Charcot-Marie-Tooth disease type 1D

Summary

Charcot-Marie-Tooth disease type 1D (MONDO:0011890) is a disease caused by EGR2 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Causal gene: EGR2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 50
• 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 1D
Mondo ID	MONDO:0011890
MeSH	C537985
OMIM	607678
Orphanet	101084
DOID	DOID:0110150
ICD-11	2062905967
SNOMED CT	719979008
UMLS	C1843247
MedGen	334709
GARD	0009189
Is cancer (heuristic)	no

Also known as: Charcot Marie Tooth disease type 1D · Charcot-Marie-Tooth disease type 1 caused by mutation in EGR2 · Charcot-Marie-Tooth disease, demyelinating, type 1D · Charcot-Marie-Tooth disease, type 1D · CMT 1D · CMT1D · EGR2 Charcot-Marie-Tooth disease type 1 · hereditary motor and sensory neuropathy 1D · HMSN1D

Data availability: 50 ClinVar variants · 3 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 1 › Charcot-Marie-Tooth disease type 1D

Related subtypes (5): Charcot-Marie-Tooth disease type 1B, Charcot-Marie-Tooth disease type 1A, Charcot-Marie-Tooth disease type 1E, Charcot-Marie-Tooth disease type 1C, Charcot-Marie-Tooth disease type 1F

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

50 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 9 conflicting classifications of pathogenicity, 6 pathogenic, 6 benign, 4 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
16750	NM_000399.5(EGR2):c.1225C>T (p.Arg409Trp)	EGR2	Pathogenic	criteria provided, multiple submitters, no conflicts
16752	NM_000399.5(EGR2):c.1075C>T (p.Arg359Trp)	EGR2	Pathogenic	criteria provided, multiple submitters, no conflicts
409979	NM_000399.5(EGR2):c.1235A>G (p.Glu412Gly)	EGR2	Pathogenic	criteria provided, single submitter
41007	NM_000399.5(EGR2):c.1076G>A (p.Arg359Gln)	EGR2	Pathogenic	criteria provided, single submitter
41008	NM_000399.5(EGR2):c.1142G>A (p.Arg381His)	EGR2	Pathogenic	criteria provided, multiple submitters, no conflicts
637524	NM_000399.5(EGR2):c.1141C>T (p.Arg381Cys)	EGR2	Pathogenic	criteria provided, multiple submitters, no conflicts
1422578	NM_000399.5(EGR2):c.1075C>G (p.Arg359Gly)	EGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
16749	NM_000399.5(EGR2):c.803T>A (p.Ile268Asn)	EGR2	Conflicting classifications of pathogenicity	no assertion criteria provided
1684711	NM_000399.5(EGR2):c.1064A>G (p.Asp355Gly)	EGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2431049	NM_000399.5(EGR2):c.1190C>A (p.Pro397His)	EGR2	Conflicting classifications of pathogenicity	no assertion criteria provided
246013	NM_000399.5(EGR2):c.644C>T (p.Thr215Met)	EGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246186	NM_000399.5(EGR2):c.192G>C (p.Met64Ile)	EGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
300276	NM_000399.5(EGR2):c.924C>T (p.Ala308=)	EGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
300277	NM_000399.5(EGR2):c.918C>T (p.Ala306=)	EGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
462785	NM_000399.5(EGR2):c.457A>C (p.Thr153Pro)	EGR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1476279	NM_000399.5(EGR2):c.770G>A (p.Arg257Gln)	EGR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2580933	NM_000399.5(EGR2):c.524C>A (p.Ser175Tyr)	EGR2	Uncertain significance	criteria provided, single submitter
300265	NM_000399.5(EGR2):c.*919G>C	EGR2	Uncertain significance	criteria provided, single submitter
300268	NM_000399.5(EGR2):c.*655G>A	EGR2	Uncertain significance	criteria provided, single submitter
300269	NM_000399.5(EGR2):c.*646C>T	EGR2	Uncertain significance	criteria provided, single submitter
300270	NM_000399.5(EGR2):c.*456G>A	EGR2	Uncertain significance	criteria provided, single submitter
300274	NM_000399.5(EGR2):c.*145T>A	EGR2	Uncertain significance	criteria provided, single submitter
300275	NM_000399.5(EGR2):c.1360T>G (p.Cys454Gly)	EGR2	Uncertain significance	criteria provided, single submitter
300278	NM_000399.5(EGR2):c.541C>T (p.Leu181Phe)	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
41009	NM_000399.5(EGR2):c.1160C>A (p.Thr387Asn)	EGR2	Uncertain significance	criteria provided, single submitter
548617	NM_000399.5(EGR2):c.1084C>T (p.Arg362Ter)	EGR2	Uncertain significance	criteria provided, single submitter
637521	NM_000399.5(EGR2):c.1064A>T (p.Asp355Val)	EGR2	Uncertain significance	no assertion criteria provided
637522	NM_000399.5(EGR2):c.1147G>C (p.Asp383His)	EGR2	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 3 · 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

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
EGR2	HGNC:3239	ENSG00000122877	P11161	E3 SUMO-protein ligase EGR2	gencc,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.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EGR2	Transcription factor	no		Znf_C2H2_type, EGR_N, Znf_C2H2_sf

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
gall bladder	1
granulocyte	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EGR2	143	ubiquitous	marker	gall bladder, tibial nerve, granulocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EGR2	3,269

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EGR2	P11161	49.02

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	368.4×	0.007	EGR2
NGF-stimulated transcription	1	285.5×	0.007	EGR2
Transcriptional regulation of white adipocyte differentiation	1	129.8×	0.010	EGR2
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	91.4×	0.011	EGR2

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
rhombomere 3 structural organization	1	16852.0×	4e-04	EGR2
rhombomere 3 formation	1	16852.0×	4e-04	EGR2
rhombomere 5 structural organization	1	16852.0×	4e-04	EGR2
rhombomere 5 formation	1	16852.0×	4e-04	EGR2
rhythmic behavior	1	8426.0×	5e-04	EGR2
positive regulation of Schwann cell differentiation	1	8426.0×	5e-04	EGR2
brain segmentation	1	5617.3×	6e-04	EGR2
Schwann cell differentiation	1	2407.4×	0.001	EGR2
facial nerve structural organization	1	1872.4×	0.001	EGR2
regulation of ossification	1	1203.7×	0.002	EGR2
positive regulation of myelination	1	766.0×	0.003	EGR2
motor neuron axon guidance	1	702.2×	0.003	EGR2
peripheral nervous system development	1	581.1×	0.003	EGR2
aorta development	1	561.7×	0.003	EGR2
protein export from nucleus	1	510.7×	0.003	EGR2
skeletal muscle cell differentiation	1	343.9×	0.004	EGR2
protein sumoylation	1	324.1×	0.004	EGR2
myelination	1	251.5×	0.005	EGR2
fat cell differentiation	1	181.2×	0.007	EGR2
gene expression	1	79.9×	0.014	EGR2
brain development	1	79.5×	0.014	EGR2
positive regulation of DNA-templated transcription	1	27.9×	0.039	EGR2
positive regulation of transcription by RNA polymerase II	1	14.9×	0.070	EGR2
regulation of transcription by RNA polymerase II	1	11.7×	0.086	EGR2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	EGR2

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)
EGR2	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