Spinocerebellar ataxia type 4

Summary

Spinocerebellar ataxia type 4 (MONDO:0010847) is a disease caused by ZFHX3 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: ZFHX3 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 2
• Phenotypes (HPO): 12
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0002495	Impaired vibratory sensation	Very frequent (80-99%)
HP:0003438	Absent Achilles reflex	Very frequent (80-99%)
HP:0010830	Impaired tactile sensation	Very frequent (80-99%)
HP:0010831	Impaired proprioception	Very frequent (80-99%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002333	Motor deterioration	Frequent (30-79%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0003390	Sensory axonal neuropathy	Occasional (5-29%)
HP:0007002	Motor axonal neuropathy	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia type 4
Mondo ID	MONDO:0010847
OMIM	600223
Orphanet	98765
DOID	DOID:0050957
ICD-11	1686006145
SNOMED CT	715755008
UMLS	C0752122
MedGen	199815
GARD	0009970
Is cancer (heuristic)	no

Also known as: SCA4 · spinocerebellar ataxia 4 · spinocerebellar ataxia autosomal dominant with sensory axonal neuropathy

Data availability: 2 ClinVar variants · 2 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 dominant disease › autosomal dominant cerebellar ataxia › autosomal dominant cerebellar ataxia type I › spinocerebellar ataxia type 4

Related subtypes (29): Machado-Joseph disease, spinocerebellar ataxia type 29, spinocerebellar ataxia type 34, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, autosomal dominant cerebellar ataxia, deafness and narcolepsy, spinocerebellar ataxia type 12, spinocerebellar ataxia type 13, spinocerebellar ataxia type 14, spinocerebellar ataxia type 15/16, spinocerebellar ataxia type 17, spinocerebellar ataxia type 19/22, spinocerebellar ataxia type 21, spinocerebellar ataxia type 18, spinocerebellar ataxia type 20, spinocerebellar ataxia type 25, spinocerebellar ataxia type 8, spinocerebellar ataxia type 27, spinocerebellar ataxia type 23, spinocerebellar ataxia type 28, spinocerebellar ataxia type 35, spinocerebellar ataxia type 32, spinocerebellar ataxia type 36, cerebellar dysfunction with variable cognitive and behavioral abnormalities, spinocerebellar ataxia type 37, spinocerebellar ataxia type 40, spinocerebellar ataxia 46, neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2671874	NM_006885.4:c.10519GGC[42-74]	ZFHX3	Pathogenic	no assertion criteria provided
932894	NM_015378.4(VPS13D):c.12416C>T (p.Ala4139Val)	VPS13D	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
ZFHX3	Strong	Autosomal dominant	spinocerebellar ataxia type 4	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VPS13D	Orphanet:95434	Autosomal recessive cerebellar ataxia-movement disorder 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
ZFHX3	HGNC:777	ENSG00000140836	Q15911	Zinc finger homeobox protein 3	gencc,clinvar
VPS13D	HGNC:23595	ENSG00000048707	Q5THJ4	Intermembrane lipid transfer protein VPS13D	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZFHX3	Zinc finger homeobox protein 3	Transcriptional regulator which can act as an activator or a repressor.
VPS13D	Intermembrane lipid transfer protein VPS13D	Mediates the transfer of lipids between membranes at organelle contact sites.

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)
ZFHX3	Transcription factor	no		HD, Matrin/U1-like-C_Znf_C2H2, Homeodomain-like_sf
VPS13D	Other/Unknown	no		UBA-like_sf, VPS13_VAB, UBA

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
buccal mucosa cell	1
saphenous vein	1
synovial joint	1
skin of abdomen	1
skin of leg	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZFHX3	274	ubiquitous	marker	saphenous vein, buccal mucosa cell, synovial joint
VPS13D	299	ubiquitous	marker	skin of leg, skin of abdomen, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZFHX3	1,649
VPS13D	1,171

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ZFHX3	Q15911	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VPS13D	Q5THJ4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
RUNX3 regulates CDKN1A transcription	1	1631.4×	6e-04	ZFHX3

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 locomotor rhythm	1	4213.0×	0.004	ZFHX3
protein retention in Golgi apparatus	1	1685.2×	0.005	VPS13D
response to transforming growth factor beta	1	936.2×	0.006	ZFHX3
protein targeting to vacuole	1	648.1×	0.006	VPS13D
positive regulation of mitophagy	1	561.7×	0.006	VPS13D
regulation of neuron differentiation	1	366.4×	0.008	ZFHX3
negative regulation of myoblast differentiation	1	312.1×	0.008	ZFHX3
positive regulation of myoblast differentiation	1	183.2×	0.012	ZFHX3
positive regulation of cell adhesion	1	135.9×	0.014	ZFHX3
lipid transport	1	131.7×	0.014	VPS13D
circadian regulation of gene expression	1	117.0×	0.014	ZFHX3
muscle organ development	1	83.4×	0.018	ZFHX3
mitochondrion organization	1	75.9×	0.018	VPS13D
regulation of DNA-templated transcription	1	15.8×	0.080	ZFHX3
positive regulation of DNA-templated transcription	1	14.0×	0.084	ZFHX3
negative regulation of transcription by RNA polymerase II	1	8.9×	0.123	ZFHX3
positive regulation of transcription by RNA polymerase II	1	7.4×	0.138	ZFHX3
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ZFHX3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
ZFHX3	0	0
VPS13D	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	2	ZFHX3, VPS13D

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ZFHX3	0	—
VPS13D	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