Giant axonal neuropathy 1

Summary

Giant axonal neuropathy 1 (MONDO:0009749) is a disease caused by GAN (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: GAN (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 746
• Phenotypes (HPO): 26
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0001284	Areflexia	Very frequent (80-99%)
HP:0001290	Generalized hypotonia	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0002235	Pili canaliculi	Very frequent (80-99%)
HP:0003405	Diffuse axonal swelling	Very frequent (80-99%)
HP:0003429	CNS hypomyelination	Very frequent (80-99%)
HP:0003701	Proximal muscle weakness	Very frequent (80-99%)
HP:0005109	Abnormality of the Achilles tendon	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001317	Abnormal cerebellum morphology	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0002224	Woolly hair	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002936	Distal sensory impairment	Frequent (30-79%)
HP:0005922	Abnormal hand morphology	Frequent (30-79%)
HP:0010628	Facial palsy	Frequent (30-79%)
HP:0002527	Falls	Occasional (5-29%)
HP:0002857	Genu valgum	Occasional (5-29%)
HP:0003487	Babinski sign	Occasional (5-29%)
HP:0003690	Limb muscle weakness	Occasional (5-29%)
HP:0012503	Abnormality of the pituitary gland	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	giant axonal neuropathy 1
Mondo ID	MONDO:0009749
OMIM	256850
Orphanet	643
DOID	DOID:0090068
UMLS	C1850386
MedGen	376775
GARD	0006500
Is cancer (heuristic)	no

Also known as: GAN · gan · GAN giant axonal neuropathy · gan giant axonal neuropathy · GAN1 · giant axonal neuropathy 1 · giant axonal neuropathy 1, autosomal recessive · giant axonal neuropathy caused by mutation in GAN · giant axonal neuropathy caused by mutation in gan · giant axonal neuropathy type 1 · giant axonal neuropathy-1 · neuropathy, giant axonal

Data availability: 746 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › axonal neuropathy › giant axonal neuropathy › giant axonal neuropathy 1

Related subtypes (1): giant axonal neuropathy 2

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:

271 uncertain significance, 216 likely benign, 32 pathogenic, 30 benign, 23 conflicting classifications of pathogenicity, 14 likely pathogenic, 9 benign/likely benign, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
584186	NC_000016.9:g.(?80623263)(81411221_?)del	ATMIN	Pathogenic	criteria provided, single submitter
1069095	NM_022041.4(GAN):c.902dup (p.Pro301_Asn302insTer)	GAN	Pathogenic	criteria provided, single submitter
1069107	NM_022041.4(GAN):c.1485C>A (p.Tyr495Ter)	GAN	Pathogenic	criteria provided, single submitter
1075713	NM_022041.4(GAN):c.384del (p.Gly127_Cys128insTer)	GAN	Pathogenic	criteria provided, single submitter
1076942	NM_022041.4(GAN):c.993del (p.Phe331fs)	GAN	Pathogenic	criteria provided, single submitter
1382301	NM_022041.4(GAN):c.502G>T (p.Glu168Ter)	GAN	Pathogenic	criteria provided, single submitter
1438802	NM_022041.4(GAN):c.301dup (p.Thr101fs)	GAN	Pathogenic	criteria provided, single submitter
1451193	NM_022041.4(GAN):c.307C>T (p.Gln103Ter)	GAN	Pathogenic	criteria provided, single submitter
1795359	NM_022041.4(GAN):c.1112_1124delinsGA (p.Glu371fs)	GAN	Pathogenic	criteria provided, multiple submitters, no conflicts
1996143	NM_022041.4(GAN):c.1182C>A (p.Tyr394Ter)	GAN	Pathogenic	criteria provided, single submitter
2041538	NM_022041.4(GAN):c.1191T>A (p.Tyr397Ter)	GAN	Pathogenic	criteria provided, single submitter
2431042	NM_022041.4(GAN):c.215A>T (p.Lys72Met)	GAN	Pathogenic	no assertion criteria provided
2431043	NM_022041.4(GAN):c.1387G>A (p.Ala463Thr)	GAN	Pathogenic	no assertion criteria provided
2440411	NM_022041.4(GAN):c.626del (p.Ile209fs)	GAN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
246282	NM_022041.4(GAN):c.851+1G>A	GAN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2498221	NM_022041.4(GAN):c.861dup (p.Pro288fs)	GAN	Pathogenic	criteria provided, single submitter
2759652	NM_022041.4(GAN):c.779_780del (p.Glu260fs)	GAN	Pathogenic	criteria provided, single submitter
2808332	NM_022041.4(GAN):c.206_213dup (p.Lys72fs)	GAN	Pathogenic	criteria provided, single submitter
2839021	NM_022041.4(GAN):c.582T>A (p.Tyr194Ter)	GAN	Pathogenic	criteria provided, single submitter
2857348	NM_022041.4(GAN):c.384C>A (p.Cys128Ter)	GAN	Pathogenic	criteria provided, single submitter
2871112	NM_022041.4(GAN):c.118G>T (p.Glu40Ter)	GAN	Pathogenic	criteria provided, single submitter
2991358	NM_022041.4(GAN):c.1182C>G (p.Tyr394Ter)	GAN	Pathogenic	criteria provided, single submitter
3243433	NC_000016.9:g.(?81348719)(81411201_?)del	GAN	Pathogenic	criteria provided, single submitter
3243434	NC_000016.9:g.(?81348719)(81348905_?)del	GAN	Pathogenic	criteria provided, single submitter
3243435	NC_000016.9:g.(?81385168)(81391556_?)del	GAN	Pathogenic	criteria provided, single submitter
3701765	NM_022041.4(GAN):c.1494del (p.Glu498fs)	GAN	Pathogenic	criteria provided, single submitter
3729264	NM_022041.4(GAN):c.737_738del (p.Lys246fs)	GAN	Pathogenic	criteria provided, single submitter
3775527	NM_022041.4(GAN):c.625_626insCT (p.Ile209fs)	GAN	Pathogenic	criteria provided, single submitter
3776270	NM_022041.4(GAN):c.1506del (p.Arg501_Trp502insTer)	GAN	Pathogenic	criteria provided, single submitter
4279051	NM_022041.4(GAN):c.1361delinsAA (p.Leu454fs)	GAN	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
GAN	Definitive	Autosomal recessive	giant axonal neuropathy 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GAN	Orphanet:643	Giant axonal neuropathy

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
GAN	HGNC:4137	ENSG00000261609	Q9H2C0	Gigaxonin	gencc,clinvar
ATMIN	HGNC:29034	ENSG00000166454	O43313	ATM interactor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GAN	Gigaxonin	Probable cytoskeletal component that directly or indirectly plays an important role in neurofilament architecture.
ATMIN	ATM interactor	Transcription factor.

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)
GAN	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
ATMIN	Transcription factor	no		Znf_C2H2_type, ATMIN, Znf_C2H2_ASCIZ_4th

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
penis	1
skin of hip	1
upper leg skin	1
Brodmann (1909) area 23	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GAN	252	ubiquitous	marker	upper leg skin, skin of hip, penis
ATMIN	299	ubiquitous	marker	sperm, male germ cell, Brodmann (1909) area 23

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GAN	1,414
ATMIN	973

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GAN	Q9H2C0	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATMIN	O43313	47.67

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Neddylation	1	47.4×	0.027	GAN
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.027	GAN

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
positive regulation of non-motile cilium assembly	1	936.2×	0.011	ATMIN
motile cilium assembly	1	290.6×	0.017	ATMIN
cytoskeleton organization	1	66.3×	0.050	GAN
DNA damage response	1	26.8×	0.073	ATMIN
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.073	GAN
protein ubiquitination	1	20.7×	0.073	GAN
positive regulation of gene expression	1	19.4×	0.073	ATMIN
positive regulation of DNA-templated transcription	1	14.0×	0.088	ATMIN
positive regulation of transcription by RNA polymerase II	1	7.4×	0.144	ATMIN
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ATMIN

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
GAN	0	0
ATMIN	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	GAN, ATMIN

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)
GAN	0	—
ATMIN	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
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders