Charcot-Marie-Tooth disease type 4D

Summary

Charcot-Marie-Tooth disease type 4D (MONDO:0011085) is a disease caused by NDRG1 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: NDRG1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 230
• Phenotypes (HPO): 22
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0003431	Decreased motor nerve conduction velocity	Very frequent (80-99%)
HP:0007078	Decreased amplitude of sensory action potentials	Very frequent (80-99%)
HP:0007108	Demyelinating peripheral neuropathy	Very frequent (80-99%)
HP:0009053	Distal lower limb muscle weakness	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001760	Abnormal foot morphology	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0007210	Lower limb amyotrophy	Frequent (30-79%)
HP:0001171	Split hand	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0001765	Hammertoe	Occasional (5-29%)
HP:0002174	Postural tremor	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0002936	Distal sensory impairment	Occasional (5-29%)
HP:0003474	Somatic sensory dysfunction	Occasional (5-29%)
HP:0003701	Proximal muscle weakness	Occasional (5-29%)
HP:0008959	Distal upper limb muscle weakness	Occasional (5-29%)
HP:0009129	Upper limb amyotrophy	Occasional (5-29%)
HP:0032649	Skewfoot	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 4D
Mondo ID	MONDO:0011085
MeSH	C535716
OMIM	601455
Orphanet	99950
DOID	DOID:0110186
ICD-11	616686295
SNOMED CT	715798007
UMLS	C1832334
MedGen	371304
GARD	0003973
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease type 4 caused by mutation in NDRG1 · Charcot-Marie-Tooth disease type 4D · Charcot-Marie-Tooth disease, type 4D · CMT4D · hereditary motor ABD sensory neuropathy Lom type · hereditary motor and sensory neuropathy, Lom type · HMSN, Lom type · HMSN-Lom · HMSN4D · HMSNL · NDRG1 Charcot-Marie-Tooth disease type 4 · NMSL

Data availability: 230 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 › hereditary peripheral neuropathy › Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease type 4 › Charcot-Marie-Tooth disease type 4D

Related subtypes (11): Charcot-Marie-Tooth disease type 4A, Charcot-Marie-Tooth disease type 4B1, Charcot-Marie-Tooth disease type 4C, Charcot-Marie-Tooth disease type 4B2, Charcot-Marie-Tooth disease type 4E, Charcot-Marie-Tooth disease type 4G, Charcot-Marie-Tooth disease type 4H, Charcot-Marie-Tooth disease type 4J, Charcot-Marie-Tooth disease type 4F, Charcot-Marie-Tooth disease type 4B3, Charcot-Marie-Tooth disease type 4K

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

230 retrieved; paginated sample, class counts are floors:

123 uncertain significance, 28 conflicting classifications of pathogenicity, 22 likely benign, 22 benign, 14 likely pathogenic, 8 benign/likely benign, 7 pathogenic, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048598	NM_006096.4(NDRG1):c.237C>A (p.Tyr79Ter)	NDRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1210121	NM_006096.4(NDRG1):c.537+2_537+10del	NDRG1	Pathogenic	no assertion criteria provided
1323335	NM_006096.4(NDRG1):c.327-1G>A	NDRG1	Pathogenic	criteria provided, single submitter
132796	NG_007943.1:g.(43089_43830)_(47717_51712)dup	NDRG1	Pathogenic	no assertion criteria provided
218919	NM_006096.4(NDRG1):c.389+92_594+1717dup	NDRG1	Pathogenic	criteria provided, single submitter
246500	NM_006096.4(NDRG1):c.681dup (p.Ile228fs)	NDRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2752793	NM_006096.4(NDRG1):c.510_511insTGTGTGGA (p.Gly171fs)	NDRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2788864	NM_006096.4(NDRG1):c.40A>T (p.Lys14Ter)	NDRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3233483	NM_006096.4(NDRG1):c.580del (p.His194fs)	NDRG1	Pathogenic	criteria provided, single submitter
3775959	NM_006096.4(NDRG1):c.390-1G>A	NDRG1	Pathogenic	criteria provided, single submitter
410952	NM_006096.4(NDRG1):c.205+1G>A	NDRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5120	NM_006096.4(NDRG1):c.442C>T (p.Arg148Ter)	NDRG1	Pathogenic	criteria provided, multiple submitters, no conflicts
800890	NM_006096.4(NDRG1):c.944-1G>T	NDRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3595283	NM_006096.4(NDRG1):c.807+2T>C	LOC126860531	Likely pathogenic	criteria provided, single submitter
1705646	NM_006096.4(NDRG1):c.390-2A>G	NDRG1	Likely pathogenic	criteria provided, single submitter
2432078	NM_006096.4(NDRG1):c.259C>T (p.Gln87Ter)	NDRG1	Likely pathogenic	criteria provided, single submitter
3362561	NM_006096.4(NDRG1):c.761del (p.Pro254fs)	NDRG1	Likely pathogenic	criteria provided, single submitter
3595282	NM_006096.4(NDRG1):c.892-1G>C	NDRG1	Likely pathogenic	criteria provided, single submitter
3595284	NM_006096.4(NDRG1):c.575_591dup (p.Lys198fs)	NDRG1	Likely pathogenic	criteria provided, single submitter
3595285	NM_006096.4(NDRG1):c.516G>A (p.Trp172Ter)	NDRG1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4058375	NM_006096.4(NDRG1):c.63+1G>C	NDRG1	Likely pathogenic	criteria provided, single submitter
4815491	NM_006096.4(NDRG1):c.1058del (p.Arg353fs)	NDRG1	Likely pathogenic	criteria provided, single submitter
4815492	NM_006096.4(NDRG1):c.206-2A>G	NDRG1	Likely pathogenic	criteria provided, single submitter
4815493	NM_006096.4(NDRG1):c.458del (p.Asn153fs)	NDRG1	Likely pathogenic	criteria provided, single submitter
4815494	NM_006096.4(NDRG1):c.588del (p.Phe196fs)	NDRG1	Likely pathogenic	criteria provided, single submitter
4815495	NM_006096.4(NDRG1):c.693C>A (p.Tyr231Ter)	NDRG1	Likely pathogenic	criteria provided, single submitter
4815496	NM_006096.4(NDRG1):c.944-1G>C	NDRG1	Likely pathogenic	criteria provided, single submitter
1068301	NM_006096.4(NDRG1):c.755+1G>A	LOC126860531	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
379907	NM_006096.4(NDRG1):c.789G>A (p.Ser263=)	LOC126860531	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033071	NM_006096.4(NDRG1):c.537+18C>T	NDRG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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
NDRG1	Definitive	Autosomal recessive	Charcot-Marie-Tooth disease type 4D	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDRG1	Orphanet:99950	Charcot-Marie-Tooth disease type 4D

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NDRG1	HGNC:7679	ENSG00000104419	Q92597	Protein NDRG1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDRG1	Protein NDRG1	Stress-responsive protein involved in hormone responses, cell growth, and differentiation.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NDRG1	Other/Unknown	no		NDRG, AB_hydrolase_fold

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
medial globus pallidus	1
olfactory bulb	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDRG1	294	ubiquitous	marker	olfactory bulb, medial globus pallidus, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDRG1	2,778

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDRG1	Q92597	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 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
TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain	1	761.3×	0.006	NDRG1
TP53 Regulates Transcription of Cell Death Genes	1	543.8×	0.006	NDRG1
Transcriptional Regulation by TP53	1	62.1×	0.032	NDRG1
RNA Polymerase II Transcription	1	22.5×	0.066	NDRG1
Gene expression (Transcription)	1	17.8×	0.066	NDRG1
Generic Transcription Pathway	1	15.1×	0.066	NDRG1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mast cell activation	1	2407.4×	0.002	NDRG1
response to metal ion	1	1532.0×	0.002	NDRG1
peripheral nervous system myelin maintenance	1	1532.0×	0.002	NDRG1
DNA damage response, signal transduction by p53 class mediator	1	358.6×	0.005	NDRG1
cellular response to hypoxia	1	121.2×	0.012	NDRG1
negative regulation of cell population proliferation	1	42.1×	0.028	NDRG1
signal transduction	1	16.1×	0.062	NDRG1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NDRG1	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
NDRG1	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	NDRG1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NDRG1	4	—

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