Charcot-Marie-Tooth disease type 4E

Summary

Charcot-Marie-Tooth disease type 4E (MONDO:0011527) is a disease caused by EGR2 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: EGR2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 18
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 4E
Mondo ID	MONDO:0011527
MeSH	C535301
OMIM	605253
Orphanet	99951
DOID	DOID:0110195
ICD-11	225958466
SNOMED CT	763135001
UMLS	C4721436
MedGen	1648303
GARD	0009203
NORD	1506
Is cancer (heuristic)	no

Also known as: autosomal recessive congenital hypomyelinating neuropathy · Charcot Marie Tooth disease type 4E · Charcot-Marie-Tooth disease type 4E · CHN · CHN1 · CMT 4E · CMT4E · congenital hypomyelinating neuropathy (CHN) · congenital hypomyelination neuropathy · hypomyelinating neuropathy, congenital, 1 · neuropathy, congenital hypomyelinating · neuropathy, congenital hypomyelinating or AMYELINATING, autosomal recessive · Neuropathy, Congenital Hypomyelination

Data availability: 18 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 4E

Related subtypes (11): Charcot-Marie-Tooth disease type 4A, Charcot-Marie-Tooth disease type 4B1, Charcot-Marie-Tooth disease type 4D, Charcot-Marie-Tooth disease type 4C, Charcot-Marie-Tooth disease type 4B2, 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

18 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 4 pathogenic, 4 conflicting classifications of pathogenicity, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
14170	NM_000530.8(MPZ):c.499G>C (p.Gly167Arg)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
14181	NM_000530.8(MPZ):c.371C>T (p.Thr124Met)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
14191	NM_000530.8(MPZ):c.434A>C (p.Tyr145Ser)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
374304	GRCh37/hg19 1q23.3(chr1:161255241-161276497)	MPZ	Pathogenic	no assertion criteria provided
462797	NM_000530.8(MPZ):c.397C>A (p.Pro133Thr)	MPZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16749	NM_000399.5(EGR2):c.803T>A (p.Ile268Asn)	EGR2	Conflicting classifications of pathogenicity	no assertion criteria provided
462785	NM_000399.5(EGR2):c.457A>C (p.Thr153Pro)	EGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216963	NM_000530.8(MPZ):c.451C>A (p.Pro151Thr)	MPZ	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246524	NM_000530.8(MPZ):c.133C>T (p.Arg45Trp)	MPZ	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3242211	NM_003632.3(CNTNAP1):c.1228G>A (p.Val410Met)	CNTNAP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1476279	NM_000399.5(EGR2):c.770G>A (p.Arg257Gln)	EGR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3393066	NM_000399.5(EGR2):c.-49A>G	EGR2	Uncertain significance	criteria provided, single submitter
38873	NM_000399.5(EGR2):c.1146T>G (p.Ser382Arg)	EGR2	Uncertain significance	no assertion criteria provided
38874	NM_000399.5(EGR2):c.1147G>T (p.Asp383Tyr)	EGR2	Uncertain significance	no assertion criteria provided
548617	NM_000399.5(EGR2):c.1084C>T (p.Arg362Ter)	EGR2	Uncertain significance	criteria provided, single submitter
842568	NM_000399.5(EGR2):c.910GCC[8] (p.Ala308_Ala309dup)	EGR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
955998	NM_000399.5(EGR2):c.897AGC[7] (p.Ala308_Ala309dup)	EGR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
285766	NM_000399.5(EGR2):c.627= (p.Pro209=)	EGR2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 12 · 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
EGR2	Definitive	Autosomal recessive	Charcot-Marie-Tooth disease type 4E	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EGR2	Orphanet:101084	Charcot-Marie-Tooth disease type 1D
EGR2	Orphanet:64748	Dejerine-Sottas syndrome
EGR2	Orphanet:99951	Charcot-Marie-Tooth disease type 4E
MPZ	Orphanet:100046	Autosomal dominant intermediate Charcot-Marie-Tooth disease type D
MPZ	Orphanet:101082	Charcot-Marie-Tooth disease type 1B
MPZ	Orphanet:3115	Roussy-Lévy syndrome
MPZ	Orphanet:324585	Autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain
MPZ	Orphanet:538574	Palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome
MPZ	Orphanet:64748	Dejerine-Sottas syndrome
MPZ	Orphanet:99942	Autosomal dominant Charcot-Marie-Tooth disease type 2I
MPZ	Orphanet:99943	Autosomal dominant Charcot-Marie-Tooth disease type 2J
CNTNAP1	Orphanet:2680	Hypomyelination neuropathy-arthrogryposis syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EGR2	HGNC:3239	ENSG00000122877	P11161	E3 SUMO-protein ligase EGR2	gencc,clinvar
MPZ	HGNC:7225	ENSG00000158887	P25189	Myelin protein P0	clinvar
CNTNAP1	HGNC:8011	ENSG00000108797	P78357	Contactin-associated protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EGR2	E3 SUMO-protein ligase EGR2	Sequence-specific DNA-binding transcription factor.
MPZ	Myelin protein P0	Is an adhesion molecule necessary for normal myelination in the peripheral nervous system.
CNTNAP1	Contactin-associated protein 1	Required, with CNTNAP2, for radial and longitudinal organization of myelinated axons.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Antibody/Immunoglobulin	1	9.7×	0.298
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EGR2	Transcription factor	no		Znf_C2H2_type, EGR_N, Znf_C2H2_sf
MPZ	Antibody/Immunoglobulin	yes		Myelin_P0-rel, Ig_sub, Ig-like_dom
CNTNAP1	Other/Unknown	no		FA58C, EGF, Laminin_G

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tibial nerve	2
gall bladder	1
granulocyte	1
olfactory bulb	1
sural nerve	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EGR2	143	ubiquitous	marker	gall bladder, tibial nerve, granulocyte
MPZ	178	ubiquitous	marker	tibial nerve, sural nerve, olfactory bulb
CNTNAP1	209	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EGR2	3,269
CNTNAP1	1,292
MPZ	25

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MPZ	P25189	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CNTNAP1	P78357	81.51
EGR2	P11161	49.02

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 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
EGR2 and SOX10-mediated initiation of Schwann cell myelination	2	245.6×	1e-04	EGR2, MPZ
Neurofascin interactions	1	475.8×	0.007	CNTNAP1
NGF-stimulated transcription	1	95.2×	0.024	EGR2
Transcriptional regulation of white adipocyte differentiation	1	43.3×	0.040	EGR2
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	30.4×	0.045	EGR2
Nervous system development	1	14.3×	0.080	MPZ
Developmental Biology	1	4.8×	0.194	MPZ

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
rhombomere 3 structural organization	1	5617.3×	0.001	EGR2
rhombomere 3 formation	1	5617.3×	0.001	EGR2
rhombomere 5 structural organization	1	5617.3×	0.001	EGR2
rhombomere 5 formation	1	5617.3×	0.001	EGR2
neuromuscular junction development, skeletal muscle fiber	1	5617.3×	0.001	CNTNAP1
myelination	2	167.7×	0.001	EGR2, MPZ
rhythmic behavior	1	2808.7×	0.001	EGR2
positive regulation of Schwann cell differentiation	1	2808.7×	0.001	EGR2
postsynaptic density organization	1	2808.7×	0.001	CNTNAP1
cell aggregation	1	2808.7×	0.001	MPZ
paranodal junction maintenance	1	2808.7×	0.001	CNTNAP1
brain segmentation	1	1872.4×	0.002	EGR2
protein localization to paranode region of axon	1	1404.3×	0.002	CNTNAP1
protein localization to juxtaparanode region of axon	1	1404.3×	0.002	CNTNAP1
paranodal junction assembly	1	936.2×	0.003	CNTNAP1
Schwann cell differentiation	1	802.5×	0.004	EGR2
facial nerve structural organization	1	624.1×	0.004	EGR2
neuronal action potential propagation	1	468.1×	0.005	CNTNAP1
regulation of ossification	1	401.2×	0.006	EGR2
obsolete cell-cell adhesion via plasma-membrane adhesion molecules	1	374.5×	0.006	MPZ
neuromuscular process controlling posture	1	351.1×	0.006	CNTNAP1
central nervous system myelination	1	330.4×	0.006	CNTNAP1
regulation of synapse maturation	1	312.1×	0.006	CNTNAP1
myelination in peripheral nervous system	1	295.6×	0.006	CNTNAP1
positive regulation of myelination	1	255.3×	0.007	EGR2
motor neuron axon guidance	1	234.1×	0.007	EGR2
peripheral nervous system development	1	193.7×	0.009	EGR2
aorta development	1	187.2×	0.009	EGR2
protein export from nucleus	1	170.2×	0.009	EGR2
skeletal muscle cell differentiation	1	114.6×	0.013	EGR2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
EGR2	0	0
MPZ	0	0
CNTNAP1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	MPZ
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	EGR2, CNTNAP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EGR2	0	—
MPZ	0	—
CNTNAP1	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