Spinocerebellar ataxia type 27

Summary

Spinocerebellar ataxia type 27 (MONDO:0012247) is a disease caused by FGF14 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FGF14 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 55
• Phenotypes (HPO): 20
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0000640	Gaze-evoked nystagmus	Very frequent (80-99%)
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0001337	Tremor	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0000718	Aggressive behavior	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002070	Limb ataxia	Frequent (30-79%)
HP:0002078	Truncal ataxia	Frequent (30-79%)
HP:0002354	Memory impairment	Frequent (30-79%)
HP:0003390	Sensory axonal neuropathy	Frequent (30-79%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000642	Red-green dyschromatopsia	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0002378	Hand tremor	Occasional (5-29%)
HP:0002304	Akinesia	Very rare (<1-4%)
HP:0010526	Dysgraphia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia type 27
Mondo ID	MONDO:0012247
MeSH	C537204
OMIM	609307
Orphanet	98764
DOID	DOID:0050976
ICD-11	1408059647
SNOMED CT	719252002
UMLS	C1836383
MedGen	373075
GARD	0009963
Is cancer (heuristic)	no

Also known as: cerebellar ataxia autosomal dominant FGF14-related · SCA27 · spinocerebellar ataxia 27 · spinocerebellar ataxia type 27

Data availability: 55 ClinVar variants · 3 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 27

Related subtypes (29): Machado-Joseph disease, spinocerebellar ataxia type 29, spinocerebellar ataxia type 34, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 4, 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 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

55 retrieved; paginated sample, class counts are floors:

27 uncertain significance, 10 benign, 8 benign/likely benign, 4 pathogenic, 3 likely benign, 2 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1704305	GRCh37/hg19 13q33.1(chr13:102535482-102815349)x3	FGF14	Pathogenic	criteria provided, single submitter
489406	NM_004115.4(FGF14):c.529A>T (p.Lys177Ter)	FGF14	Pathogenic	no assertion criteria provided
976772	GRCh37/hg19 13q33.1(chr13:102521075-102568995)	FGF14	Pathogenic	criteria provided, single submitter
1704304	GRCh37/hg19 13q33.1(chr13:102250764-102412039)x1	ITGBL1	Pathogenic	criteria provided, single submitter
1723288	NM_004115.4(FGF14):c.408+1G>A	FGF14	Likely pathogenic	criteria provided, multiple submitters, no conflicts
560058	Single allele	FGF14	Likely pathogenic	criteria provided, single submitter
310888	NM_004115.4(FGF14):c.*414T>C	FGF14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
310860	NM_004115.4(FGF14):c.*1761G>C	FGF14	Uncertain significance	criteria provided, single submitter
310871	NM_004115.4(FGF14):c.*1072G>A	FGF14	Uncertain significance	criteria provided, single submitter
310872	NM_004115.4(FGF14):c.*1071C>T	FGF14	Uncertain significance	criteria provided, single submitter
310875	NM_004115.4(FGF14):c.*993C>T	FGF14	Uncertain significance	criteria provided, single submitter
310876	NM_004115.4(FGF14):c.*974G>A	FGF14	Uncertain significance	criteria provided, single submitter
310882	NM_004115.4(FGF14):c.*783C>G	FGF14	Uncertain significance	criteria provided, single submitter
310883	NM_004115.4(FGF14):c.*777C>A	FGF14	Uncertain significance	criteria provided, single submitter
310894	NM_004115.4(FGF14):c.664G>A (p.Gly222Arg)	FGF14	Uncertain significance	criteria provided, single submitter
310895	NM_004115.4(FGF14):c.651G>A (p.Thr217=)	FGF14	Uncertain significance	criteria provided, single submitter
310897	NM_004115.4(FGF14):c.620G>A (p.Arg207Gln)	FGF14	Uncertain significance	criteria provided, multiple submitters, no conflicts
310900	NM_004115.4(FGF14):c.477C>T (p.Ser159=)	FGF14	Uncertain significance	criteria provided, single submitter
873432	NM_004115.4(FGF14):c.652G>T (p.Val218Phe)	FGF14	Uncertain significance	criteria provided, single submitter
880904	NM_004115.4(FGF14):c.*1948C>T	FGF14	Uncertain significance	criteria provided, single submitter
880905	NM_004115.4(FGF14):c.*1918T>C	FGF14	Uncertain significance	criteria provided, single submitter
880906	NM_004115.4(FGF14):c.*1772C>A	FGF14	Uncertain significance	criteria provided, single submitter
880959	NM_004115.4(FGF14):c.*535G>T	FGF14	Uncertain significance	criteria provided, single submitter
880960	NM_004115.4(FGF14):c.*369A>G	FGF14	Uncertain significance	criteria provided, single submitter
880961	NM_004115.4(FGF14):c.*361C>T	FGF14	Uncertain significance	criteria provided, single submitter
882269	NM_004115.4(FGF14):c.*1296A>C	FGF14	Uncertain significance	criteria provided, single submitter
882270	NM_004115.4(FGF14):c.*1251G>A	FGF14	Uncertain significance	criteria provided, single submitter
882540	NM_004115.4(FGF14):c.*1199A>G	FGF14	Uncertain significance	criteria provided, single submitter
882541	NM_004115.4(FGF14):c.*863G>C	FGF14	Uncertain significance	criteria provided, single submitter
883322	NM_004115.4(FGF14):c.*699T>C	FGF14	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
FGF14	Strong	Autosomal dominant	spinocerebellar ataxia 27A	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGF14	Orphanet:675216	Spinocerebellar ataxia type 27B
FGF14	Orphanet:98764	Spinocerebellar ataxia type 27A

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
FGF14	HGNC:3671	ENSG00000102466	Q92915	Fibroblast growth factor 14	gencc,clinvar
ITGBL1	HGNC:6164	ENSG00000198542	O95965	Integrin beta-like protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGF14	Fibroblast growth factor 14	Probably involved in nervous system development and function.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FGF14	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
ITGBL1	Other/Unknown	no		EGF, EGF_extracell, Integrin_bsu

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
bronchial epithelial cell	1
middle temporal gyrus	1
secondary oocyte	1
frontal pole	1
middle frontal gyrus	1
paraflocculus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGF14	200	broad	marker	secondary oocyte, middle temporal gyrus, bronchial epithelial cell
ITGBL1	243	broad	marker	frontal pole, paraflocculus, middle frontal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGF14	1,675
ITGBL1	1,086

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ITGBL1	O95965	84.28
FGF14	Q92915	79.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RUNX2 regulates genes involved in cell migration	1	713.8×	0.008	ITGBL1
Phase 0 - rapid depolarisation	1	173.0×	0.016	FGF14
Transcriptional regulation by RUNX2	1	126.9×	0.016	ITGBL1
RNA Polymerase II Transcription	1	11.3×	0.128	ITGBL1
Gene expression (Transcription)	1	8.9×	0.128	ITGBL1
Generic Transcription Pathway	1	7.5×	0.128	ITGBL1

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
cell adhesion mediated by integrin	1	337.0×	0.027	ITGBL1
JNK cascade	1	135.9×	0.027	FGF14
neurogenesis	1	104.0×	0.027	FGF14
cell-matrix adhesion	1	81.8×	0.027	ITGBL1
integrin-mediated signaling pathway	1	80.2×	0.027	ITGBL1
cell-cell adhesion	1	50.8×	0.036	ITGBL1
cell-cell signaling	1	34.8×	0.044	FGF14
cell migration	1	30.8×	0.044	ITGBL1
nervous system development	1	23.0×	0.053	FGF14
cell adhesion	1	18.7×	0.058	ITGBL1
signal transduction	1	8.0×	0.121	FGF14

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGF14	0	0
ITGBL1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
FGF14	16	Binding:16

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	FGF14, ITGBL1

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)
FGF14	16	—
ITGBL1	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