Charcot-Marie-Tooth disease X-linked dominant 6

Summary

Charcot-Marie-Tooth disease X-linked dominant 6 (MONDO:0010479) is a disease caused by PDK3 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PDK3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 197
• Phenotypes (HPO): 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000762	Decreased nerve conduction velocity	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001761	Pes cavus	Very frequent (80-99%)
HP:0002378	Hand tremor	Very frequent (80-99%)
HP:0002936	Distal sensory impairment	Very frequent (80-99%)
HP:0003438	Absent Achilles reflex	Very frequent (80-99%)
HP:0003482	EMG: axonal abnormality	Very frequent (80-99%)
HP:0007141	Sensorimotor neuropathy	Very frequent (80-99%)
HP:0007340	Lower limb muscle weakness	Very frequent (80-99%)
HP:0008944	Distal lower limb amyotrophy	Very frequent (80-99%)
HP:0002166	Impaired vibration sensation in the lower limbs	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003376	Steppage gait	Frequent (30-79%)
HP:0003393	Thenar muscle atrophy	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease X-linked dominant 6
Mondo ID	MONDO:0010479
OMIM	300905
Orphanet	352675
DOID	DOID:0110207
SNOMED CT	763347000
UMLS	C3806702
MedGen	813032
GARD	0012445
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease X-linked dominant type 6 · Charcot-Marie-Tooth disease, X-linked dominant, 6 · Charcot-Marie-Tooth disease, X-linked dominant, 6, X-linked dominant · Charcot-Marie-Tooth disease, X-linked dominant, type 6 · CMT6X · CMTX6 · X-linked Charcot-Marie-Tooth disease type 6

Data availability: 197 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › Charcot-Marie-Tooth disease type X › Charcot-Marie-Tooth disease X-linked dominant 6

Related subtypes (5): Charcot-Marie-Tooth disease X-linked dominant 1, Charcot-Marie-Tooth disease X-linked recessive 2, Charcot-Marie-Tooth disease X-linked recessive 3, Charcot-Marie-Tooth disease X-linked recessive 4, Charcot-Marie-Tooth disease X-linked recessive 5

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

197 retrieved; paginated sample, class counts are floors:

93 uncertain significance, 73 likely benign, 15 benign, 10 conflicting classifications of pathogenicity, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1164540	NM_005391.5(PDK3):c.523G>A (p.Asp175Asn)	PDK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1600516	NM_005391.5(PDK3):c.671A>G (p.Asn224Ser)	PDK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1979912	NM_005391.5(PDK3):c.42G>C (p.Lys14Asn)	PDK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2501167	NM_005391.5(PDK3):c.249-15T>C	PDK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3210967	NM_005391.5(PDK3):c.680C>T (p.Ala227Val)	PDK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
382040	NM_005391.5(PDK3):c.376A>G (p.Met126Val)	PDK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
60682	NM_005391.5(PDK3):c.473G>A (p.Arg158His)	PDK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
618265	NM_005391.5(PDK3):c.304C>T (p.Pro102Ser)	PDK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
697832	NM_005391.5(PDK3):c.341A>C (p.Lys114Thr)	PDK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
810537	NM_005391.5(PDK3):c.485G>A (p.Arg162His)	PDK3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
541117	NC_000023.10:g.(?24483553)(24557301_?)dup	LOC130068067	Uncertain significance	criteria provided, single submitter
1022450	NM_005391.5(PDK3):c.1148C>T (p.Thr383Met)	PDK3	Uncertain significance	criteria provided, single submitter
1024498	NM_005391.5(PDK3):c.595+3A>G	PDK3	Uncertain significance	criteria provided, single submitter
1034744	NM_005391.5(PDK3):c.577G>A (p.Val193Met)	PDK3	Uncertain significance	criteria provided, single submitter
1036293	NM_005391.5(PDK3):c.1211C>T (p.Ala404Val)	PDK3	Uncertain significance	criteria provided, single submitter
1045059	NM_005391.5(PDK3):c.1205A>G (p.Tyr402Cys)	PDK3	Uncertain significance	criteria provided, single submitter
1046094	NM_005391.5(PDK3):c.505+3A>T	PDK3	Uncertain significance	criteria provided, single submitter
1063907	NM_005391.5(PDK3):c.1028A>C (p.Lys343Thr)	PDK3	Uncertain significance	criteria provided, single submitter
1313041	NM_005391.5(PDK3):c.335T>C (p.Leu112Pro)	PDK3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1346997	NM_005391.5(PDK3):c.577G>C (p.Val193Leu)	PDK3	Uncertain significance	criteria provided, single submitter
1373654	NC_000023.10:g.(?24483573)(24557281_?)del	PDK3	Uncertain significance	criteria provided, single submitter
1373655	NC_000023.10:g.(?24483573)(24483698_?)del	PDK3	Uncertain significance	criteria provided, single submitter
1375083	NM_005391.5(PDK3):c.707A>G (p.Tyr236Cys)	PDK3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1377962	NM_005391.5(PDK3):c.1218dup (p.Ter407ValextTer?)	PDK3	Uncertain significance	criteria provided, single submitter
1399657	NC_000023.10:g.(?24512849)(24537137_?)dup	PDK3	Uncertain significance	criteria provided, single submitter
1402804	NM_005391.5(PDK3):c.338T>C (p.Ile113Thr)	PDK3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1403008	NM_005391.5(PDK3):c.427A>G (p.Ile143Val)	PDK3	Uncertain significance	criteria provided, single submitter
1410075	NM_005391.5(PDK3):c.203C>T (p.Pro68Leu)	PDK3	Uncertain significance	criteria provided, single submitter
1416191	NM_005391.5(PDK3):c.820G>A (p.Val274Ile)	PDK3	Uncertain significance	criteria provided, single submitter
1416871	NM_005391.5(PDK3):c.49G>C (p.Glu17Gln)	PDK3	Uncertain significance	criteria provided, single submitter

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
PDK3	Strong	X-linked	Charcot-Marie-Tooth disease X-linked dominant 6	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDK3	Orphanet:352675	X-linked Charcot-Marie-Tooth disease type 6

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
PDK3	HGNC:8811	ENSG00000067992	Q15120	[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 3, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PDK3	[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 3, mitochondrial	Inhibits pyruvate dehydrogenase activity by phosphorylation of the E1 subunit PDHA1, and thereby regulates glucose metabolism and aerobic respiration.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PDK3	Kinase	yes	2.7.11.2	HATPase_dom, His_kinase_dom, BCDHK/PDK_N

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
Brodmann (1909) area 23	1
corpus epididymis	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PDK3	269	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, corpus epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDK3	3,427

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDK3	Q15120	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Regulation of pyruvate dehydrogenase (PDH) complex	1	713.8×	0.002	PDK3
Signaling by Retinoic Acid	1	407.9×	0.002	PDK3

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
hypoxia-inducible factor-1alpha signaling pathway	1	4213.0×	0.001	PDK3
regulation of pyruvate decarboxylation to acetyl-CoA	1	2808.7×	0.001	PDK3
peroxisome proliferator activated receptor signaling pathway	1	1532.0×	0.002	PDK3
regulation of reactive oxygen species metabolic process	1	732.7×	0.002	PDK3
cellular response to fatty acid	1	702.2×	0.002	PDK3
regulation of glucose metabolic process	1	561.7×	0.002	PDK3
peptidyl-serine phosphorylation	1	495.6×	0.002	PDK3
cellular response to glucose stimulus	1	267.5×	0.004	PDK3

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
PDK3	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
PDK3	53	Binding:52, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PDK3	2.7.11.2	[pyruvate dehydrogenase (acetyl-transferring)] kinase

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	1	PDK3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
PDK3	53	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.