Cerebrooculofacioskeletal syndrome 4

Summary

Cerebrooculofacioskeletal syndrome 4 (MONDO:0012554) is a disease caused by ERCC1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ERCC1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebrooculofacioskeletal syndrome 4
Mondo ID	MONDO:0012554
MeSH	C565184
OMIM	610758
DOID	DOID:0080914
NCIT	C173104
UMLS	C1853100
MedGen	342798
GARD	0015498
Is cancer (heuristic)	no

Also known as: cerebrooculofacioskeletal syndrome 4 · cerebrooculofacioskeletal syndrome type 4 · COFS syndrome caused by mutation in ERCC1 · COFS4 · ERCC1 COFS syndrome

Data availability: 15 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › COFS syndrome › cerebrooculofacioskeletal syndrome 4

Related subtypes (4): cerebrooculofacioskeletal syndrome 1, xeroderma pigmentosum group G, cerebrooculofacioskeletal syndrome 2, cerebrooculofacioskeletal syndrome 3

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

15 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 3 pathogenic, 3 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1322828	NM_001983.4(ERCC1):c.121C>T (p.Arg41Ter)	ERCC1	Pathogenic	criteria provided, multiple submitters, no conflicts
16777	NM_001983.4(ERCC1):c.472C>T (p.Gln158Ter)	ERCC1	Pathogenic	no assertion criteria provided
16778	NM_001983.4(ERCC1):c.693C>G (p.Phe231Leu)	ERCC1	Pathogenic	no assertion criteria provided
1683582	NM_001983.4(ERCC1):c.231del (p.Thr78fs)	ERCC1	Likely pathogenic	criteria provided, single submitter
225348	NM_001983.4(ERCC1):c.184G>T (p.Glu62Ter)	ERCC1	Likely pathogenic	criteria provided, single submitter
3391184	NM_001983.4(ERCC1):c.23dup (p.Val10fs)	ERCC1	Likely pathogenic	criteria provided, single submitter
592147	NM_001983.4(ERCC1):c.796G>A (p.Ala266Thr)	ERCC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
708637	NM_001983.4(ERCC1):c.191C>T (p.Ala64Val)	ERCC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1989888	NM_001983.4(ERCC1):c.329A>G (p.Asn110Ser)	ERCC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2442006	NM_001983.4(ERCC1):c.467G>A (p.Arg156Gln)	ERCC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3583952	NM_001983.4(ERCC1):c.843+32G>C	ERCC1	Uncertain significance	criteria provided, single submitter
3583953	NM_001983.4(ERCC1):c.124T>A (p.Ser42Thr)	ERCC1	Uncertain significance	criteria provided, single submitter
638523	NM_001983.4(ERCC1):c.799T>C (p.Ser267Pro)	ERCC1	Uncertain significance	criteria provided, multiple submitters, no conflicts
235480	NM_012099.3(POLR1G):c.844A>G (p.Thr282Ala)	ERCC1	Benign	criteria provided, multiple submitters, no conflicts
329534	NM_001983.4(ERCC1):c.843+32G>A	ERCC1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

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
ERCC1	Definitive	Autosomal recessive	cerebrooculofacioskeletal syndrome 4	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERCC1	Orphanet:1466	COFS syndrome
ERCC1	Orphanet:90322	Cockayne syndrome type 2

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
ERCC1	HGNC:3433	ENSG00000012061	P07992	DNA excision repair protein ERCC-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERCC1	DNA excision repair protein ERCC-1	Non-catalytic component of a structure-specific DNA repair endonuclease responsible for the 5’-incision during DNA repair.

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)
ERCC1	Other/Unknown	no		ERCC1/RAD10/SWI10, RuvA_2-like, Restrct_endonuc-II-like

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
parotid gland	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERCC1	285	ubiquitous	marker	apex of heart, parotid gland, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERCC1	2,085

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERCC1	P07992	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
HDR through Single Strand Annealing (SSA)	1	292.8×	0.005	ERCC1
Fanconi Anemia Pathway	1	278.5×	0.005	ERCC1
Dual Incision in GG-NER	1	259.6×	0.005	ERCC1
Formation of Incision Complex in GG-NER	1	253.8×	0.005	ERCC1
Dual incision in TC-NER	1	173.0×	0.006	ERCC1

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
pyrimidine dimer repair by nucleotide-excision repair	1	4213.0×	0.001	ERCC1
obsolete syncytium formation	1	4213.0×	0.001	ERCC1
telomeric DNA-containing double minutes formation	1	4213.0×	0.001	ERCC1
positive regulation of t-circle formation	1	4213.0×	0.001	ERCC1
negative regulation of protection from non-homologous end joining at telomere	1	4213.0×	0.001	ERCC1
mitotic recombination	1	2808.7×	0.001	ERCC1
negative regulation of telomere maintenance	1	2808.7×	0.001	ERCC1
post-embryonic hemopoiesis	1	2808.7×	0.001	ERCC1
t-circle formation	1	1404.3×	0.002	ERCC1
UV-damage excision repair	1	1296.3×	0.002	ERCC1
UV protection	1	1203.7×	0.002	ERCC1
replicative senescence	1	991.3×	0.002	ERCC1
response to X-ray	1	887.0×	0.002	ERCC1
isotype switching	1	842.6×	0.002	ERCC1
insulin-like growth factor receptor signaling pathway	1	495.6×	0.004	ERCC1
determination of adult lifespan	1	432.1×	0.004	ERCC1
interstrand cross-link repair	1	432.1×	0.004	ERCC1
double-strand break repair via nonhomologous end joining	1	421.3×	0.004	ERCC1
nucleotide-excision repair	1	383.0×	0.004	ERCC1
oogenesis	1	383.0×	0.004	ERCC1
positive regulation of transcription initiation by RNA polymerase II	1	271.8×	0.005	ERCC1
male gonad development	1	156.0×	0.008	ERCC1
multicellular organism growth	1	137.0×	0.009	ERCC1
response to oxidative stress	1	130.6×	0.009	ERCC1
cell population proliferation	1	102.8×	0.011	ERCC1
DNA repair	1	63.8×	0.016	ERCC1
spermatogenesis	1	35.2×	0.028	ERCC1

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
ERCC1	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
ERCC1	28	Binding:28

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	ERCC1

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)
ERCC1	28	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.