Charcot-Marie-Tooth disease type 4H

Summary

Charcot-Marie-Tooth disease type 4H (MONDO:0012250) is a disease caused by FGD4 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FGD4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 217
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 4H
Mondo ID	MONDO:0012250
MeSH	C563740
OMIM	609311
Orphanet	99954
DOID	DOID:0110192
ICD-11	214411126
SNOMED CT	715802008
UMLS	C1836336
MedGen	324487
GARD	0012442
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease type 4 caused by mutation in FGD4 · Charcot-Marie-Tooth disease type 4H · Charcot-Marie-Tooth disease, type 4H · CMT4H · FGD4 Charcot-Marie-Tooth disease type 4

Data availability: 217 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 4 › Charcot-Marie-Tooth disease type 4H

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 4E, Charcot-Marie-Tooth disease type 4G, 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

217 retrieved; paginated sample, class counts are floors:

115 uncertain significance, 44 benign, 19 conflicting classifications of pathogenicity, 13 likely benign, 11 benign/likely benign, 9 pathogenic, 3 likely pathogenic, 2 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1011	NM_001370298.3(FGD4):c.1081C>T (p.Arg361Ter)	FGD4	Pathogenic	criteria provided, multiple submitters, no conflicts
1016	NM_001370298.3(FGD4):c.1234C>T (p.Arg412Ter)	FGD4	Pathogenic	criteria provided, single submitter
1184559	NM_001370298.3(FGD4):c.1097_1101del (p.Asp366fs)	FGD4	Pathogenic	criteria provided, single submitter
1445638	NM_001370298.3(FGD4):c.1930C>T (p.Gln644Ter)	FGD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279806	NM_001370298.3(FGD4):c.1740C>A (p.Tyr580Ter)	FGD4	Pathogenic	criteria provided, multiple submitters, no conflicts
38445	NM_001370298.3(FGD4):c.1304T>G (p.Met435Arg)	FGD4	Pathogenic	criteria provided, single submitter
419181	NM_001370298.3(FGD4):c.2298_2302del (p.Lys767fs)	FGD4	Pathogenic	criteria provided, multiple submitters, no conflicts
447322	NM_001370298.3(FGD4):c.1363_1364del (p.Glu455fs)	FGD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4688917	NC_000012.11:g.(32778003_32778587)_(32778714_32786482)del	FGD4	Pathogenic	criteria provided, single submitter
598938	NM_001370298.3(FGD4):c.925del (p.Ala309fs)	FGD4	Pathogenic	no assertion criteria provided
598939	NM_001370298.3(FGD4):c.2622dup (p.Ala875fs)	FGD4	Pathogenic	no assertion criteria provided
1895449	NM_001370298.3(FGD4):c.1573dup (p.Ser525fs)	FGD4	Likely pathogenic	criteria provided, single submitter
4279590	NM_001370298.3(FGD4):c.2123del (p.Pro708fs)	FGD4	Likely pathogenic	criteria provided, single submitter
598942	GRCh37/hg19 12p11.21(chr12:32717818-32778686)x4	FGD4	Likely pathogenic	no assertion criteria provided
1013	NM_001370298.3(FGD4):c.2039_2040del (p.Glu680fs)	FGD4	Conflicting classifications of pathogenicity	no assertion criteria provided
1014	NM_001370298.3(FGD4):c.2167G>T (p.Gly723Ter)	FGD4	Conflicting classifications of pathogenicity	no assertion criteria provided
1015	NM_001370298.3(FGD4):c.1304T>C (p.Met435Thr)	FGD4	Conflicting classifications of pathogenicity	no assertion criteria provided
1017	NM_001370298.3(FGD4):c.2173-2A>G	FGD4	Conflicting classifications of pathogenicity	no assertion criteria provided
188187	NM_001370298.3(FGD4):c.1777C>A (p.Pro593Thr)	FGD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
188373	NM_001370298.3(FGD4):c.2560G>A (p.Val854Met)	FGD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215968	NM_001370298.3(FGD4):c.666A>T (p.Ala222=)	FGD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242314	NM_001370298.3(FGD4):c.740T>C (p.Leu247Pro)	FGD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245601	NM_001370298.3(FGD4):c.890G>A (p.Gly297Asp)	FGD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308282	NM_001370298.3(FGD4):c.167-61790C>T	FGD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308284	NM_001370298.3(FGD4):c.376C>A (p.Pro126Thr)	FGD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308290	NM_001370298.3(FGD4):c.1263A>G (p.Arg421=)	FGD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308295	NM_001370298.3(FGD4):c.1543+13T>C	FGD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
543490	NM_001370298.3(FGD4):c.1046A>G (p.Asn349Ser)	FGD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
658814	NM_001370298.3(FGD4):c.2506A>G (p.Met836Val)	FGD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
697392	NM_001370298.3(FGD4):c.785C>T (p.Thr262Met)	FGD4	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
FGD4	Definitive	Autosomal recessive	Charcot-Marie-Tooth disease	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGD4	Orphanet:99954	Charcot-Marie-Tooth disease type 4H

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
FGD4	HGNC:19125	ENSG00000139132	Q96M96	FYVE, RhoGEF and PH domain-containing protein 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 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)
FGD4	Transcription factor	no		DH_dom, Znf_FYVE, PH_domain

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
calcaneal tendon	1
ileal mucosa	1
jejunal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGD4	252	ubiquitous	marker	jejunal mucosa, calcaneal tendon, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGD4	885

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FGD4	Q96M96	70.85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
NRAGE signals death through JNK	1	184.2×	0.011	FGD4
G alpha (12/13) signalling events	1	137.6×	0.011	FGD4
CDC42 GTPase cycle	1	72.3×	0.014	FGD4

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
filopodium assembly	1	648.1×	0.006	FGD4
regulation of GTPase activity	1	510.7×	0.006	FGD4
regulation of small GTPase mediated signal transduction	1	144.0×	0.010	FGD4
cytoskeleton organization	1	132.7×	0.010	FGD4
regulation of cell shape	1	123.0×	0.010	FGD4
actin cytoskeleton organization	1	79.1×	0.013	FGD4

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
FGD4	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	FGD4

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)
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