Cerebrooculofacioskeletal syndrome 2

Summary

Cerebrooculofacioskeletal syndrome 2 (MONDO:0012553) is a disease caused by ERCC2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: ERCC2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 185

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebrooculofacioskeletal syndrome 2
Mondo ID	MONDO:0012553
MeSH	C565185
OMIM	610756
DOID	DOID:0080912
UMLS	C1853102
MedGen	342799
GARD	0015497
Is cancer (heuristic)	no

Also known as: cerebrooculofacioskeletal syndrome 2 · cerebrooculofacioskeletal syndrome type 2 · COFS syndrome caused by mutation in ERCC2 · COFS2 · ERCC2 COFS syndrome

Data availability: 185 ClinVar variants · 1 GenCC gene-disease record.

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 2

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

185 retrieved; paginated sample, class counts are floors:

61 likely pathogenic, 58 pathogenic/likely pathogenic, 24 uncertain significance, 17 pathogenic, 13 conflicting classifications of pathogenicity, 5 benign/likely benign, 4 benign, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028729	NM_000400.4(ERCC2):c.2006_2007insA (p.Lys671fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1176083	NM_000400.4(ERCC2):c.2009del (p.Gly670fs)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1176084	NM_000400.4(ERCC2):c.139G>A (p.Gly47Arg)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1319436	NM_000400.4(ERCC2):c.1984C>T (p.Gln662Ter)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1319438	NM_000400.4(ERCC2):c.1759-2A>G	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1319444	NM_000400.4(ERCC2):c.1007dup (p.Leu337fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322829	NM_000400.4(ERCC2):c.591_594del (p.Arg196_Tyr197insTer)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1322830	NM_000400.4(ERCC2):c.1684C>T (p.Gln562Ter)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
134095	NM_000400.4(ERCC2):c.1703_1704del (p.Phe568fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
134102	NM_000400.4(ERCC2):c.2150C>G (p.Ala717Gly)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1346864	NM_000400.4(ERCC2):c.1480-2A>C	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1363277	NM_000400.4(ERCC2):c.1867dup (p.Val623fs)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1415975	NM_000400.4(ERCC2):c.1996C>T (p.Arg666Trp)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455083	NM_000400.4(ERCC2):c.1354C>T (p.Gln452Ter)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1499293	NM_000400.4(ERCC2):c.1973G>A (p.Arg658His)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1511660	NM_000400.4(ERCC2):c.2190+1del	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16781	NM_000400.4(ERCC2):c.2173G>C (p.Ala725Pro)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16784	NM_000400.4(ERCC2):c.335G>A (p.Arg112His)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
16785	NM_000400.4(ERCC2):c.1972C>T (p.Arg658Cys)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16788	NM_000400.4(ERCC2):c.1846C>T (p.Arg616Trp)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16792	NM_000400.4(ERCC2):c.2164C>T (p.Arg722Trp)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
16793	NM_000400.4(ERCC2):c.2047C>T (p.Arg683Trp)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705082	NM_000400.4(ERCC2):c.2141_2148del (p.Val714fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705248	NM_000400.4(ERCC2):c.195_196delinsTT (p.Glu66Ter)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2138307	NM_000400.4(ERCC2):c.1378-1G>T	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2168783	NM_000400.4(ERCC2):c.1480-1G>C	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2169658	NM_000400.4(ERCC2):c.1017C>A (p.Tyr339Ter)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2184510	NM_000400.4(ERCC2):c.586C>T (p.Arg196Ter)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
2506192	NM_000400.4(ERCC2):c.262C>T (p.Arg88Ter)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2573404	NM_000400.4(ERCC2):c.1802G>T (p.Arg601Leu)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 4 · 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
ERCC2	Definitive	Autosomal recessive	cerebrooculofacioskeletal syndrome 2	19

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

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
ERCC2	HGNC:3434	ENSG00000104884	P18074	General transcription and DNA repair factor IIH helicase subunit XPD	gencc,clinvar
KLC3	HGNC:20717	ENSG00000104892	Q6P597	Kinesin light chain 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERCC2	General transcription and DNA repair factor IIH helicase subunit XPD	ATP-dependent 5’-3’ DNA helicase.
KLC3	Kinesin light chain 3	Kinesin is a microtubule-associated force-producing protein that may play a role in organelle transport.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ERCC2	Enzyme (other)	yes	3.6.4.12	RAD3/XPD, DNA/RNA_helicase_DEAH_CS, Helicase-like_DEXD_c2
KLC3	Other/Unknown	no		Kinesin_light, TPR-like_helical_dom_sf, TPR_rpt

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
left adrenal gland	1
right adrenal gland	1
stromal cell of endometrium	1
skin of abdomen	1
skin of leg	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERCC2	184	ubiquitous	marker	stromal cell of endometrium, right adrenal gland, left adrenal gland
KLC3	189	broad	marker	upper arm skin, skin of abdomen, skin of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERCC2	2,746
KLC3	2,698

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERCC2	P18074	51

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KLC3	Q6P597	76.05

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 46. Enrichment computed across 2 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
RHO GTPases activate KTN1	1	519.1×	0.018	KLC3
Cytosolic iron-sulfur cluster assembly	1	380.7×	0.018	ERCC2
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	1	203.9×	0.018	ERCC2
RNA Pol II CTD phosphorylation and interaction with CE	1	203.9×	0.018	ERCC2
mRNA Capping	1	190.3×	0.018	ERCC2
Formation of the Early Elongation Complex	1	167.9×	0.018	ERCC2
Formation of the HIV-1 Early Elongation Complex	1	167.9×	0.018	ERCC2
RNA Polymerase I Transcription Termination	1	163.1×	0.018	ERCC2
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1	132.8×	0.018	ERCC2
Formation of HIV-1 elongation complex containing HIV-1 Tat	1	129.8×	0.018	ERCC2
Tat-mediated elongation of the HIV-1 transcript	1	129.8×	0.018	ERCC2
Dual Incision in GG-NER	1	129.8×	0.018	ERCC2
Formation of Incision Complex in GG-NER	1	126.9×	0.018	ERCC2
Formation of HIV elongation complex in the absence of HIV Tat	1	124.1×	0.018	ERCC2
HIV Transcription Initiation	1	116.5×	0.018	ERCC2
RNA Polymerase II HIV Promoter Escape	1	116.5×	0.018	ERCC2
RNA Polymerase II Promoter Escape	1	116.5×	0.018	ERCC2
RNA Polymerase II Transcription Pre-Initiation And Promoter Opening	1	116.5×	0.018	ERCC2
RNA Polymerase II Transcription Initiation	1	116.5×	0.018	ERCC2
RNA Polymerase II Transcription Initiation And Promoter Clearance	1	116.5×	0.018	ERCC2
RNA Polymerase I Transcription Initiation	1	112.0×	0.018	ERCC2
Formation of TC-NER Pre-Incision Complex	1	105.7×	0.018	ERCC2
Formation of RNA Pol II elongation complex	1	96.8×	0.018	ERCC2
RNA Polymerase II Transcription Elongation	1	96.8×	0.018	ERCC2
TP53 Regulates Transcription of DNA Repair Genes	1	90.6×	0.018	ERCC2
Gap-filling DNA repair synthesis and ligation in TC-NER	1	89.2×	0.018	ERCC2
Kinesins	1	89.2×	0.018	KLC3
Transcription of the HIV genome	1	86.5×	0.018	ERCC2
Dual incision in TC-NER	1	86.5×	0.018	ERCC2
RNA Polymerase II Pre-transcription Events	1	68.8×	0.022	ERCC2

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
positive regulation of mitotic recombination	1	4213.0×	0.005	ERCC2
axo-dendritic transport	1	2106.5×	0.005	KLC3
central nervous system myelin formation	1	1203.7×	0.005	ERCC2
transcription elongation by RNA polymerase I	1	1053.2×	0.005	ERCC2
hair cell differentiation	1	1053.2×	0.005	ERCC2
hair follicle maturation	1	1053.2×	0.005	ERCC2
sperm mitochondrial sheath assembly	1	1053.2×	0.005	KLC3
embryonic cleavage	1	842.6×	0.005	ERCC2
regulation of mitotic cell cycle phase transition	1	842.6×	0.005	ERCC2
transcription-coupled nucleotide-excision repair	1	601.9×	0.005	ERCC2
UV protection	1	601.9×	0.005	ERCC2
erythrocyte maturation	1	421.3×	0.007	ERCC2
hematopoietic stem cell differentiation	1	383.0×	0.007	ERCC2
maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1	337.0×	0.007	ERCC2
hematopoietic stem cell proliferation	1	324.1×	0.007	ERCC2
intrinsic apoptotic signaling pathway by p53 class mediator	1	290.6×	0.008	ERCC2
spinal cord development	1	255.3×	0.008	ERCC2
insulin-like growth factor receptor signaling pathway	1	247.8×	0.008	ERCC2
embryonic organ development	1	240.7×	0.008	ERCC2
determination of adult lifespan	1	216.1×	0.008	ERCC2
nucleotide-excision repair	1	191.5×	0.009	ERCC2
transcription initiation at RNA polymerase II promoter	1	187.2×	0.009	ERCC2
microtubule-based movement	1	147.8×	0.011	KLC3
bone mineralization	1	135.9×	0.011	ERCC2
post-embryonic development	1	102.8×	0.014	ERCC2
chromosome segregation	1	86.9×	0.016	ERCC2
spermatid development	1	72.6×	0.018	KLC3
multicellular organism growth	1	68.5×	0.019	ERCC2
response to oxidative stress	1	65.3×	0.019	ERCC2
extracellular matrix organization	1	61.1×	0.020	ERCC2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
KLC3	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: 2; 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	1	KLC3

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)
KLC3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.