Charcot-Marie-Tooth disease type 4K

Summary

Charcot-Marie-Tooth disease type 4K (MONDO:0014733) is a disease caused by SURF1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SURF1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 52

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 4K
Mondo ID	MONDO:0014733
OMIM	616684
Orphanet	391351
DOID	DOID:0110187
SNOMED CT	765047006
UMLS	C4225246
MedGen	895560
GARD	0017616
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease type 4 caused by mutation in SURF1 · Charcot-Marie-Tooth disease type 4K · Charcot-Marie-Tooth disease, type 4k · CMT4K · SURF1 Charcot-Marie-Tooth disease type 4 · SURF1-related Charcot-Marie-Tooth disease type 4 · SURF1-related CMT4 · SURF1-related severe demyelinating Charcot-Marie-Tooth disease

Data availability: 52 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › Charcot-Marie-Tooth disease type 4K

Related subtypes (47): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, autosomal dominant optic atrophy, classic form, Leigh syndrome, mitochondrial non-syndromic sensorineural hearing loss, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, NARP syndrome, deafness, aminoglycoside-induced, hereditary spastic paraplegia 7, spinocerebellar ataxia type 28, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, spastic ataxia 3, pontocerebellar hypoplasia type 6, autosomal recessive optic atrophy, OPA7 type, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, spastic ataxia 4, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome, hereditary spastic paraplegia 77, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, mitochondrial DNA depletion syndrome, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

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

52 retrieved; paginated sample, class counts are floors:

18 pathogenic/likely pathogenic, 17 pathogenic, 9 likely pathogenic, 4 uncertain significance, 3 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1182215	NM_003172.4(SURF1):c.367_368del (p.Arg123fs)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
12762	NM_003172.4(SURF1):c.751C>T (p.Gln251Ter)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
12770	NM_003172.4(SURF1):c.845_846del (p.Ser282fs)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1329011	NM_003172.4(SURF1):c.575G>A (p.Arg192Gln)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1413577	NM_003172.4(SURF1):c.632_642del (p.Glu211fs)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1416074	NM_003172.4(SURF1):c.552del (p.Lys185fs)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1939932	NM_003172.4(SURF1):c.769G>A (p.Gly257Arg)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2147072	NM_003172.4(SURF1):c.606_610dup (p.Ile204fs)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215235	NM_003172.4(SURF1):c.574C>T (p.Arg192Trp)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215237	NM_003172.4(SURF1):c.312_321delinsAT (p.Pro104_Leu105insTer)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
215238	NM_003172.4(SURF1):c.792_793del (p.Arg264fs)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
215241	NM_003172.4(SURF1):c.-11_13del (p.Met1_Ala5del)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2152654	NM_003172.4(SURF1):c.515+1del	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218301	NM_003172.4(SURF1):c.107-2A>G	SURF1	Pathogenic	criteria provided, single submitter
218303	NM_003172.4(SURF1):c.799_800del (p.Leu267fs)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2186243	NM_003172.4(SURF1):c.109dup	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
243077	NM_003172.4(SURF1):c.586C>T (p.Gln196Ter)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
2580921	NM_003172.4(SURF1):c.38_44del (p.Ala13fs)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2727846	NM_003172.4(SURF1):c.804del (p.Asn269fs)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2735360	NM_003172.4(SURF1):c.820_824dup (p.Val276fs)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2762239	NM_003172.4(SURF1):c.159_199dup (p.Leu67fs)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280010	NM_003172.4(SURF1):c.688C>T (p.Arg230Ter)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
2835305	NM_003172.4(SURF1):c.535dup (p.Arg179fs)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3007554	NM_003172.4(SURF1):c.533dup (p.Asn178fs)	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3375467	NM_003172.4(SURF1):c.312T>G (p.Pro104=)	SURF1	Pathogenic	criteria provided, single submitter
3596599	NM_003172.4(SURF1):c.751del (p.Gln251fs)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts
3596603	NM_003172.4(SURF1):c.169del (p.Glu57fs)	SURF1	Pathogenic	criteria provided, single submitter
3596604	NM_003172.4(SURF1):c.54+1G>T	SURF1	Pathogenic	criteria provided, single submitter
365526	NM_003172.4(SURF1):c.754_755del	SURF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372717	NM_003172.4(SURF1):c.758_759del (p.Thr253fs)	SURF1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
SURF1	Strong	Autosomal recessive	Charcot-Marie-Tooth disease type 4K	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SURF1	Orphanet:391351	SURF1-related Charcot-Marie-Tooth disease type 4

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
SURF1	HGNC:11474	ENSG00000148290	Q15526	Surfeit locus protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SURF1	Surfeit locus protein 1	Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SURF1	Other/Unknown	no		Surf1/Shy1, Surf1/Surf4

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
apex of heart	1
body of pancreas	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SURF1	183	ubiquitous	marker	apex of heart, body of pancreas, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SURF1	1,721

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SURF1	Q15526	82.62

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Complex IV assembly	1	228.4×	0.015	SURF1
Respiratory electron transport	1	95.2×	0.015	SURF1
Aerobic respiration and respiratory electron transport	1	88.5×	0.015	SURF1
Metabolism	1	11.6×	0.086	SURF1

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
respiratory chain complex IV assembly	1	2407.4×	0.001	SURF1
mitochondrial respiratory chain complex IV assembly	1	624.1×	0.002	SURF1
aerobic respiration	1	247.8×	0.004	SURF1

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
SURF1	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	SURF1

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)
SURF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.