Cockayne syndrome type 2

Summary

Cockayne syndrome type 2 (MONDO:0019570) is a disease caused by ERCC6 (GenCC Definitive), with 5 cohort genes. The dominant Reactome pathway is Dual incision in TC-NER (3 cohort genes).

At a glance

• Causal gene: ERCC6 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 398
• Phenotypes (HPO): 41

Clinical features

Signs & symptoms

Clinical features (HPO)

41 HPO clinical features (Orphanet curated; top 41 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002545	Patchy demyelination of subcortical white matter	Very frequent (80-99%)
HP:0007346	Subcortical white matter calcifications	Very frequent (80-99%)
HP:0012758	Neurodevelopmental delay	Very frequent (80-99%)
HP:0000276	Long face	Frequent (30-79%)
HP:0000303	Mandibular prognathia	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002172	Postural instability	Frequent (30-79%)
HP:0005328	Progeroid facial appearance	Frequent (30-79%)
HP:0000331	Short chin	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000400	Macrotia	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000509	Conjunctivitis	Occasional (5-29%)
HP:0000519	Developmental cataract	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:0001371	Flexion contracture	Occasional (5-29%)
HP:0002061	Lower limb spasticity	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002509	Limb hypertonia	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0006297	Enamel hypoplasia	Occasional (5-29%)
HP:0006313	Widely spaced primary teeth	Occasional (5-29%)
HP:0006334	Hypoplasia of the primary teeth	Occasional (5-29%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0008936	Axial hypotonia	Occasional (5-29%)
HP:0100699	Scarring	Occasional (5-29%)
HP:0000026	Male hypogonadism	Very rare (<1-4%)
HP:0000028	Cryptorchidism	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Cockayne syndrome type 2
Mondo ID	MONDO:0019570
OMIM	133540
Orphanet	90322
DOID	DOID:0080908
ICD-11	1604701958
NCIT	C135726
UMLS	C0751038
MedGen	155487
GARD	0001420
Is cancer (heuristic)	no

Also known as: Cockayne syndrome B · Cockayne syndrome type 2 · Cockayne syndrome type B · Cockayne syndrome type II · Cockayne syndrome, type B · CSB

Data availability: 398 ClinVar variants · 7 GenCC gene-disease records · 36 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 2

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

398 retrieved; paginated sample, class counts are floors:

110 uncertain significance, 108 likely pathogenic, 72 conflicting classifications of pathogenicity, 46 pathogenic, 28 pathogenic/likely pathogenic, 14 benign, 13 benign/likely benign, 7 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2663790	NC_000010.10:g.(?49383876)(52383915_?)del	AGAP6	Pathogenic	criteria provided, single submitter
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
143186	NM_000124.4(ERCC6):c.543+4del	ERCC6	Pathogenic	criteria provided, single submitter
1679951	NM_000124.4(ERCC6):c.850G>T (p.Glu284Ter)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
1700	NM_000124.4(ERCC6):c.1550G>A (p.Trp517Ter)	ERCC6	Pathogenic	criteria provided, single submitter
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
1704	NM_000124.4(ERCC6):c.972dup (p.Glu325fs)	ERCC6	Pathogenic	no assertion criteria provided
1705	NM_000124.4(ERCC6):c.1971_1974dup (p.Thr659fs)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
1708	NM_000124.4(ERCC6):c.229C>T (p.Arg77Ter)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
1710	NM_000124.4(ERCC6):c.1034_1035insT (p.Lys345fs)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
1711	NM_000124.4(ERCC6):c.2047C>T (p.Arg683Ter)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1725967	NM_000124.4(ERCC6):c.1040del (p.Gly347fs)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1800797	NM_000124.4(ERCC6):c.3259C>T (p.Arg1087Ter)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190146	NM_000124.4(ERCC6):c.1280dup (p.Ser429fs)	ERCC6	Pathogenic	criteria provided, multiple submitters, no conflicts
190147	NM_000124.4(ERCC6):c.1526+1G>T	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190148	NM_000124.4(ERCC6):c.1850dup (p.Cys617fs)	ERCC6	Pathogenic	criteria provided, single submitter
190150	NM_000124.4(ERCC6):c.1518del (p.Lys506fs)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190152	NM_000124.3(ERCC6):c.1684_1705del	ERCC6	Pathogenic	criteria provided, single submitter
190155	NM_000124.4(ERCC6):c.1954C>T (p.Arg652Ter)	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190157	NM_000124.4(ERCC6):c.1999del (p.Thr667fs)	ERCC6	Pathogenic	criteria provided, single submitter
190158	NM_000124.4(ERCC6):c.2008C>T (p.Arg670Trp)	ERCC6	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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 28 · Orphanet: 11 · 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
ERCC8	Definitive	Autosomal recessive	Cockayne syndrome type 1	10
ERCC1	Supportive	Autosomal recessive	Cockayne syndrome type 2	7

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
ERCC1	Orphanet:1466	COFS syndrome
ERCC1	Orphanet:90322	Cockayne syndrome type 2
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

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ERCC6	HGNC:3438	ENSG00000225830	P0DP91	Chimeric ERCC6-PGBD3 protein	gencc,clinvar
ERCC1	HGNC:3433	ENSG00000012061	P07992	DNA excision repair protein ERCC-1	gencc
ERCC8	HGNC:3439	ENSG00000049167	Q13216	DNA excision repair protein ERCC-8	gencc
PGBD3	HGNC:19400		Q8N328	PiggyBac transposable element-derived protein 3	clinvar
AGAP6	HGNC:23466	ENSG00000204149	Q5VW22	Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 6	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.
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.
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…
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.
AGAP6	Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 6	Putative GTPase-activating protein.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 3 · 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	2	6.9×	0.059
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ERCC6	Other/Unknown	no		PGBD, PiggyBac_TE-derived, CC_ERCC-6_N
ERCC1	Other/Unknown	no		ERCC1/RAD10/SWI10, RuvA_2-like, Restrct_endonuc-II-like
ERCC8	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
PGBD3	Other/Unknown	no		PGBD, PiggyBac_TE-derived
AGAP6	Scaffold/PPI	no		ArfGAP_dom, PH_domain, Ankyrin_rpt

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)	4
unknown	1

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
oocyte	1
secondary oocyte	1
apex of heart	1
parotid gland	1
right atrium auricular region	1
adrenal tissue	1
primordial germ cell in gonad	1
ventricular zone	1
adenohypophysis	1
pituitary gland	1
right hemisphere of cerebellum	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
ERCC1	285	ubiquitous	marker	apex of heart, parotid gland, right atrium auricular region
ERCC8	218	ubiquitous	yes	adrenal tissue, ventricular zone, primordial germ cell in gonad
PGBD3
AGAP6	132		yes	pituitary gland, adenohypophysis, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERCC1	2,085
ERCC8	1,550
AGAP6	204
ERCC6	13
PGBD3	10

Intra-cohort edges

A	B	Sources
ERCC1	ERCC8	string_interaction
ERCC6	ERCC8	biogrid_interaction

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERCC8	Q13216	16
ERCC1	P07992	14
ERCC6	P0DP91	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PGBD3	Q8N328	84.30
AGAP6	Q5VW22	63.73

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Dual incision in TC-NER	3	173.0×	2e-06	ERCC6, ERCC1, ERCC8
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	2	177.1×	2e-04	ERCC6, ERCC8
Formation of TC-NER Pre-Incision Complex	2	141.0×	3e-04	ERCC6, ERCC8
Gap-filling DNA repair synthesis and ligation in TC-NER	2	119.0×	3e-04	ERCC6, ERCC8
HDR through Single Strand Annealing (SSA)	1	97.6×	0.018	ERCC1
Fanconi Anemia Pathway	1	92.8×	0.018	ERCC1
Dual Incision in GG-NER	1	86.5×	0.018	ERCC1
Formation of Incision Complex in GG-NER	1	84.6×	0.018	ERCC1
RNA Polymerase I Transcription Initiation	1	74.6×	0.018	ERCC6
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	1	50.8×	0.023	ERCC6
B-WICH complex positively regulates rRNA expression	1	40.5×	0.027	ERCC6
Neddylation	1	15.8×	0.062	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to X-ray	3	887.0×	8e-08	ERCC6, ERCC1, ERCC8
response to oxidative stress	3	130.6×	1e-05	ERCC6, ERCC1, ERCC8
double-strand break repair via classical nonhomologous end joining	2	1123.5×	2e-05	ERCC6, ERCC8
single strand break repair	2	936.2×	2e-05	ERCC6, ERCC8
transcription-coupled nucleotide-excision repair	2	802.5×	3e-05	ERCC6, ERCC8
positive regulation of DNA repair	2	239.0×	3e-04	ERCC6, ERCC8
positive regulation of transcription initiation by RNA polymerase II	2	181.2×	4e-04	ERCC6, ERCC1
multicellular organism growth	2	91.3×	0.001	ERCC6, ERCC1
regulation of transcription-coupled nucleotide-excision repair	1	5617.3×	0.001	ERCC8
positive regulation of peptidyl-serine phosphorylation of STAT protein	1	2808.7×	0.002	ERCC6
pyrimidine dimer repair by nucleotide-excision repair	1	1404.3×	0.003	ERCC1
pyrimidine dimer repair	1	1404.3×	0.003	ERCC6
obsolete syncytium formation	1	1404.3×	0.003	ERCC1
telomeric DNA-containing double minutes formation	1	1404.3×	0.003	ERCC1
positive regulation of t-circle formation	1	1404.3×	0.003	ERCC1
negative regulation of protection from non-homologous end joining at telomere	1	1404.3×	0.003	ERCC1
DNA repair	2	42.6×	0.003	ERCC6, ERCC1
response to superoxide	1	1123.5×	0.003	ERCC6
mitotic recombination	1	936.2×	0.003	ERCC1
negative regulation of telomere maintenance	1	936.2×	0.003	ERCC1
regulation of DNA-templated transcription elongation	1	936.2×	0.003	ERCC6
post-embryonic hemopoiesis	1	936.2×	0.003	ERCC1
DNA protection	1	936.2×	0.003	ERCC6
transcription elongation by RNA polymerase I	1	702.2×	0.004	ERCC6
negative regulation of double-strand break repair via nonhomologous end joining	1	702.2×	0.004	ERCC6
response to UV-B	1	624.1×	0.004	ERCC6
t-circle formation	1	468.1×	0.005	ERCC1
positive regulation of DNA-templated transcription, elongation	1	432.1×	0.005	ERCC6
UV-damage excision repair	1	432.1×	0.005	ERCC1
UV protection	1	401.2×	0.006	ERCC1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) 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
ERCC1	0	0
ERCC8	0	0
PGBD3	0	0
AGAP6	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: 5; 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	5	ERCC6, ERCC1, ERCC8, PGBD3, AGAP6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ERCC6	0	—
ERCC1	28	—
ERCC8	0	—
PGBD3	0	—
AGAP6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.