Charcot-Marie-Tooth disease dominant intermediate E
disease diseaseOn this page
Also known as autosomal dominant intermediate Charcot-Marie-Tooth disease type ECharcot-Marie-Tooth disease - nephropathyCharcot-Marie-Tooth disease dominant intermediate type ECharcot-Marie-Tooth disease, dominant intermediate ECharcot-Marie-Tooth disease, dominant Intermediate type ECharcot-Marie-Tooth disease-nephropathy syndromeCharcot-Marie-Tooth neuropathy with focal segmental glomerulonephritisCMTDIE
Summary
Charcot-Marie-Tooth disease dominant intermediate E (MONDO:0013758) is a disease caused by INF2 (GenCC Definitive), with 2 cohort genes.
At a glance
- Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
- Causal gene: INF2 (GenCC Definitive)
- Cohort genes: 2
- ClinVar variants: 1,498
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 |
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | Charcot-Marie-Tooth disease dominant intermediate E |
| Mondo ID | MONDO:0013758 |
| OMIM | 614455 |
| Orphanet | 93114 |
| DOID | DOID:0110205 |
| SNOMED CT | 722294004 |
| UMLS | C4302667 |
| MedGen | 928336 |
| GARD | 0012011 |
| Is cancer (heuristic) | no |
Also known as: autosomal dominant intermediate Charcot-Marie-Tooth disease type E · Charcot-Marie-Tooth disease - nephropathy · Charcot-Marie-Tooth disease dominant intermediate E · Charcot-Marie-Tooth disease dominant intermediate type E · Charcot-Marie-Tooth disease, dominant intermediate E · Charcot-Marie-Tooth disease, dominant Intermediate type E · Charcot-Marie-Tooth disease-nephropathy syndrome · Charcot-Marie-Tooth neuropathy with focal segmental glomerulonephritis · CMTDIE
Data availability: 1,498 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 › autosomal genetic disease › autosomal dominant disease › autosomal dominant intermediate Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease dominant intermediate E
Related subtypes (7): Charcot-Marie-Tooth disease dominant intermediate B, Charcot-Marie-Tooth Disease, axonal, type 2GG, Charcot-Marie-Tooth disease dominant intermediate D, Charcot-Marie-Tooth disease dominant intermediate C, Charcot-Marie-Tooth disease dominant intermediate F, autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain, Charcot-Marie-Tooth disease, dominant intermediate A
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:
294 likely benign, 188 uncertain significance, 59 conflicting classifications of pathogenicity, 32 benign, 18 benign/likely benign, 5 likely pathogenic, 4 pathogenic/likely pathogenic
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 1051 | NM_022489.4(INF2):c.653G>A (p.Arg218Gln) | INF2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1052 | NM_022489.4(INF2):c.652C>T (p.Arg218Trp) | INF2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1053 | NM_022489.4(INF2):c.641G>A (p.Arg214His) | INF2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1999164 | NM_022489.4(INF2):c.218G>A (p.Gly73Asp) | INF2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1179196 | NM_022489.4(INF2):c.1735+1G>A | INF2 | Likely pathogenic | criteria provided, single submitter |
| 1184454 | NM_022489.4(INF2):c.485T>C (p.Leu162Pro) | INF2 | Likely pathogenic | criteria provided, single submitter |
| 1518638 | NM_022489.4(INF2):c.470G>A (p.Gly157Asp) | INF2 | Likely pathogenic | criteria provided, single submitter |
| 1697256 | NM_022489.4(INF2):c.605A>G (p.Asn202Ser) | INF2 | Likely pathogenic | criteria provided, single submitter |
| 2574145 | NM_022489.4(INF2):c.286del (p.Leu96fs) | INF2 | Likely pathogenic | criteria provided, single submitter |
| 1003777 | NM_022489.4(INF2):c.509C>T (p.Thr170Met) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1009065 | NM_022489.4(INF2):c.2602C>T (p.Arg868Cys) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1014934 | NM_022489.4(INF2):c.695G>A (p.Arg232His) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1019747 | NM_022489.4(INF2):c.1262CACCCC[1] (p.Pro423_Pro428del) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1021555 | NM_022489.4(INF2):c.359G>A (p.Ser120Asn) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1024088 | NM_022489.4(INF2):c.2101G>A (p.Ala701Thr) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1040453 | NM_022489.4(INF2):c.3209G>A (p.Arg1070Gln) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1041727 | NM_022489.4(INF2):c.3257T>C (p.Leu1086Pro) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1112132 | NM_022489.4(INF2):c.636C>T (p.Arg212=) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1128266 | NM_022489.4(INF2):c.2776-5T>C | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1137635 | NM_022489.4(INF2):c.1458C>T (p.Phe486=) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1201695 | NM_022489.4(INF2):c.1615G>A (p.Val539Met) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1303866 | NM_022489.4(INF2):c.1316C>T (p.Pro439Leu) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1312229 | NM_022489.4(INF2):c.3611C>T (p.Ser1204Leu) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1315296 | NM_022489.4(INF2):c.1774G>A (p.Ala592Thr) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1330811 | NM_022489.4(INF2):c.1979G>A (p.Arg660Gln) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1386847 | NM_022489.4(INF2):c.2254C>T (p.Arg752Cys) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1393855 | NM_022489.4(INF2):c.1792G>A (p.Asp598Asn) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1414577 | NM_022489.4(INF2):c.2843A>C (p.Glu948Ala) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1423962 | NM_022489.4(INF2):c.1097A>G (p.Gln366Arg) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1428952 | NM_022489.4(INF2):c.685G>A (p.Val229Ile) | INF2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 7 · 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 |
|---|---|---|---|---|
| INF2 | Definitive | Autosomal dominant | Charcot-Marie-Tooth disease dominant intermediate E | 7 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| INF2 | Orphanet:656 | Hereditary steroid-resistant nephrotic syndrome |
| INF2 | Orphanet:93114 | Autosomal dominant intermediate Charcot-Marie-Tooth disease type E |
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 |
|---|---|---|---|---|---|
| INF2 | HGNC:23791 | ENSG00000203485 | Q27J81 | Inverted formin-2 | gencc,clinvar |
| PLD4 | HGNC:23792 | ENSG00000166428 | Q96BZ4 | 5’-3’ exonuclease PLD4 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| INF2 | Inverted formin-2 | Severs actin filaments and accelerates their polymerization and depolymerization. |
| PLD4 | 5’-3’ exonuclease PLD4 | 5’->3’ exonuclease that hydrolyzes the phosphodiester bond of single-stranded DNA (ssDNA) and RNA molecules to form nucleoside 3’-monophosphates and 5’-end 5’-hydroxy deoxyribonucleotide/ribonucleotide fragments. |
Protein-family classification
Druggable: 0 · Difficult: 0 · Unknown: 2 · 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 |
|---|---|---|---|
| Other/Unknown | 2 | 1.8× | 0.312 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| INF2 | Other/Unknown | no | WH2_dom, FH3_dom, GTPase-bd | |
| PLD4 | Other/Unknown | no | PLipase_D/transphosphatidylase, PLDc_3, Diverse_PLD-related |
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 |
|---|---|
| nerve | 1 |
| sural nerve | 1 |
| tibial nerve | 1 |
| granulocyte | 1 |
| leukocyte | 1 |
| monocyte | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| INF2 | 260 | ubiquitous | marker | sural nerve, nerve, tibial nerve |
| PLD4 | 163 | broad | marker | granulocyte, leukocyte, monocyte |
Protein interactions among cohort
Intra-cohort edges: 0.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| INF2 | 2,070 |
| PLD4 | 1,054 |
Structural data
PDB: 2 · AlphaFold-only: 0 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| INF2 | Q27J81 | 10 |
| PLD4 | Q96BZ4 | 3 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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 |
|---|---|---|---|---|
| Synthesis of PG | 1 | 1268.9× | 0.002 | PLD4 |
| Role of phospholipids in phagocytosis | 1 | 456.8× | 0.002 | PLD4 |
| Synthesis of IP3 and IP4 in the cytosol | 1 | 423.0× | 0.002 | PLD4 |
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 |
|---|---|---|---|---|
| regulation of mitochondrial fission | 1 | 1053.2× | 0.005 | INF2 |
| regulation of cytokine production involved in inflammatory response | 1 | 936.2× | 0.005 | PLD4 |
| actin filament polymerization | 1 | 240.7× | 0.012 | INF2 |
| phagocytosis | 1 | 120.4× | 0.015 | PLD4 |
| hematopoietic progenitor cell differentiation | 1 | 118.7× | 0.015 | PLD4 |
| establishment of localization in cell | 1 | 80.2× | 0.019 | PLD4 |
| lipid metabolic process | 1 | 45.8× | 0.028 | PLD4 |
| inflammatory response | 1 | 18.9× | 0.059 | PLD4 |
| innate immune response | 1 | 16.8× | 0.059 | PLD4 |
Therapeutics
Drug target analysis
Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2
Druggability breadth: 2 of 2 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 |
|---|---|---|
| INF2 | 0 | 0 |
| PLD4 | 0 | 0 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 0.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| PLD4 | 10 | Binding:10 |
| INF2 | 1 | Binding:1 |
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 | 0 | |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 2 | INF2, PLD4 |
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) |
|---|---|---|
| INF2 | 1 | — |
| PLD4 | 10 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.