Cerebrooculofacioskeletal syndrome 1

Summary

Cerebrooculofacioskeletal syndrome 1 (MONDO:0008955) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 305

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebrooculofacioskeletal syndrome 1
Mondo ID	MONDO:0008955
OMIM	214150
DOID	DOID:0080911
NCIT	C173085
UMLS	C0220722
MedGen	66320
GARD	0015150
Is cancer (heuristic)	no

Also known as: cerebrooculofacioskeletal syndrome 1 · cerebrooculofacioskeletal syndrome type 1 · COFS syndrome · COFS syndrome caused by mutation in ERCC6 · COFS1 · ERCC6 COFS syndrome

Data availability: 305 ClinVar variants · 5 cell lines.

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 1

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

305 retrieved; paginated sample, class counts are floors:

109 uncertain significance, 71 conflicting classifications of pathogenicity, 38 likely pathogenic, 31 pathogenic, 22 pathogenic/likely pathogenic, 14 benign, 13 benign/likely benign, 7 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
998032	NM_000124.4(ERCC6):c.[1727C>G;1834C>T]		Pathogenic	no assertion criteria provided
1034077	NM_000124.4(ERCC6):c.2093dup (p.Thr699fs)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
1068941	NM_000124.4(ERCC6):c.2792_2802del (p.Ile931fs)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073323	NM_000124.4(ERCC6):c.2170-1G>A	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1701	NM_000124.4(ERCC6):c.2203C>T (p.Arg735Ter)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
1703	NM_000124.4(ERCC6):c.1357C>T (p.Arg453Ter)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
1705	NM_000124.4(ERCC6):c.1971_1974dup (p.Thr659fs)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
1706	NM_000124.4(ERCC6):c.3715_3716del (p.Lys1239fs)	ERCC6	Pathogenic	criteria provided, single submitter
1711	NM_000124.4(ERCC6):c.2047C>T (p.Arg683Ter)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1713	NM_000124.4(ERCC6):c.2254A>G (p.Met752Val)	ERCC6	Pathogenic	no assertion criteria provided
190147	NM_000124.4(ERCC6):c.1526+1G>T	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190150	NM_000124.4(ERCC6):c.1518del (p.Lys506fs)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190155	NM_000124.4(ERCC6):c.1954C>T (p.Arg652Ter)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190159	NM_000124.4(ERCC6):c.2096dup (p.Leu700fs)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190160	NM_000124.4(ERCC6):c.2167C>T (p.Gln723Ter)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190162	NM_000124.4(ERCC6):c.2599-26A>G	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190163	NM_000124.4(ERCC6):c.2830-2A>G	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
190166	NM_000124.4(ERCC6):c.3412dup (p.Thr1138fs)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
190167	NM_000124.4(ERCC6):c.3536del (p.Tyr1179fs)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
190168	NM_000124.4(ERCC6):c.3607_3608insGGGCTGGCTGCTTAAGGTCCACCTTA (p.Lys1203fs)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
190170	NM_000124.4(ERCC6):c.3904C>T (p.Gln1302Ter)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
190171	NM_000124.4(ERCC6):c.3952_3953del (p.Arg1318fs)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2000913	NM_000124.4(ERCC6):c.1717_1720del (p.Cys573fs)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
210955	NM_000124.4(ERCC6):c.2551T>C (p.Trp851Arg)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212733	NM_000124.4(ERCC6):c.466C>T (p.Gln156Ter)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225905	NM_000124.4(ERCC6):c.643G>T (p.Glu215Ter)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
2430381	NM_000124.4(ERCC6):c.22del (p.His8fs)	ERCC6	Pathogenic	criteria provided, single submitter
2445951	NM_000124.4(ERCC6):c.1738C>T (p.Gln580Ter)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2577221	NM_000124.4(ERCC6):c.2218_2221del (p.Pro740fs)	ERCC6	Pathogenic	criteria provided, single submitter
31578	NM_000124.4(ERCC6):c.3862C>T (p.Arg1288Ter)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERCC2	Orphanet:1466	COFS syndrome
ERCC2	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC2	Orphanet:33364	Trichothiodystrophy
ERCC2	Orphanet:910	Xeroderma pigmentosum
ERCC6	Orphanet:1466	COFS syndrome
ERCC6	Orphanet:178338	UV-sensitive syndrome
ERCC6	Orphanet:90321	Cockayne syndrome type 1
ERCC6	Orphanet:90322	Cockayne syndrome type 2
ERCC6	Orphanet:90324	Cockayne syndrome type 3

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PGBD3	HGNC:19400		Q8N328	PiggyBac transposable element-derived protein 3	clinvar
ERCC2	HGNC:3434	ENSG00000104884	P18074	General transcription and DNA repair factor IIH helicase subunit XPD	clinvar
ERCC6	HGNC:3438	ENSG00000225830	P0DP91	Chimeric ERCC6-PGBD3 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PGBD3	PiggyBac transposable element-derived protein 3	Binds in vitro to PGBD3-related transposable elements, called MER85s; these non-autonomous 140 bp elements are characterized by the presence of PGBD3 terminal inverted repeats and the absence of internal transposase ORF.
ERCC2	General transcription and DNA repair factor IIH helicase subunit XPD	ATP-dependent 5’-3’ DNA helicase.
ERCC6	Chimeric ERCC6-PGBD3 protein	Involved in repair of DNA damage following UV irradiation, acting either in the absence of ERCC6 or synergistically with ERCC6.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PGBD3	Other/Unknown	no		PGBD, PiggyBac_TE-derived
ERCC2	Enzyme (other)	yes	3.6.4.12	RAD3/XPD, DNA/RNA_helicase_DEAH_CS, Helicase-like_DEXD_c2
ERCC6	Other/Unknown	no		PGBD, PiggyBac_TE-derived, CC_ERCC-6_N

Expression context

Cohort genes with no expression data: 1.

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	1

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	1
right adrenal gland	1
stromal cell of endometrium	1
male germ line stem cell (sensu Vertebrata) in testis	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PGBD3
ERCC2	184	ubiquitous	marker	stromal cell of endometrium, right adrenal gland, left adrenal gland
ERCC6	257	ubiquitous	marker	oocyte, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERCC2	2,746
ERCC6	13
PGBD3	10

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERCC2	P18074	51
ERCC6	P0DP91	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PGBD3	Q8N328	84.30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	2	265.6×	2e-04	ERCC2, ERCC6
RNA Polymerase I Transcription Initiation	2	223.9×	2e-04	ERCC2, ERCC6
Formation of TC-NER Pre-Incision Complex	2	211.5×	2e-04	ERCC2, ERCC6
Gap-filling DNA repair synthesis and ligation in TC-NER	2	178.4×	2e-04	ERCC2, ERCC6
Dual incision in TC-NER	2	173.0×	2e-04	ERCC2, ERCC6
Cytosolic iron-sulfur cluster assembly	1	380.7×	0.012	ERCC2
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	1	203.9×	0.012	ERCC2
RNA Pol II CTD phosphorylation and interaction with CE	1	203.9×	0.012	ERCC2
mRNA Capping	1	190.3×	0.012	ERCC2
Formation of the Early Elongation Complex	1	167.9×	0.012	ERCC2
Formation of the HIV-1 Early Elongation Complex	1	167.9×	0.012	ERCC2
RNA Polymerase I Transcription Termination	1	163.1×	0.012	ERCC2
Formation of HIV-1 elongation complex containing HIV-1 Tat	1	129.8×	0.012	ERCC2
Tat-mediated elongation of the HIV-1 transcript	1	129.8×	0.012	ERCC2
Dual Incision in GG-NER	1	129.8×	0.012	ERCC2
Formation of Incision Complex in GG-NER	1	126.9×	0.012	ERCC2
Formation of HIV elongation complex in the absence of HIV Tat	1	124.1×	0.012	ERCC2
HIV Transcription Initiation	1	116.5×	0.012	ERCC2
RNA Polymerase II HIV Promoter Escape	1	116.5×	0.012	ERCC2
RNA Polymerase II Promoter Escape	1	116.5×	0.012	ERCC2
RNA Polymerase II Transcription Pre-Initiation And Promoter Opening	1	116.5×	0.012	ERCC2
RNA Polymerase II Transcription Initiation	1	116.5×	0.012	ERCC2
RNA Polymerase II Transcription Initiation And Promoter Clearance	1	116.5×	0.012	ERCC2
Formation of RNA Pol II elongation complex	1	96.8×	0.013	ERCC2
RNA Polymerase II Transcription Elongation	1	96.8×	0.013	ERCC2
TP53 Regulates Transcription of DNA Repair Genes	1	90.6×	0.014	ERCC2
Transcription of the HIV genome	1	86.5×	0.014	ERCC2
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	1	76.1×	0.015	ERCC6
RNA Polymerase II Pre-transcription Events	1	68.8×	0.016	ERCC2
B-WICH complex positively regulates rRNA expression	1	60.7×	0.017	ERCC6

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
transcription elongation by RNA polymerase I	2	2106.5×	1e-05	ERCC2, ERCC6
transcription-coupled nucleotide-excision repair	2	1203.7×	2e-05	ERCC2, ERCC6
multicellular organism growth	2	137.0×	9e-04	ERCC2, ERCC6
response to oxidative stress	2	130.6×	9e-04	ERCC2, ERCC6
positive regulation of peptidyl-serine phosphorylation of STAT protein	1	4213.0×	0.002	ERCC6
positive regulation of mitotic recombination	1	4213.0×	0.002	ERCC2
transcription by RNA polymerase II	2	70.5×	0.002	ERCC2, ERCC6
pyrimidine dimer repair	1	2106.5×	0.004	ERCC6
response to superoxide	1	1685.2×	0.004	ERCC6
regulation of DNA-templated transcription elongation	1	1404.3×	0.004	ERCC6
DNA protection	1	1404.3×	0.004	ERCC6
central nervous system myelin formation	1	1203.7×	0.004	ERCC2
hair cell differentiation	1	1053.2×	0.004	ERCC2
hair follicle maturation	1	1053.2×	0.004	ERCC2
negative regulation of double-strand break repair via nonhomologous end joining	1	1053.2×	0.004	ERCC6
response to UV-B	1	936.2×	0.004	ERCC6
embryonic cleavage	1	842.6×	0.004	ERCC2
double-strand break repair via classical nonhomologous end joining	1	842.6×	0.004	ERCC6
regulation of mitotic cell cycle phase transition	1	842.6×	0.004	ERCC2
single strand break repair	1	702.2×	0.005	ERCC6
positive regulation of DNA-templated transcription, elongation	1	648.1×	0.005	ERCC6
UV protection	1	601.9×	0.005	ERCC2
positive regulation of transcription by RNA polymerase III	1	468.1×	0.006	ERCC6
response to X-ray	1	443.5×	0.006	ERCC6
erythrocyte maturation	1	421.3×	0.006	ERCC2
regulation of transcription elongation by RNA polymerase II	1	401.2×	0.006	ERCC6
hematopoietic stem cell differentiation	1	383.0×	0.006	ERCC2
maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1	337.0×	0.007	ERCC2
positive regulation of transcription by RNA polymerase I	1	324.1×	0.007	ERCC6
hematopoietic stem cell proliferation	1	324.1×	0.007	ERCC2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ERCC2	SUNITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERCC2	16	4
PGBD3	0	0
ERCC6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SUNITINIB	4	ERCC2
DINACICLIB	3	ERCC2
DEFACTINIB	3	ERCC2
ALVOCIDIB	3	ERCC2
SELICICLIB	2	ERCC2
ZOTIRACICLIB	2	ERCC2
DANUSERTIB	2	ERCC2
MILCICLIB	2	ERCC2
PF-00562271	1	ERCC2
PHA-793887	1	ERCC2
KW-2449	1	ERCC2
BMS-387032	1	ERCC2
PF-03758309	1	ERCC2
TAK-901	1	ERCC2
RGB-286638	1	ERCC2
XL-228	1	ERCC2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ERCC2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ERCC2	3.6.4.12	DNA helicase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

16 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.

Compound	Max phase	Cohort target (bioactivity)
SUNITINIB	4	ERCC2
DINACICLIB	3	ERCC2
DEFACTINIB	3	ERCC2
ALVOCIDIB	3	ERCC2
SELICICLIB	2	ERCC2
ZOTIRACICLIB	2	ERCC2
DANUSERTIB	2	ERCC2
MILCICLIB	2	ERCC2
PF-00562271	1	ERCC2
PHA-793887	1	ERCC2
KW-2449	1	ERCC2
BMS-387032	1	ERCC2
PF-03758309	1	ERCC2
TAK-901	1	ERCC2
RGB-286638	1	ERCC2
XL-228	1	ERCC2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ERCC2
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	PGBD3, ERCC6

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)
PGBD3	0	—
ERCC6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.