Charcot-Marie-Tooth disease axonal type 2Z

Summary

Charcot-Marie-Tooth disease axonal type 2Z (MONDO:0014736) is a disease caused by MORC2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MORC2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 848
• Phenotypes (HPO): 72

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		21	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

72 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001315	Reduced tendon reflexes	Very frequent (80-99%)
HP:0002460	Distal muscle weakness	Very frequent (80-99%)
HP:0003390	Sensory axonal neuropathy	Very frequent (80-99%)
HP:0007210	Lower limb amyotrophy	Very frequent (80-99%)
HP:0007327	Mixed demyelinating and axonal polyneuropathy	Very frequent (80-99%)
HP:0008944	Distal lower limb amyotrophy	Very frequent (80-99%)
HP:0009053	Distal lower limb muscle weakness	Very frequent (80-99%)
HP:0100290	Abnormality of peripheral somatosensory evoked potentials	Very frequent (80-99%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0002493	Upper motor neuron dysfunction	Frequent (30-79%)
HP:0002495	Impaired vibratory sensation	Frequent (30-79%)
HP:0003130	Abnormal peripheral myelination	Frequent (30-79%)
HP:0003474	Somatic sensory dysfunction	Frequent (30-79%)
HP:0003484	Upper limb muscle weakness	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0004302	Functional motor deficit	Frequent (30-79%)
HP:0007002	Motor axonal neuropathy	Frequent (30-79%)
HP:0007230	Decreased distal sensory nerve action potential	Frequent (30-79%)
HP:0008948	Proximal upper limb amyotrophy	Frequent (30-79%)
HP:0009046	Difficulty running	Frequent (30-79%)
HP:0009129	Upper limb amyotrophy	Frequent (30-79%)
HP:0009473	Joint contracture of the hand	Frequent (30-79%)
HP:0010830	Impaired tactile sensation	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0012785	Flexion contracture of finger	Frequent (30-79%)
HP:0040131	Abnormal motor nerve conduction velocity	Frequent (30-79%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000467	Neck muscle weakness	Occasional (5-29%)
HP:0001047	Atopic dermatitis	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001620	Abnormally high-pitched voice	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002167	Abnormality of speech or vocalization	Occasional (5-29%)
HP:0002380	Fasciculations	Occasional (5-29%)
HP:0002411	Myokymia	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0003324	Generalized muscle weakness	Occasional (5-29%)
HP:0003325	Limb-girdle muscle weakness	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0003701	Proximal muscle weakness	Occasional (5-29%)
HP:0003797	Limb-girdle muscle atrophy	Occasional (5-29%)
HP:0005879	Congenital finger flexion contractures	Occasional (5-29%)
HP:0006827	Atrophy of the spinal cord	Occasional (5-29%)
HP:0006970	Periventricular leukomalacia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease axonal type 2Z
Mondo ID	MONDO:0014736
OMIM	616688
Orphanet	466768
DOID	DOID:0110181
UMLS	C5569025
MedGen	1800448
GARD	0017829
Is cancer (heuristic)	no

Also known as: autosomal dominant Charcot-Marie-Tooth disease type 2 due to MORC2 mutation · Charcot-Marie-Tooth disease caused by mutation in MORC2 · Charcot-Marie-Tooth disease, axonal, type 2z · CMT2Z · MORC2 Charcot-Marie-Tooth disease

Data availability: 848 ClinVar variants · 4 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 2Z

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 axonal type 2Q, 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 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

600 retrieved; paginated sample, class counts are floors:

299 likely benign, 264 uncertain significance, 11 benign, 8 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 5 pathogenic, 4 likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1415141	NM_001303256.3(MORC2):c.1270A>G (p.Thr424Ala)	MORC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2138437	NM_001303256.3(MORC2):c.1396G>A (p.Asp466Asn)	MORC2	Pathogenic	criteria provided, single submitter
218307	NM_001303256.3(MORC2):c.754C>T (p.Arg252Trp)	MORC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218308	NM_001303256.3(MORC2):c.260C>T (p.Ser87Leu)	MORC2	Pathogenic	criteria provided, multiple submitters, no conflicts
254251	NM_001303256.3(MORC2):c.707A>G (p.Glu236Gly)	MORC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2737036	NM_001303256.3(MORC2):c.1271C>G (p.Thr424Arg)	MORC2	Pathogenic	criteria provided, single submitter
3602082	NM_001303256.3(MORC2):c.1397A>G (p.Asp466Gly)	MORC2	Pathogenic	criteria provided, single submitter
3897854	NM_001303256.3(MORC2):c.755G>T (p.Arg252Leu)	MORC2	Pathogenic	criteria provided, single submitter
422103	NM_001303256.3(MORC2):c.394C>T (p.Arg132Cys)	MORC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
423564	NM_001303256.3(MORC2):c.798G>C (p.Arg266Ser)	MORC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
432089	NM_001303256.3(MORC2):c.1181A>G (p.Tyr394Cys)	MORC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1802195	NM_001303256.3(MORC2):c.3031G>A (p.Asp1011Asn)	MORC2	Likely pathogenic	criteria provided, single submitter
2810254	NM_001303256.3(MORC2):c.1271C>A (p.Thr424Lys)	MORC2	Likely pathogenic	criteria provided, single submitter
3256794	NM_001303256.3(MORC2):c.229G>C (p.Asp77His)	MORC2	Likely pathogenic	no assertion criteria provided
4687916	NM_001303256.3(MORC2):c.1219T>C (p.Cys407Arg)	MORC2	Likely pathogenic	criteria provided, single submitter
1007030	NM_001303256.3(MORC2):c.2270A>G (p.Glu757Gly)	MORC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1017541	NM_001303256.3(MORC2):c.905-3C>T	MORC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1350683	NM_001303256.3(MORC2):c.2072T>C (p.Leu691Pro)	MORC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1354348	NM_001303256.3(MORC2):c.1822C>T (p.Arg608Cys)	MORC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1477446	NM_001303256.3(MORC2):c.1280A>G (p.Lys427Arg)	MORC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1643373	NM_001303256.3(MORC2):c.598A>G (p.Ile200Val)	MORC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1708086	NM_001303256.3(MORC2):c.733G>A (p.Ala245Thr)	MORC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2970391	NM_001303256.3(MORC2):c.2134C>T (p.Pro712Ser)	MORC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001259	NM_001303256.3(MORC2):c.2171A>G (p.Glu724Gly)	MORC2	Uncertain significance	criteria provided, single submitter
1001538	NM_001303256.3(MORC2):c.2411A>G (p.Asn804Ser)	MORC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1001688	NM_001303256.3(MORC2):c.931A>G (p.Ser311Gly)	MORC2	Uncertain significance	criteria provided, single submitter
1001986	NM_001303256.3(MORC2):c.700A>G (p.Lys234Glu)	MORC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1005093	NM_001303256.3(MORC2):c.1346A>G (p.Gln449Arg)	MORC2	Uncertain significance	criteria provided, single submitter
1005422	NM_001303256.3(MORC2):c.1305G>T (p.Glu435Asp)	MORC2	Uncertain significance	criteria provided, single submitter
1006738	NM_001303256.3(MORC2):c.564T>G (p.Phe188Leu)	MORC2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
MORC2	Definitive	Autosomal dominant	Charcot-Marie-Tooth disease axonal type 2Z	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MORC2	Orphanet:466768	Autosomal dominant Charcot-Marie-Tooth disease type 2Z

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
MORC2	HGNC:23573	ENSG00000133422	Q9Y6X9	ATPase MORC2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MORC2	ATPase MORC2	ATP-dependent chromatin remodeler essential for epigenetic silencing by the HUSH (human silencing hub) complex.

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)
MORC2	Transcription factor	no		Znf_CW, HATPase_C_sf, Morc_S5

Expression context

Cohort genes with no expression data: 0.

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
cervix squamous epithelium	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MORC2	292	ubiquitous	yes	cervix squamous epithelium, sperm, male germ cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MORC2	1,187

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MORC2	Q9Y6X9	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Fatty acyl-CoA biosynthesis	1	439.2×	0.011	MORC2
Regulation of endogenous retroelements	1	368.4×	0.011	MORC2
Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex	1	163.1×	0.015	MORC2
Fatty acid metabolism	1	131.3×	0.015	MORC2
Epigenetic regulation of gene expression	1	71.4×	0.022	MORC2
Metabolism of lipids	1	31.6×	0.042	MORC2
Gene expression (Transcription)	1	17.8×	0.064	MORC2
Metabolism	1	11.6×	0.086	MORC2

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
constitutive heterochromatin formation	1	2407.4×	0.002	MORC2
transposable element silencing by heterochromatin formation	1	1404.3×	0.002	MORC2
fatty acid metabolic process	1	193.7×	0.009	MORC2
chromatin remodeling	1	73.0×	0.017	MORC2
DNA damage response	1	53.5×	0.019	MORC2

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
MORC2	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	MORC2

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)
MORC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.