular response to transforming growth factor beta stimulus	1	92.1×	0.017	WWOX
osteoblast differentiation	1	40.4×	0.036	WWOX
Wnt signaling pathway	1	33.2×	0.041	WWOX
in utero embryonic development	1	24.0×	0.051	MAF
transcription by RNA polymerase II	1	23.5×	0.051	MAF
positive regulation of gene expression	1	12.9×	0.087	MAF
negative regulation of transcription by RNA polymerase II	1	5.9×	0.176	MAF
positive regulation of transcription by RNA polymerase II	1	5.0×	0.197	WWOX
regulation of transcription by RNA polymerase II	1	3.9×	0.236	MAF

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
WWOX	0	0
DYNLRB2	0	0
MAF	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	WWOX, DYNLRB2, MAF

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
WWOX	0	—
DYNLRB2	0	—
MAF	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford