Autosomal recessive cerebellar ataxia

Summary

Autosomal recessive cerebellar ataxia (MONDO:0015244) is a disease (an umbrella term covering 29 Mondo subtypes) with 8 cohort genes and 2 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Umbrella term: 29 Mondo subtypes
• Cohort genes: 8
• ClinVar variants: 74
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3.3	Worldwide	Validated
Point prevalence	1-9 / 100 000	3.6	Europe	Validated
Point prevalence	1-9 / 100 000	3.3	Portugal	Validated
Point prevalence	1-9 / 100 000	5.3	France	Validated
Point prevalence	1-9 / 100 000	2.3	Norway	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive cerebellar ataxia
Mondo ID	MONDO:0015244
OMIM	213200
Orphanet	1172
DOID	DOID:0050950
UMLS	C5575375
MedGen	1843058
GARD	0018718
Is cancer (heuristic)	no

Also known as: ARCA · arca · cerebellar ataxia, autosomal recessive

Data availability: 74 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 29 Mondo subtypes.

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

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Subtypes (29): Charlevoix-Saguenay spastic ataxia, infantile-onset autosomal recessive nonprogressive cerebellar ataxia, autosomal recessive spinocerebellar ataxia 7, autosomal recessive ataxia, Beauce type, RIDDLE syndrome, autosomal recessive ataxia due to ubiquinone deficiency, autosomal recessive spinocerebellar ataxia 10, ataxia with oculomotor apraxia type 3, autosomal recessive spinocerebellar ataxia 14, autosomal recessive spinocerebellar ataxia 16, Lichtenstein-Knorr syndrome, autosomal recessive spinocerebellar ataxia 20, spinocerebellar ataxia, autosomal recessive 22, spinocerebellar ataxia, autosomal recessive 24, autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome, autosomal recessive congenital cerebellar ataxia, autosomal recessive metabolic cerebellar ataxia, autosomal recessive degenerative and progressive cerebellar ataxia, autosomal recessive syndromic cerebellar ataxia, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy, spinocerebellar ataxia, autosomal recessive 29, spinocerebellar ataxia, autosomal recessive 30, spinocerebellar ataxia, autosomal recessive 31, spinocerebellar ataxia, autosomal recessive 27, spinocerebellar ataxia, autosomal recessive 28, spinocerebellar ataxia, autosomal recessive 25, spinocerebellar ataxia, autosomal recessive 26, spinocerebellar ataxia, autosomal recessive 32, spinocerebellar ataxia, autosomal recessive 33

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

74 retrieved; paginated sample, class counts are floors:

34 uncertain significance, 26 conflicting classifications of pathogenicity, 6 benign, 4 pathogenic/likely pathogenic, 2 benign/likely benign, 1 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
162016	NM_018075.5(ANO10):c.132dup (p.Asp45fs)	ANO10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
55829	NM_005236.3(ERCC4):c.1765C>T (p.Arg589Trp)	ERCC4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325883	NM_006793.5(PRDX3):c.43C>T (p.Arg15Ter)	PRDX3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
667389	NM_182961.4(SYNE1):c.16390-2A>G	SYNE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500953	NM_015378.4(VPS13D):c.10142-2A>G	VPS13D	Pathogenic	criteria provided, single submitter
136587	NM_021830.5(TWNK):c.639C>T (p.Gly213=)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
136594	NM_021830.5(TWNK):c.1735-14C>A	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214177	NM_021830.5(TWNK):c.1697A>G (p.Lys566Arg)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214178	NM_021830.5(TWNK):c.1975G>A (p.Ala659Thr)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214180	NM_021830.5(TWNK):c.2045G>A (p.Arg682His)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214185	NM_021830.5(TWNK):c.1196A>G (p.Asn399Ser)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
279715	NM_021830.5(TWNK):c.241C>G (p.Leu81Val)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
281415	NM_021830.5(TWNK):c.384C>T (p.Ser128=)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298484	NM_021830.5(TWNK):c.-650A>G	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298491	NM_021830.5(TWNK):c.-290G>C	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298494	NM_021830.5(TWNK):c.76G>A (p.Gly26Ser)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298498	NM_021830.5(TWNK):c.492C>T (p.Leu164=)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298499	NM_021830.5(TWNK):c.922T>C (p.Leu308=)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298500	NM_021830.5(TWNK):c.1042G>A (p.Gly348Arg)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298501	NM_021830.5(TWNK):c.1101C>T (p.Ile367=)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298502	NM_021830.5(TWNK):c.1488T>C (p.Thr496=)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298505	NM_021830.5(TWNK):c.*204G>A	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298507	NM_021830.5(TWNK):c.*301C>T	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
298509	NM_021830.5(TWNK):c.*419A>T	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
383137	NM_021830.5(TWNK):c.1609T>C (p.Tyr537His)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
426493	NM_021830.5(TWNK):c.56G>A (p.Gly19Glu)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
507889	NM_021830.5(TWNK):c.1244-14C>T	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
877318	NM_021830.5(TWNK):c.1572C>T (p.His524=)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878401	NM_021830.5(TWNK):c.1953G>A (p.Lys651=)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
878844	NM_021830.5(TWNK):c.672T>C (p.Ala224=)	TWNK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 17 · 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
TWNK	Orphanet:1186	Infantile-onset spinocerebellar ataxia
TWNK	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
TWNK	Orphanet:363534	Mitochondrial DNA depletion syndrome, hepatocerebrorenal form
TWNK	Orphanet:642945	Perrault syndrome type 1
TWNK	Orphanet:642976	Perrault syndrome type 2
TWNK	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
SYNE1	Orphanet:319332	Autosomal recessive myogenic arthrogryposis multiplex congenita
SYNE1	Orphanet:88644	Autosomal recessive ataxia, Beauce type
SYNE1	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
VPS13D	Orphanet:95434	Autosomal recessive cerebellar ataxia-movement disorder syndrome
ANO10	Orphanet:284289	Adult-onset autosomal recessive cerebellar ataxia
ERCC4	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC4	Orphanet:84	Fanconi anemia
ERCC4	Orphanet:90321	Cockayne syndrome type 1
ERCC4	Orphanet:910	Xeroderma pigmentosum

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FGF14	HGNC:3671	ENSG00000102466	Q92915	Fibroblast growth factor 14	gencc
TWNK	HGNC:1160	ENSG00000107815	Q96RR1	Twinkle mtDNA helicase	clinvar
SYNE1	HGNC:17089	ENSG00000131018	Q8NF91	Nesprin-1	clinvar
VPS13D	HGNC:23595	ENSG00000048707	Q5THJ4	Intermembrane lipid transfer protein VPS13D	clinvar
ANO10	HGNC:25519	ENSG00000160746	Q9NW15	Anoctamin-10	clinvar
SEPTIN11	HGNC:25589	ENSG00000138758	Q9NVA2	Septin-11	clinvar
ERCC4	HGNC:3436	ENSG00000175595	Q92889	DNA repair endonuclease XPF	clinvar
PRDX3	HGNC:9354	ENSG00000165672	P30048	Thioredoxin-dependent peroxide reductase, mitochondrial	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.
TWNK	Twinkle mtDNA helicase	Mitochondrial helicase involved in mtDNA replication and repair.
SYNE1	Nesprin-1	Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization.
VPS13D	Intermembrane lipid transfer protein VPS13D	Mediates the transfer of lipids between membranes at organelle contact sites.
ANO10	Anoctamin-10	Does not exhibit calcium-activated chloride channel (CaCC) activity.
SEPTIN11	Septin-11	Filament-forming cytoskeletal GTPase.
ERCC4	DNA repair endonuclease XPF	Catalytic component of a structure-specific DNA repair endonuclease responsible for the 5-prime incision during DNA repair, and which is essential for nucleotide excision repair (NER) and interstrand cross-link (ICL) repair.
PRDX3	Thioredoxin-dependent peroxide reductase, mitochondrial	Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 7 · Druggable fraction: 0.12

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	7	1.6×	0.138
Enzyme (other)	1	1.5×	0.502

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FGF14	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
TWNK	Enzyme (other)	yes	3.6.4.12	DNA_helicase_DnaB-like_C, Twinkle-like, P-loop_NTPase
SYNE1	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
VPS13D	Other/Unknown	no		UBA-like_sf, VPS13_VAB, UBA
ANO10	Other/Unknown	no		Anoctamin, Anoctamin_TM
SEPTIN11	Other/Unknown	no		Septin, P-loop_NTPase, G_SEPTIN_dom
ERCC4	Other/Unknown	no		ERCC4_domain, XPF, RuvA_2-like
PRDX3	Other/Unknown	no		AhpC/TSA, Thioredoxin_domain, Peroxiredoxin_C

Expression context

Cohort genes with no expression data: 0.

7 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
calcaneal tendon	2
adrenal tissue	2
bronchial epithelial cell	1
middle temporal gyrus	1
secondary oocyte	1
gastrocnemius	1
tendon of biceps brachii	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
skin of abdomen	1
skin of leg	1
sural nerve	1
duodenum	1
mucosa of transverse colon	1
stromal cell of endometrium	1
ganglionic eminence	1
ventricular zone	1
sperm	1
right adrenal gland	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
TWNK	211	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, tendon of biceps brachii, gastrocnemius
SYNE1	275	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, calcaneal tendon
VPS13D	299	ubiquitous	marker	skin of leg, skin of abdomen, sural nerve
ANO10	271	ubiquitous	marker	stromal cell of endometrium, mucosa of transverse colon, duodenum
SEPTIN11	299	ubiquitous	marker	ventricular zone, ganglionic eminence, calcaneal tendon
ERCC4	242	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue, sperm
PRDX3	294	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRDX3	4,736
SYNE1	2,886
ERCC4	2,102
FGF14	1,675
TWNK	1,390
SEPTIN11	1,226
VPS13D	1,171
ANO10	766

Intra-cohort edges

A	B	Sources
ANO10	SYNE1	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERCC4	Q92889	13
ANO10	Q9NW15	5
SYNE1	Q8NF91	3
TWNK	Q96RR1	2
PRDX3	P30048	2
SEPTIN11	Q9NVA2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FGF14	Q92915	79.77
VPS13D	Q5THJ4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. Enrichment computed across 8 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Strand-asynchronous mitochondrial DNA replication	1	190.3×	0.056	TWNK
Induction of Cell-Cell Fusion	1	146.4×	0.056	ANO10
Phase 0 - rapid depolarisation	1	57.7×	0.056	FGF14
Detoxification of Reactive Oxygen Species	1	50.1×	0.056	PRDX3
HDR through Single Strand Annealing (SSA)	1	48.8×	0.056	ERCC4
Late SARS-CoV-2 Infection Events	1	48.8×	0.056	ANO10
Meiosis	1	47.6×	0.056	SYNE1
Fanconi Anemia Pathway	1	46.4×	0.056	ERCC4
Dual Incision in GG-NER	1	43.3×	0.056	ERCC4
Formation of Incision Complex in GG-NER	1	42.3×	0.056	ERCC4
Transcriptional activation of mitochondrial biogenesis	1	34.0×	0.062	TWNK
Reproduction	1	31.7×	0.062	SYNE1
Dual incision in TC-NER	1	28.8×	0.063	ERCC4
Meiotic synapsis	1	23.5×	0.069	SYNE1
Stimuli-sensing channels	1	22.7×	0.069	ANO10
Mitochondrial protein degradation	1	19.0×	0.077	TWNK
Ion channel transport	1	16.0×	0.086	ANO10
SARS-CoV-2 Infection	1	13.4×	0.096	ANO10
SARS-CoV Infections	1	9.2×	0.131	ANO10
Cell Cycle	1	6.0×	0.187	SYNE1
Viral Infection Pathways	1	5.1×	0.205	ANO10
Transport of small molecules	1	4.2×	0.228	ANO10
Infectious disease	1	4.1×	0.228	ANO10
Disease	1	2.2×	0.380	ANO10

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nuclear matrix anchoring at nuclear membrane	1	702.2×	0.016	SYNE1
nucleotide-excision repair involved in interstrand cross-link repair	1	702.2×	0.016	ERCC4
negative regulation of kinase activity	1	526.6×	0.016	PRDX3
telomeric DNA-containing double minutes formation	1	526.6×	0.016	ERCC4
negative regulation of protection from non-homologous end joining at telomere	1	526.6×	0.016	ERCC4
mitochondrion organization	2	38.0×	0.016	VPS13D, PRDX3
protein retention in Golgi apparatus	1	421.3×	0.018	VPS13D
negative regulation of telomere maintenance	1	351.1×	0.018	ERCC4
mitochondrial transcription	1	300.9×	0.019	TWNK
maternal placenta development	1	191.5×	0.023	PRDX3
mitochondrial DNA replication	1	191.5×	0.023	TWNK
protein hexamerization	1	175.5×	0.023	TWNK
negative regulation of telomere maintenance via telomere lengthening	1	175.5×	0.023	ERCC4
protein targeting to vacuole	1	162.0×	0.023	VPS13D
UV protection	1	150.5×	0.023	ERCC4
positive regulation of mitophagy	1	140.4×	0.023	VPS13D
resolution of meiotic recombination intermediates	1	117.0×	0.026	ERCC4
muscle cell differentiation	1	105.3×	0.027	SYNE1
cytoskeleton-dependent cytokinesis	1	100.3×	0.027	SEPTIN11
hydrogen peroxide catabolic process	1	84.3×	0.030	PRDX3
myeloid cell differentiation	1	81.0×	0.030	PRDX3
DNA-templated DNA replication	1	70.2×	0.032	TWNK
nucleus organization	1	70.2×	0.032	SYNE1
regulation of mitochondrial membrane potential	1	68.0×	0.032	PRDX3
response to hydrogen peroxide	1	58.5×	0.035	PRDX3
double-strand break repair via nonhomologous end joining	1	52.7×	0.037	ERCC4
cellular response to reactive oxygen species	1	51.4×	0.037	PRDX3
nucleotide-excision repair	1	47.9×	0.038	ERCC4
response to UV	1	45.8×	0.039	ERCC4
cell redox homeostasis	1	43.0×	0.040	PRDX3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 8

Druggability breadth: 3 of 8 evidence-associated genes (38%) 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
TWNK	0	0
SYNE1	0	0
VPS13D	0	0
ANO10	0	0
SEPTIN11	0	0
ERCC4	0	0
PRDX3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ERCC4	28	Binding:28
FGF14	16	Binding:16
PRDX3	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TWNK	3.6.4.12	DNA helicase

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; 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	1	TWNK
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	7	FGF14, SYNE1, VPS13D, ANO10, SEPTIN11, ERCC4, PRDX3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FGF14	16	—
TWNK	0	—
SYNE1	0	—
VPS13D	0	—
ANO10	0	—
SEPTIN11	0	—
ERCC4	28	—
PRDX3	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

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
NCT04261127	Not specified	RECRUITING	Validation of the RADIAL Algorithm for Diagnosis of Autosomal Recessive Cerebellar Ataxia