Cockayne spectrum with or without cerebrooculofacioskeletal syndrome

Summary

Cockayne spectrum with or without cerebrooculofacioskeletal syndrome (MONDO:0100506) is a disease caused by ERCC6 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ERCC6 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Cockayne spectrum with or without cerebrooculofacioskeletal syndrome
Mondo ID	MONDO:0100506
GARD	0026255
Is cancer (heuristic)	no

Data availability: 4 ClinVar variants · 2 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 recessive disease › Cockayne syndrome › Cockayne spectrum with or without cerebrooculofacioskeletal syndrome

Related subtypes (3): Cockayne syndrome type 3, Cockayne syndrome type 1, Cockayne syndrome type 2

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

4 retrieved; paginated sample, class counts are floors:

2 pathogenic/likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
190147	NM_000124.4(ERCC6):c.1526+1G>T	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2889314	NM_000124.4(ERCC6):c.145del (p.Ser49fs)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
4531463	NM_000124.4(ERCC6):c.3774dup (p.Ser1259fs)	ERCC6	Pathogenic	criteria provided, single submitter
549960	NM_000124.4(ERCC6):c.4063-1G>C	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 5 · 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
ERCC6	Definitive	Autosomal recessive	Cockayne spectrum with or without cerebrooculofacioskeletal syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ERCC6	HGNC:3438	ENSG00000225830	P0DP91	Chimeric ERCC6-PGBD3 protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 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)
ERCC6	Other/Unknown	no		PGBD, PiggyBac_TE-derived, CC_ERCC-6_N

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
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
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
ERCC6	13

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERCC6	P0DP91	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1	265.6×	0.008	ERCC6
RNA Polymerase I Transcription Initiation	1	223.9×	0.008	ERCC6
Formation of TC-NER Pre-Incision Complex	1	211.5×	0.008	ERCC6
Gap-filling DNA repair synthesis and ligation in TC-NER	1	178.4×	0.008	ERCC6
Dual incision in TC-NER	1	173.0×	0.008	ERCC6
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	1	152.3×	0.008	ERCC6
B-WICH complex positively regulates rRNA expression	1	121.5×	0.008	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 1 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 peptidyl-serine phosphorylation of STAT protein	1	8426.0×	0.003	ERCC6
pyrimidine dimer repair	1	4213.0×	0.003	ERCC6
response to superoxide	1	3370.4×	0.003	ERCC6
regulation of DNA-templated transcription elongation	1	2808.7×	0.003	ERCC6
DNA protection	1	2808.7×	0.003	ERCC6
transcription elongation by RNA polymerase I	1	2106.5×	0.003	ERCC6
negative regulation of double-strand break repair via nonhomologous end joining	1	2106.5×	0.003	ERCC6
response to UV-B	1	1872.4×	0.003	ERCC6
double-strand break repair via classical nonhomologous end joining	1	1685.2×	0.003	ERCC6
single strand break repair	1	1404.3×	0.003	ERCC6
positive regulation of DNA-templated transcription, elongation	1	1296.3×	0.003	ERCC6
transcription-coupled nucleotide-excision repair	1	1203.7×	0.003	ERCC6
positive regulation of transcription by RNA polymerase III	1	936.2×	0.003	ERCC6
response to X-ray	1	887.0×	0.003	ERCC6
regulation of transcription elongation by RNA polymerase II	1	802.5×	0.003	ERCC6
positive regulation of transcription by RNA polymerase I	1	648.1×	0.004	ERCC6
response to gamma radiation	1	581.1×	0.004	ERCC6
protein localization to chromatin	1	581.1×	0.004	ERCC6
positive regulation of defense response to virus by host	1	526.6×	0.004	ERCC6
base-excision repair	1	468.1×	0.004	ERCC6
DNA damage checkpoint signaling	1	391.9×	0.004	ERCC6
positive regulation of double-strand break repair via homologous recombination	1	383.0×	0.004	ERCC6
photoreceptor cell maintenance	1	358.6×	0.004	ERCC6
positive regulation of DNA repair	1	358.6×	0.004	ERCC6
intrinsic apoptotic signaling pathway in response to DNA damage	1	324.1×	0.005	ERCC6
JNK cascade	1	271.8×	0.005	ERCC6
positive regulation of transcription initiation by RNA polymerase II	1	271.8×	0.005	ERCC6
response to toxic substance	1	210.7×	0.006	ERCC6
neurogenesis	1	208.1×	0.006	ERCC6
multicellular organism growth	1	137.0×	0.009	ERCC6

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
ERCC6	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	ERCC6

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)
ERCC6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.