Charcot-Marie-Tooth disease type 4A

Summary

Charcot-Marie-Tooth disease type 4A (MONDO:0008961) is a disease caused by GDAP1 (GenCC Strong), with 4 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: GDAP1 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 404
• Phenotypes (HPO): 40
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

40 HPO clinical features (Orphanet curated; top 40 by frequency):

HPO ID	Term	Frequency
HP:0000762	Decreased nerve conduction velocity	Very frequent (80-99%)
HP:0001760	Abnormal foot morphology	Very frequent (80-99%)
HP:0001761	Pes cavus	Very frequent (80-99%)
HP:0002460	Distal muscle weakness	Very frequent (80-99%)
HP:0002936	Distal sensory impairment	Very frequent (80-99%)
HP:0003457	EMG abnormality	Very frequent (80-99%)
HP:0003693	Distal amyotrophy	Very frequent (80-99%)
HP:0007010	Poor fine motor coordination	Very frequent (80-99%)
HP:0007015	Poor gross motor coordination	Very frequent (80-99%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0001604	Vocal cord paresis	Frequent (30-79%)
HP:0001609	Hoarse voice	Frequent (30-79%)
HP:0001765	Hammertoe	Frequent (30-79%)
HP:0001776	Bilateral talipes equinovarus	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002540	Inability to walk	Frequent (30-79%)
HP:0003387	Decreased number of large peripheral myelinated nerve fibers	Frequent (30-79%)
HP:0006064	Limited interphalangeal movement	Frequent (30-79%)
HP:0006248	Limited wrist movement	Frequent (30-79%)
HP:0006858	Impaired distal proprioception	Frequent (30-79%)
HP:0006886	Impaired distal vibration sensation	Frequent (30-79%)
HP:0006937	Impaired distal tactile sensation	Frequent (30-79%)
HP:0007267	Chronic axonal neuropathy	Frequent (30-79%)
HP:0007328	Impaired pain sensation	Frequent (30-79%)
HP:0009072	Decreased Achilles reflex	Frequent (30-79%)
HP:0009473	Joint contracture of the hand	Frequent (30-79%)
HP:0012391	Hyporeflexia of upper limbs	Frequent (30-79%)
HP:0030237	Hand muscle weakness	Frequent (30-79%)
HP:0002091	Restrictive ventilatory defect	Occasional (5-29%)
HP:0002359	Frequent falls	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003547	Shoulder girdle muscle weakness	Occasional (5-29%)
HP:0003731	Quadriceps muscle weakness	Occasional (5-29%)
HP:0007108	Demyelinating peripheral neuropathy	Occasional (5-29%)
HP:0008443	Spinal deformities	Occasional (5-29%)
HP:0008935	Generalized neonatal hypotonia	Occasional (5-29%)
HP:0009109	Denervation of the diaphragm	Occasional (5-29%)
HP:0012078	Motor conduction block	Occasional (5-29%)
HP:0030319	Weakness of facial musculature	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 4A
Mondo ID	MONDO:0008961
MeSH	C535419
OMIM	214400
Orphanet	99948
DOID	DOID:0110185
ICD-11	1476665103
SNOMED CT	715796006
UMLS	C1859198
MedGen	347821
GARD	0001252
Is cancer (heuristic)	no

Also known as: Charcot Marie Tooth disease type 4A · Charcot-Marie-Tooth disease type 4 caused by mutation in GDAP1 · Charcot-Marie-Tooth disease, type 4A · CMT4A · GDAP1 Charcot-Marie-Tooth disease type 4

Data availability: 404 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 recessive disease › autosomal recessive intermediate Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease recessive intermediate A › Charcot-Marie-Tooth disease type 4A

Related subtypes (1): Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive

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

404 retrieved; paginated sample, class counts are floors:

182 uncertain significance, 99 likely benign, 46 pathogenic, 31 conflicting classifications of pathogenicity, 19 pathogenic/likely pathogenic, 16 likely pathogenic, 7 benign, 3 benign/likely benign, 1 uncertain significance/vus-high

ClinVar	Variant (HGVS)	Gene	Classification	Review
424778	NM_018972.2(GDAP1):c.[347T>C];[62delA]		Pathogenic	criteria provided, single submitter
1069226	NM_018972.4(GDAP1):c.361del (p.Val121fs)	GDAP1	Pathogenic	criteria provided, single submitter
1069651	NM_018972.4(GDAP1):c.326T>A (p.Leu109Ter)	GDAP1	Pathogenic	criteria provided, single submitter
1071208	NM_018972.4(GDAP1):c.235_239del (p.Val79fs)	GDAP1	Pathogenic	criteria provided, single submitter
1072856	NM_018972.4(GDAP1):c.577A>T (p.Lys193Ter)	GDAP1	Pathogenic	criteria provided, single submitter
1076570	NM_018972.4(GDAP1):c.22C>T (p.Gln8Ter)	GDAP1	Pathogenic	criteria provided, single submitter
1379981	NM_018972.4(GDAP1):c.536del (p.Pro179fs)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1408842	NM_018972.4(GDAP1):c.544C>T (p.Gln182Ter)	GDAP1	Pathogenic	criteria provided, single submitter
1452369	NM_018972.4(GDAP1):c.250del (p.Glu84fs)	GDAP1	Pathogenic	criteria provided, single submitter
1455723	NM_018972.4(GDAP1):c.13C>T (p.Gln5Ter)	GDAP1	Pathogenic	criteria provided, single submitter
1456646	NC_000008.10:g.(?75262697)(75276602_?)del	GDAP1	Pathogenic	criteria provided, single submitter
1457963	NM_018972.4(GDAP1):c.928C>T (p.Arg310Trp)	GDAP1	Pathogenic	criteria provided, single submitter
1458809	NM_018972.4(GDAP1):c.27_28del (p.Gly10fs)	GDAP1	Pathogenic	criteria provided, single submitter
2000577	NM_018972.4(GDAP1):c.1del (p.Met1fs)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2028969	NM_018972.4(GDAP1):c.934del (p.Ala312fs)	GDAP1	Pathogenic	criteria provided, single submitter
2089246	NM_018972.4(GDAP1):c.367del (p.His123fs)	GDAP1	Pathogenic	criteria provided, single submitter
2099188	NM_018972.4(GDAP1):c.549del (p.Ala184fs)	GDAP1	Pathogenic	criteria provided, single submitter
217229	NM_018972.4(GDAP1):c.373C>T (p.Arg125Ter)	GDAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2176526	NM_018972.4(GDAP1):c.714G>A (p.Trp238Ter)	GDAP1	Pathogenic	criteria provided, single submitter
220379	NM_018972.4(GDAP1):c.579+1G>A	GDAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2423924	NM_018972.4(GDAP1):c.1A>G (p.Met1Val)	GDAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
245608	NM_018972.4(GDAP1):c.769C>T (p.Arg257Ter)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2724844	NM_018972.4(GDAP1):c.395del (p.Pro132fs)	GDAP1	Pathogenic	criteria provided, single submitter
2730373	NM_018972.4(GDAP1):c.167dup (p.Ser57fs)	GDAP1	Pathogenic	criteria provided, single submitter
280104	NM_018972.4(GDAP1):c.501del (p.Glu168fs)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2801876	NM_018972.4(GDAP1):c.139A>T (p.Lys47Ter)	GDAP1	Pathogenic	criteria provided, single submitter
2815780	NM_018972.4(GDAP1):c.550dup (p.Ala184fs)	GDAP1	Pathogenic	criteria provided, single submitter
3595879	NM_018972.4(GDAP1):c.400del (p.Asp134fs)	GDAP1	Pathogenic	criteria provided, single submitter
3643714	NM_018972.4(GDAP1):c.697G>T (p.Glu233Ter)	GDAP1	Pathogenic	criteria provided, single submitter
38411	NM_018972.4(GDAP1):c.347T>G (p.Met116Arg)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · 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
GDAP1	Strong	Autosomal dominant	Charcot-Marie-Tooth disease axonal type 2K	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GDAP1	Orphanet:101097	Autosomal recessive Charcot-Marie-Tooth disease with hoarseness
GDAP1	Orphanet:101102	Charcot-Marie-Tooth disease type 2H
GDAP1	Orphanet:217055	Autosomal recessive intermediate Charcot-Marie-Tooth disease type A
GDAP1	Orphanet:99944	Autosomal dominant Charcot-Marie-Tooth disease type 2K
GDAP1	Orphanet:99948	Charcot-Marie-Tooth disease type 4A
FGD4	Orphanet:99954	Charcot-Marie-Tooth disease type 4H

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GDAP1	HGNC:15968	ENSG00000104381	Q8TB36	Ganglioside-induced differentiation-associated protein 1	gencc,clinvar
JPH1	HGNC:14201	ENSG00000104369	Q9HDC5	Junctophilin-1	clinvar
LY96	HGNC:17156	ENSG00000154589	Q9Y6Y9	Lymphocyte antigen 96	clinvar
FGD4	HGNC:19125	ENSG00000139132	Q96M96	FYVE, RhoGEF and PH domain-containing protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GDAP1	Ganglioside-induced differentiation-associated protein 1	Regulates the mitochondrial network by promoting mitochondrial fission.
JPH1	Junctophilin-1	Junctophilins contribute to the formation of junctional membrane complexes (JMCs) which link the plasma membrane with the endoplasmic or sarcoplasmic reticulum in excitable cells.
LY96	Lymphocyte antigen 96	Binds bacterial lipopolysaccharide (LPS).
FGD4	FYVE, RhoGEF and PH domain-containing protein 4	Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 3 · 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	2.1×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GDAP1	Other/Unknown	no		Glutathione_S-Trfase_N, Glutathione-S-Trfase_C-like, GST_C_GDAP1
JPH1	Other/Unknown	no		MORN, Junctophilin
LY96	Other/Unknown	no		ML_dom, Ig_E-set, LY96
FGD4	Transcription factor	no		DH_dom, Znf_FYVE, PH_domain

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	1
oocyte	1
secondary oocyte	1
quadriceps femoris	1
tibialis anterior	1
vastus lateralis	1
leukocyte	1
monocyte	1
mononuclear cell	1
calcaneal tendon	1
ileal mucosa	1
jejunal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GDAP1	244	ubiquitous	yes	endothelial cell, secondary oocyte, oocyte
JPH1	213	broad	marker	quadriceps femoris, vastus lateralis, tibialis anterior
LY96	252	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
FGD4	252	ubiquitous	marker	jejunal mucosa, calcaneal tendon, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LY96	2,007
JPH1	1,646
GDAP1	1,249
FGD4	885

Intra-cohort edges

A	B	Sources
FGD4	GDAP1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LY96	Q9Y6Y9	9
GDAP1	Q8TB36	8
JPH1	Q9HDC5	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FGD4	Q96M96	70.85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 47. Enrichment computed across 4 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
Caspase activation via extrinsic apoptotic signalling pathway	1	475.8×	0.019	LY96
TRIF-mediated programmed cell death	1	423.0×	0.019	LY96
Diseases of Immune System	1	292.8×	0.019	LY96
Diseases associated with the TLR signaling cascade	1	292.8×	0.019	LY96
Caspase activation via Death Receptors in the presence of ligand	1	253.8×	0.019	LY96
IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation	1	253.8×	0.019	LY96
Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7	1	253.8×	0.019	LY96
TRAF6-mediated induction of TAK1 complex within TLR4 complex	1	237.9×	0.019	LY96
MyD88 deficiency (TLR2/4)	1	200.3×	0.019	LY96
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1	200.3×	0.019	LY96
IRAK4 deficiency (TLR2/4)	1	190.3×	0.019	LY96
Class I peroxisomal membrane protein import	1	173.0×	0.019	GDAP1
Regulation of TLR by endogenous ligand	1	165.5×	0.019	LY96
IKK complex recruitment mediated by RIP1	1	165.5×	0.019	LY96
Respiratory syncytial virus (RSV) attachment and entry	1	165.5×	0.019	LY96
Antigen processing-Cross presentation	1	105.7×	0.028	LY96
Heme signaling	1	71.8×	0.029	LY96
Respiratory Syncytial Virus Infection Pathway	1	65.6×	0.029	LY96
TRIF (TICAM1)-mediated TLR4 signaling	1	63.4×	0.029	LY96
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1	63.4×	0.029	LY96
MyD88 dependent cascade initiated on endosome	1	63.4×	0.029	LY96
MyD88-independent TLR4 cascade	1	61.4×	0.029	LY96
Toll Like Receptor 7/8 (TLR7/8) Cascade	1	61.4×	0.029	LY96
NRAGE signals death through JNK	1	61.4×	0.029	FGD4
Toll Like Receptor 9 (TLR9) Cascade	1	58.6×	0.029	LY96
Toll Like Receptor TLR6:TLR2 Cascade	1	58.6×	0.029	LY96
Toll Like Receptor 2 (TLR2) Cascade	1	57.7×	0.029	LY96
Apoptosis	1	56.0×	0.029	LY96
Toll Like Receptor TLR1:TLR2 Cascade	1	56.0×	0.029	LY96
RSV-host interactions	1	52.1×	0.030	LY96

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
detection of lipopolysaccharide	1	842.6×	0.016	LY96
positive regulation of lipopolysaccharide-mediated signaling pathway	1	383.0×	0.016	LY96
cellular response to vitamin D	1	383.0×	0.016	GDAP1
regulation of cardiac muscle contraction by calcium ion signaling	1	324.1×	0.016	JPH1
calcium ion transport into cytosol	1	300.9×	0.016	JPH1
mitochondrial fission	1	263.3×	0.016	GDAP1
mitochondrial fusion	1	210.7×	0.016	GDAP1
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	168.5×	0.016	JPH1
filopodium assembly	1	162.0×	0.016	FGD4
toll-like receptor signaling pathway	1	150.5×	0.016	LY96
obsolete protein targeting to mitochondrion	1	145.3×	0.016	GDAP1
toll-like receptor 4 signaling pathway	1	131.7×	0.016	LY96
regulation of GTPase activity	1	127.7×	0.016	FGD4
response to retinoic acid	1	95.8×	0.019	GDAP1
cellular defense response	1	79.5×	0.022	LY96
muscle organ development	1	41.7×	0.039	JPH1
positive regulation of tumor necrosis factor production	1	38.3×	0.040	LY96
regulation of small GTPase mediated signal transduction	1	36.0×	0.040	FGD4
cytoskeleton organization	1	33.2×	0.040	FGD4
response to lipopolysaccharide	1	31.2×	0.040	LY96
regulation of cell shape	1	30.8×	0.040	FGD4
cellular response to lipopolysaccharide	1	24.5×	0.048	LY96
actin cytoskeleton organization	1	19.8×	0.056	FGD4
cell surface receptor signaling pathway	1	16.0×	0.066	LY96
inflammatory response	1	9.4×	0.106	LY96
innate immune response	1	8.4×	0.114	LY96

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GDAP1	0	0
JPH1	0	0
LY96	0	0
FGD4	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
LY96	87	Binding:86, ADMET:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	4	GDAP1, JPH1, LY96, FGD4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GDAP1	0	—
JPH1	0	—
LY96	87	—
FGD4	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
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease