Cockayne syndrome type 1

Summary

Cockayne syndrome type 1 (MONDO:0019569) is a disease caused by ERCC8 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: ERCC8 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 150
• Phenotypes (HPO): 58
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

58 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000490	Deeply set eye	Very frequent (80-99%)
HP:0000580	Pigmentary retinopathy	Very frequent (80-99%)
HP:0000992	Cutaneous photosensitivity	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002135	Basal ganglia calcification	Very frequent (80-99%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Very frequent (80-99%)
HP:0004463	Absent brainstem auditory responses	Very frequent (80-99%)
HP:0008366	Foot joint contracture	Very frequent (80-99%)
HP:0008897	Postnatal growth retardation	Very frequent (80-99%)
HP:0000093	Proteinuria	Frequent (30-79%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000276	Long face	Frequent (30-79%)
HP:0000303	Mandibular prognathia	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000633	Decreased lacrimation	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0000966	Hypohidrosis	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002172	Postural instability	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003134	Abnormality of peripheral nerve conduction	Frequent (30-79%)
HP:0003138	Increased blood urea nitrogen	Frequent (30-79%)
HP:0004370	Abnormality of temperature regulation	Frequent (30-79%)
HP:0005328	Progeroid facial appearance	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000331	Short chin	Occasional (5-29%)
HP:0000400	Macrotia	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000509	Conjunctivitis	Occasional (5-29%)
HP:0000528	Anophthalmia	Occasional (5-29%)
HP:0000554	Uveitis	Occasional (5-29%)
HP:0000613	Photophobia	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000674	Anodontia	Occasional (5-29%)
HP:0000680	Delayed eruption of primary teeth	Occasional (5-29%)
HP:0001034	Hypermelanotic macule	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002061	Lower limb spasticity	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Cockayne syndrome type 1
Mondo ID	MONDO:0019569
OMIM	216400
Orphanet	90321
DOID	DOID:0080907
ICD-11	1271368066
NCIT	C135725
UMLS	C0751039
MedGen	155488
GARD	0001415
Is cancer (heuristic)	no

Also known as: Cockayne syndrome A · Cockayne syndrome caused by mutation in ERCC8 · Cockayne syndrome classic form · Cockayne syndrome classical · Cockayne syndrome type 1 · Cockayne syndrome type A · Cockayne syndrome type a · Cockayne syndrome type I · Cockayne syndrome, type A · CSA · ERCC8 Cockayne syndrome

Data availability: 150 ClinVar variants · 7 GenCC gene-disease records · 47 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 › Cockayne syndrome › Cockayne syndrome type 1

Related subtypes (3): Cockayne syndrome type 3, Cockayne syndrome type 2, Cockayne spectrum with or without cerebrooculofacioskeletal syndrome

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

150 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 32 likely pathogenic, 28 pathogenic, 23 pathogenic/likely pathogenic, 14 conflicting classifications of pathogenicity, 10 benign, 3 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4813976	NM_000082.4(ERCC8):c.[598del;600T>A]		Pathogenic	criteria provided, single submitter
2672303	Single allele	DEPDC1B	Pathogenic	no assertion criteria provided
1075397	NM_000082.4(ERCC8):c.1041+1G>T	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1364013	NM_000082.4(ERCC8):c.174C>A (p.Tyr58Ter)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1388419	NM_000082.4(ERCC8):c.162del (p.Glu55fs)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455112	NM_000082.4(ERCC8):c.223_227del (p.Asn75fs)	ERCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1714	NM_000082.3:c.844_1122del	ERCC8	Pathogenic	no assertion criteria provided
1715	NM_000082.4(ERCC8):c.966C>A (p.Tyr322Ter)	ERCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1716	NM_000082.4(ERCC8):c.37G>T (p.Glu13Ter)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1717	NM_000082.4(ERCC8):c.479C>T (p.Ala160Val)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1718	NM_000082.4(ERCC8):c.613G>C (p.Ala205Pro)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190175	NM_000082.4(ERCC8):c.141del (p.Asn47fs)	ERCC8	Pathogenic	criteria provided, single submitter
2440094	NM_000082.4(ERCC8):c.427del (p.Thr143fs)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674622	NM_000082.4:c.[275+768_399+346del;399+347_399+2002inv;399+2003_399+2557delinsTACTTAAT]	ERCC8	Pathogenic	no assertion criteria provided
2691711	NM_000082.4(ERCC8):c.275+1G>A	ERCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
2795688	NM_000082.4(ERCC8):c.378del (p.Trp127fs)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2982172	NM_000082.4(ERCC8):c.467_468dup (p.Cys157fs)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3000695	NM_000082.4(ERCC8):c.547C>T (p.Gln183Ter)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3338104	NM_000082.4(ERCC8):c.1041G>A (p.Gln347=)	ERCC8	Pathogenic	criteria provided, single submitter
3340048	NM_000082.4(ERCC8):c.176T>C (p.Met59Thr)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3592728	NM_000082.4(ERCC8):c.370_371del (p.Leu124fs)	ERCC8	Pathogenic	criteria provided, single submitter
3592731	NM_000082.4(ERCC8):c.2T>G (p.Met1Arg)	ERCC8	Pathogenic	criteria provided, single submitter
371025	NM_000082.4(ERCC8):c.300C>G (p.Tyr100Ter)	ERCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
3711413	NM_000082.4(ERCC8):c.840_841del (p.Leu281fs)	ERCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
397640	NM_000082.4(ERCC8):c.173+1119G>C	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4072060	NM_000082.4(ERCC8):c.600del (p.Asp199_Tyr200insTer)	ERCC8	Pathogenic	criteria provided, single submitter
419231	NM_174889.5(NDUFAF2):c.114C>G (p.Tyr38Ter)	ERCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
424544	NM_000082.4(ERCC8):c.647_651dup (p.Arg218Ter)	ERCC8	Pathogenic	criteria provided, single submitter
430102	NM_000082.4(ERCC8):c.295_297delinsTG (p.Arg99fs)	ERCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
4813850	NM_000082.4(ERCC8):c.324T>A (p.Tyr108Ter)	ERCC8	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
ERCC8	Definitive	Autosomal recessive	Cockayne syndrome type 1	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERCC8	Orphanet:178338	UV-sensitive syndrome
ERCC8	Orphanet:90321	Cockayne syndrome type 1
ERCC8	Orphanet:90322	Cockayne syndrome type 2
ERCC8	Orphanet:90324	Cockayne syndrome type 3

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ERCC8	HGNC:3439	ENSG00000049167	Q13216	DNA excision repair protein ERCC-8	gencc,clinvar
DEPDC1B	HGNC:24902	ENSG00000035499	Q8WUY9	DEP domain-containing protein 1B	clinvar
ERCC8-AS1	HGNC:40220	ENSG00000233847		ERCC8 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERCC8	DNA excision repair protein ERCC-8	Substrate-recognition component of the CSA complex, a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex, involved in transcription-coupled nucleotide excision repair (TC-NER), a process during which RNA polymerase II-blocking lesio…

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ERCC8	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
DEPDC1B	Other/Unknown	no		RhoGAP_dom, DEP_dom, Rho_GTPase_activation_prot
ERCC8-AS1	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	2
ventricular zone	2
primordial germ cell in gonad	1
oocyte	1
secondary oocyte	1
ganglionic eminence	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERCC8	218	ubiquitous	yes	adrenal tissue, ventricular zone, primordial germ cell in gonad
DEPDC1B	182	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
ERCC8-AS1	110		yes	male germ line stem cell (sensu Vertebrata) in testis, ganglionic eminence, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DEPDC1B	1,898
ERCC8	1,550
ERCC8-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERCC8	Q13216	16

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DEPDC1B	Q8WUY9	77.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. 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
RHOV GTPase cycle	1	142.8×	0.019	DEPDC1B
RHOU GTPase cycle	1	139.3×	0.019	DEPDC1B
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1	132.8×	0.019	ERCC8
RND1 GTPase cycle	1	132.8×	0.019	DEPDC1B
RHOF GTPase cycle	1	129.8×	0.019	DEPDC1B
RND3 GTPase cycle	1	129.8×	0.019	DEPDC1B
RND2 GTPase cycle	1	129.8×	0.019	DEPDC1B
Formation of TC-NER Pre-Incision Complex	1	105.7×	0.019	ERCC8
RHOD GTPase cycle	1	102.0×	0.019	DEPDC1B
RHOJ GTPase cycle	1	100.2×	0.019	DEPDC1B
RHOQ GTPase cycle	1	90.6×	0.019	DEPDC1B
Gap-filling DNA repair synthesis and ligation in TC-NER	1	89.2×	0.019	ERCC8
Dual incision in TC-NER	1	86.5×	0.019	ERCC8
RHOB GTPase cycle	1	77.2×	0.019	DEPDC1B
RHOG GTPase cycle	1	74.2×	0.019	DEPDC1B
RHOC GTPase cycle	1	73.2×	0.019	DEPDC1B
RAC2 GTPase cycle	1	63.4×	0.020	DEPDC1B
RAC3 GTPase cycle	1	59.5×	0.020	DEPDC1B
RHOA GTPase cycle	1	37.3×	0.030	DEPDC1B
CDC42 GTPase cycle	1	36.1×	0.030	DEPDC1B
RAC1 GTPase cycle	1	30.5×	0.034	DEPDC1B
Neddylation	1	23.7×	0.042	ERCC8

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
regulation of transcription-coupled nucleotide-excision repair	1	8426.0×	0.002	ERCC8
double-strand break repair via classical nonhomologous end joining	1	842.6×	0.007	ERCC8
single strand break repair	1	702.2×	0.007	ERCC8
transcription-coupled nucleotide-excision repair	1	601.9×	0.007	ERCC8
response to X-ray	1	443.5×	0.008	ERCC8
response to auditory stimulus	1	366.4×	0.008	ERCC8
positive regulation of Wnt signaling pathway	1	191.5×	0.011	DEPDC1B
response to UV	1	183.2×	0.011	ERCC8
positive regulation of DNA repair	1	179.3×	0.011	ERCC8
protein autoubiquitination	1	117.0×	0.014	ERCC8
response to oxidative stress	1	65.3×	0.024	ERCC8
protein polyubiquitination	1	57.7×	0.024	ERCC8
cell migration	1	30.8×	0.042	DEPDC1B
DNA damage response	1	26.8×	0.043	ERCC8
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.043	ERCC8
protein ubiquitination	1	20.7×	0.051	ERCC8
intracellular signal transduction	1	19.1×	0.052	DEPDC1B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 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
ERCC8	0	0
DEPDC1B	0	0
ERCC8-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	3	ERCC8, DEPDC1B, ERCC8-AS1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ERCC8	0	—
DEPDC1B	0	—
ERCC8-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06009965	PHASE4	UNKNOWN	Efficacy of IST Combined With TPO-RA in the Treatment of AA and Establishment of a Recurrence Prediction System