Charcot-Marie-Tooth disease type 4F

Summary

Charcot-Marie-Tooth disease type 4F (MONDO:0013959) is a disease caused by PRX (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: PRX (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 180
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 4F
Mondo ID	MONDO:0013959
OMIM	614895
Orphanet	99952
DOID	DOID:0110193
ICD-11	330503211
SNOMED CT	715801001
UMLS	C3540453
MedGen	761704
GARD	0012441
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease type 4 caused by mutation in PRX · Charcot-Marie-Tooth disease type 4 caused by mutation in Prx · Charcot-Marie-Tooth disease, demyelinating, type 4F · Charcot-Marie-Tooth disease, type 4F · CMT4F · PRX Charcot-Marie-Tooth disease type 4 · Prx Charcot-Marie-Tooth disease type 4

Data availability: 180 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 4F

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 4H, Charcot-Marie-Tooth disease type 4J, 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

180 retrieved; paginated sample, class counts are floors:

76 uncertain significance, 51 conflicting classifications of pathogenicity, 15 benign/likely benign, 12 benign, 11 pathogenic, 8 pathogenic/likely pathogenic, 4 likely pathogenic, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1324966	NM_181882.3(PRX):c.2581del (p.Leu861fs)	PRX	Pathogenic	criteria provided, single submitter
1687279	NM_181882.3(PRX):c.3098del (p.Thr1033fs)	PRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208606	NM_181882.3(PRX):c.2289del (p.Asp765fs)	PRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4787	NM_181882.3(PRX):c.2857C>T (p.Arg953Ter)	PRX	Pathogenic	criteria provided, multiple submitters, no conflicts
4789	NM_181882.3(PRX):c.1102C>T (p.Arg368Ter)	PRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4791	NM_181882.3(PRX):c.586C>T (p.Arg196Ter)	PRX	Pathogenic	criteria provided, multiple submitters, no conflicts
4792	NM_181882.3(PRX):c.2145T>A (p.Cys715Ter)	PRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4794	NM_181882.3(PRX):c.3208C>T (p.Arg1070Ter)	PRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
543308	NM_181882.3(PRX):c.3014_3015insT (p.Lys1006fs)	PRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
549686	NM_181882.3(PRX):c.3703G>T (p.Glu1235Ter)	PRX	Pathogenic	no assertion criteria provided
580375	NM_181882.3(PRX):c.1390C>T (p.Arg464Ter)	PRX	Pathogenic	criteria provided, multiple submitters, no conflicts
634532	NM_181882.3(PRX):c.979del (p.Asp327fs)	PRX	Pathogenic	criteria provided, single submitter
637398	NM_181882.3(PRX):c.1090C>T (p.Arg364Ter)	PRX	Pathogenic	criteria provided, multiple submitters, no conflicts
637400	NM_181882.3(PRX):c.116_117del (p.Lys39fs)	PRX	Pathogenic	criteria provided, single submitter
646421	NM_181882.3(PRX):c.2689C>T (p.Arg897Ter)	PRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
653288	NM_181882.3(PRX):c.627del (p.Ala210fs)	PRX	Pathogenic	criteria provided, multiple submitters, no conflicts
803559	NM_181882.3(PRX):c.3379A>T (p.Lys1127Ter)	PRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
810637	NM_181882.3(PRX):c.27+1G>T	PRX	Pathogenic	criteria provided, single submitter
958213	NM_181882.3(PRX):c.231C>A (p.Tyr77Ter)	PRX	Pathogenic	criteria provided, multiple submitters, no conflicts
1029317	NM_181882.3(PRX):c.2719C>T (p.Gln907Ter)	PRX	Likely pathogenic	criteria provided, single submitter
4073444	NM_181882.3(PRX):c.985del (p.Ala329fs)	PRX	Likely pathogenic	no assertion criteria provided
800938	NM_181882.3(PRX):c.3085A>T (p.Arg1029Ter)	PRX	Likely pathogenic	no assertion criteria provided
930783	NM_181882.3(PRX):c.1561C>T (p.Gln521Ter)	PRX	Likely pathogenic	criteria provided, single submitter
329292	NM_181882.3(PRX):c.-114T>G	LOC130064456	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216834	NM_181882.3(PRX):c.2254G>A (p.Glu752Lys)	PRX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216835	NM_181882.3(PRX):c.3496C>T (p.Pro1166Ser)	PRX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216836	NM_181882.3(PRX):c.823C>A (p.Leu275Ile)	PRX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
220724	NM_181882.3(PRX):c.1216G>A (p.Ala406Thr)	PRX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242179	NM_181882.3(PRX):c.1574T>C (p.Val525Ala)	PRX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245663	NM_181882.3(PRX):c.3373G>A (p.Gly1125Ser)	PRX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 2 · 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
PRDX6	Definitive	Autosomal recessive	Charcot-Marie-Tooth disease type 4	7
PRX	Definitive	Autosomal recessive	Charcot-Marie-Tooth disease type 4	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRX	Orphanet:64748	Dejerine-Sottas syndrome
PRX	Orphanet:99952	Charcot-Marie-Tooth disease type 4F

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRX	HGNC:13797	ENSG00000105227	Q9BXM0	Periaxin	gencc,clinvar
PRDX6	HGNC:16753	ENSG00000117592	P30041	Peroxiredoxin-6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRX	Periaxin	Scaffolding protein that functions as part of a dystroglycan complex in Schwann cells, and as part of EZR and AHNAK-containing complexes in eye lens fiber cells.
PRDX6	Peroxiredoxin-6	Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Scaffold/PPI	1	8.6×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRX	Scaffold/PPI	no		PDZ, PDZ_sf, Myelin_sheath_structural
PRDX6	Enzyme (other)	yes	1.11.1.27	AhpC/TSA, Thioredoxin_domain, Peroxiredoxin_C

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
olfactory bulb	1
sural nerve	1
trigeminal ganglion	1
corpus epididymis	1
gastrocnemius	1
mucosa of stomach	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRX	258	ubiquitous	marker	olfactory bulb, trigeminal ganglion, sural nerve
PRDX6	295	ubiquitous	marker	corpus epididymis, gastrocnemius, mucosa of stomach

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRDX6	4,106
PRX	1,569

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRDX6	P30041	3
PRX	Q9BXM0	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (2 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 2 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	184.2×	0.010	PRX
Detoxification of Reactive Oxygen Species	1	150.3×	0.010	PRDX6
Neutrophil degranulation	1	11.5×	0.085	PRDX6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
axon ensheathment	1	1404.3×	0.004	PRX
cellular oxidant detoxification	1	936.2×	0.004	PRDX6
peripheral nervous system myelin maintenance	1	766.0×	0.004	PRX
glycerophospholipid catabolic process	1	526.6×	0.004	PRDX6
hydrogen peroxide catabolic process	1	337.0×	0.005	PRDX6
positive regulation of mRNA splicing, via spliceosome	1	271.8×	0.006	PRDX6
cell redox homeostasis	1	172.0×	0.007	PRDX6
regulation of RNA splicing	1	109.4×	0.010	PRX
response to oxidative stress	1	65.3×	0.015	PRDX6

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRX	0	0
PRDX6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PRDX6	15	Binding:15

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRDX6	1.11.1.27, 2.3.1.23, 3.1.1.4	glutathione-dependent peroxiredoxin, 1-acylglycerophosphocholine O-acyltransferase, phospholipase A2

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	PRDX6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PRX

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PRX	0	—
PRDX6	15	—

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