Charcot-Marie-Tooth disease axonal type 2Q

Summary

Charcot-Marie-Tooth disease axonal type 2Q (MONDO:0014012) is a disease caused by DHTKD1 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DHTKD1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 36
• Clinical trials: 1

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

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease axonal type 2Q
Mondo ID	MONDO:0014012
OMIM	615025
Orphanet	329258
DOID	DOID:0110170
UMLS	C3554366
MedGen	767280
GARD	0012446
Is cancer (heuristic)	no

Also known as: autosomal dominant Charcot-Marie-Tooth disease type 2Q · Charcot-Marie-Tooth disease caused by mutation in DHTKD1 · Charcot-Marie-Tooth disease type 2Q · Charcot-Marie-Tooth disease, axonal, type 2Q · CMT2Q · DHTKD1 Charcot-Marie-Tooth disease

Data availability: 36 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 2 › Charcot-Marie-Tooth disease axonal type 2Q

Related subtypes (37): Charcot-Marie-Tooth disease type 2A1, Charcot-Marie-Tooth disease type 2B, Charcot-Marie-Tooth disease type 2D, Charcot-Marie-Tooth disease type 2B1, Charcot-Marie-Tooth disease type 2B2, Charcot-Marie-Tooth disease axonal type 2C, Charcot-Marie-Tooth disease axonal type 2F, Charcot-Marie-Tooth disease type 2I, Charcot-Marie-Tooth disease type 2E, Charcot-Marie-Tooth disease axonal type 2H, Charcot-Marie-Tooth disease type 2J, Charcot-Marie-Tooth disease axonal type 2K, Charcot-Marie-Tooth disease axonal type 2L, Charcot-Marie-Tooth disease type 2A2, giant axonal neuropathy 2, Charcot-Marie-Tooth disease axonal type 2N, Charcot-Marie-Tooth disease axonal type 2O, Charcot-Marie-Tooth disease axonal type 2P, Charcot-Marie-Tooth disease type 2R, Charcot-Marie-Tooth disease axonal type 2S, Charcot-Marie-Tooth disease axonal type 2U, Charcot-Marie-Tooth disease axonal type 2V, autosomal dominant Charcot-Marie-Tooth disease type 2W, Charcot-Marie-Tooth disease axonal type 2X, Charcot-Marie-Tooth disease type 2Y, Charcot-Marie-Tooth disease axonal type 2Z, Charcot-Marie-Tooth disease axonal type 2CC, autosomal dominant Charcot-Marie-Tooth disease type 2M, Charcot-Marie-Tooth disease type 2B5, autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation, autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation, autosomal dominant Charcot-Marie-Tooth disease type 2K, Charcot-Marie-Tooth disease, axonal, type 2EE, autosomal dominant charcot-marie-tooth disease type 2 due to DGAT2 mutation, Charcot-Marie-Tooth disease type 2T, MME-related autosomal dominant Charcot Marie Tooth disease type 2, Charcot-Marie-tooth disease, axonal, type 2DD

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

36 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 9 benign, 5 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 3 likely pathogenic, 1 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033496	NM_018706.7(DHTKD1):c.1363C>T (p.Arg455Ter)	DHTKD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339491	NM_018706.7(DHTKD1):c.1409del (p.Gly470fs)	DHTKD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39565	NM_018706.7(DHTKD1):c.1228C>T (p.Arg410Ter)	DHTKD1	Pathogenic	criteria provided, multiple submitters, no conflicts
467824	NM_018706.7(DHTKD1):c.1897-1G>A	DHTKD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523837	NM_018706.7(DHTKD1):c.1386T>G (p.Tyr462Ter)	DHTKD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
644977	NM_018706.7(DHTKD1):c.2457_2458del (p.Glu821fs)	DHTKD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3720923	NM_018706.7(DHTKD1):c.1671+1G>A	DHTKD1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
39566	NM_018706.7(DHTKD1):c.1455T>G (p.Tyr485Ter)	DHTKD1	Likely pathogenic	criteria provided, single submitter
617591	NM_018706.7(DHTKD1):c.1543C>A (p.Pro515Thr)	DHTKD1	Likely pathogenic	criteria provided, single submitter
216917	NM_018706.7(DHTKD1):c.2500C>T (p.Arg834Ter)	DHTKD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3065235	NM_018706.7(DHTKD1):c.2144G>A (p.Arg715His)	DHTKD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
574714	NM_018706.7(DHTKD1):c.1309G>T (p.Glu437Ter)	DHTKD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033500	NM_018706.7(DHTKD1):c.920C>T (p.Ser307Phe)	DHTKD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1053636	NM_018706.7(DHTKD1):c.847A>G (p.Met283Val)	DHTKD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1338993	NM_018706.7(DHTKD1):c.677G>A (p.Arg226Lys)	DHTKD1	Uncertain significance	criteria provided, single submitter
1339253	NM_018706.7(DHTKD1):c.1391A>G (p.Glu464Gly)	DHTKD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1348742	NM_018706.7(DHTKD1):c.2110G>T (p.Ala704Ser)	DHTKD1	Uncertain significance	criteria provided, single submitter
1895437	NM_018706.7(DHTKD1):c.2546A>T (p.Glu849Val)	DHTKD1	Uncertain significance	criteria provided, single submitter
2333439	NM_018706.7(DHTKD1):c.1114A>G (p.Thr372Ala)	DHTKD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3065789	NM_018706.7(DHTKD1):c.63G>T (p.Trp21Cys)	DHTKD1	Uncertain significance	criteria provided, single submitter
3896835	NM_018706.7(DHTKD1):c.1994T>C (p.Phe665Ser)	DHTKD1	Uncertain significance	criteria provided, single submitter
453262	NM_018706.7(DHTKD1):c.2744C>T (p.Ala915Val)	DHTKD1	Uncertain significance	no assertion criteria provided
548564	NM_018706.7(DHTKD1):c.1792C>T (p.Arg598Cys)	DHTKD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
585057	NM_018706.7(DHTKD1):c.2747A>G (p.Lys916Arg)	DHTKD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
915264	NM_018706.7(DHTKD1):c.2659del (p.Leu887fs)	DHTKD1	Uncertain significance	no assertion criteria provided
973472	NM_018706.7(DHTKD1):c.1118C>T (p.Pro373Leu)	DHTKD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1168371	NM_018706.7(DHTKD1):c.58T>C (p.Phe20Leu)	DHTKD1	Benign	criteria provided, multiple submitters, no conflicts
1168372	NM_018706.7(DHTKD1):c.814T>G (p.Tyr272Asp)	DHTKD1	Benign	criteria provided, multiple submitters, no conflicts
1170352	NM_018706.7(DHTKD1):c.1821C>G (p.Ile607Met)	DHTKD1	Benign	criteria provided, multiple submitters, no conflicts
1170353	NM_018706.7(DHTKD1):c.1911A>C (p.Pro637=)	DHTKD1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
DHTKD1	Strong	Autosomal dominant	Charcot-Marie-Tooth disease axonal type 2Q	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DHTKD1	Orphanet:329258	Autosomal dominant Charcot-Marie-Tooth disease type 2Q
DHTKD1	Orphanet:79154	2-aminoadipic 2-oxoadipic aciduria

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
DHTKD1	HGNC:23537	ENSG00000181192	Q96HY7	2-oxoadipate dehydrogenase complex component E1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DHTKD1	2-oxoadipate dehydrogenase complex component E1	2-oxoadipate dehydrogenase (E1a) component of the 2-oxoadipate dehydrogenase complex (OADHC).

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DHTKD1	Enzyme (other)	yes	1.2.1.105	DH_E1, Transketolase-like_Pyr-bd, 2oxoglutarate_DH_E1

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
liver	1
right lobe of liver	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DHTKD1	270	ubiquitous	marker	liver, right lobe of liver, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DHTKD1	2,099

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DHTKD1	Q96HY7	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
OADH complex synthesizes glutaryl-CoA from 2-OA	1	3806.7×	3e-04	DHTKD1

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
glycolytic process	1	383.0×	0.004	DHTKD1
generation of precursor metabolites and energy	1	343.9×	0.004	DHTKD1
hematopoietic progenitor cell differentiation	1	237.3×	0.004	DHTKD1

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
DHTKD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DHTKD1	1.2.1.105	2-oxoglutarate dehydrogenase system

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	DHTKD1
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)
DHTKD1	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