Cockayne syndrome

Summary

Cockayne syndrome (MONDO:0016006) is a disease with 4 cohort genes and 9 clinical trials. The dominant Reactome pathway is Dual incision in TC-NER (4 cohort genes).

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 748
• Phenotypes (HPO): 119
• Clinical trials: 9

Clinical features

Epidemiology

Prevalence records

7 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.5	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.2	Europe	Validated
Prevalence at birth	<1 / 1 000 000	0.09	Germany	Validated
Prevalence at birth	1-9 / 1 000 000	0.18	France	Validated
Prevalence at birth	1-9 / 1 000 000	0.2	Italy	Validated
Prevalence at birth	1-9 / 1 000 000	0.45	Netherlands	Validated
Prevalence at birth	1-9 / 1 000 000	0.38	United Kingdom	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000253	Progressive microcephaly	Very frequent (80-99%)
HP:0000408	Progressive sensorineural hearing impairment	Very frequent (80-99%)
HP:0000580	Pigmentary retinopathy	Very frequent (80-99%)
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0001268	Mental deterioration	Very frequent (80-99%)
HP:0001272	Cerebellar atrophy	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0003510	Severe short stature	Very frequent (80-99%)
HP:0004326	Cachexia	Very frequent (80-99%)
HP:0007266	Cerebral dysmyelination	Very frequent (80-99%)
HP:0007703	Abnormality of retinal pigmentation	Very frequent (80-99%)
HP:0008897	Postnatal growth retardation	Very frequent (80-99%)
HP:0000490	Deeply set eye	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000529	Progressive visual loss	Frequent (30-79%)
HP:0000556	Retinal dystrophy	Frequent (30-79%)
HP:0000670	Carious teeth	Frequent (30-79%)
HP:0000762	Decreased nerve conduction velocity	Frequent (30-79%)
HP:0000992	Cutaneous photosensitivity	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001757	High-frequency sensorineural hearing impairment	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0002135	Basal ganglia calcification	Frequent (30-79%)
HP:0002171	Gliosis	Frequent (30-79%)
HP:0002213	Fine hair	Frequent (30-79%)
HP:0002461	Dense calcifications in the cerebellar dentate nucleus	Frequent (30-79%)
HP:0002514	Cerebral calcification	Frequent (30-79%)
HP:0002545	Patchy demyelination of subcortical white matter	Frequent (30-79%)
HP:0002803	Congenital contracture	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003474	Somatic sensory dysfunction	Frequent (30-79%)
HP:0003758	Reduced subcutaneous adipose tissue	Frequent (30-79%)
HP:0005781	Contractures of the large joints	Frequent (30-79%)
HP:0006297	Enamel hypoplasia	Frequent (30-79%)
HP:0007108	Demyelinating peripheral neuropathy	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0007240	Progressive gait ataxia	Frequent (30-79%)
HP:0007346	Subcortical white matter calcifications	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0011359	Dry hair	Frequent (30-79%)
HP:0012372	Abnormal eye morphology	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0100678	Premature skin wrinkling	Frequent (30-79%)
HP:0000011	Neurogenic bladder	Occasional (5-29%)
HP:0000020	Urinary incontinence	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Cockayne syndrome
Mondo ID	MONDO:0016006
MeSH	D003057
Orphanet	191
DOID	DOID:2962
ICD-11	1206275070
NCIT	C9460
SNOMED CT	21086008
UMLS	C0009207
MedGen	40363
GARD	0006122
MedDRA	10009835
NORD	982
Is cancer (heuristic)	no

Also known as: dwarfism-retinal atrophy-deafness syndrome · progeria-like syndrome · progeroid nanism

Data availability: 748 ClinVar variants · 116 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

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

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Subtypes (4): Cockayne syndrome type 3, Cockayne syndrome type 1, 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

600 retrieved; paginated sample, class counts are floors:

280 uncertain significance, 211 likely benign, 35 conflicting classifications of pathogenicity, 26 pathogenic, 19 pathogenic/likely pathogenic, 10 benign, 10 benign/likely benign, 8 likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
16778	NM_001983.4(ERCC1):c.693C>G (p.Phe231Leu)	ERCC1	Pathogenic	no assertion criteria provided
1075759	NM_005236.3(ERCC4):c.22C>T (p.Arg8Ter)	ERCC4	Pathogenic	criteria provided, single submitter
1324343	NM_005236.3(ERCC4):c.1197_1198insCA (p.Ala400fs)	ERCC4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1338473	NM_005236.3(ERCC4):c.579G>A (p.Trp193Ter)	ERCC4	Pathogenic	criteria provided, multiple submitters, no conflicts
1400031	NM_005236.3(ERCC4):c.557_558del (p.Phe186fs)	ERCC4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1422307	NM_005236.3(ERCC4):c.1251T>A (p.Cys417Ter)	ERCC4	Pathogenic	criteria provided, single submitter
1452810	NM_005236.3(ERCC4):c.58C>T (p.Arg20Ter)	ERCC4	Pathogenic	criteria provided, single submitter
2048716	NM_005236.3(ERCC4):c.1447_1450del (p.Arg483fs)	ERCC4	Pathogenic	criteria provided, single submitter
2151562	NM_005236.3(ERCC4):c.68del (p.Val23fs)	ERCC4	Pathogenic	criteria provided, single submitter
2181510	NM_005236.3(ERCC4):c.872T>A (p.Leu291Ter)	ERCC4	Pathogenic	criteria provided, single submitter
2425327	NC_000016.9:g.(?14038570)(14038702_?)del	ERCC4	Pathogenic	criteria provided, single submitter
2425329	NC_000016.9:g.(?14020398)(14022112_?)del	ERCC4	Pathogenic	criteria provided, single submitter
288748	NM_005236.3(ERCC4):c.915del (p.Asn308fs)	ERCC4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2923026	NM_005236.3(ERCC4):c.663dup (p.Met222fs)	ERCC4	Pathogenic	criteria provided, single submitter
2927079	NM_005236.3(ERCC4):c.856C>T (p.Gln286Ter)	ERCC4	Pathogenic	criteria provided, single submitter
2928951	NM_005236.3(ERCC4):c.1376C>A (p.Ser459Ter)	ERCC4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2931256	NM_005236.3(ERCC4):c.938dup (p.Arg314fs)	ERCC4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2931654	NM_005236.3(ERCC4):c.886C>T (p.Gln296Ter)	ERCC4	Pathogenic	criteria provided, single submitter
2931871	NM_005236.3(ERCC4):c.849_856del (p.Leu284fs)	ERCC4	Pathogenic	criteria provided, single submitter
2932701	NM_005236.3(ERCC4):c.148C>T (p.Gln50Ter)	ERCC4	Pathogenic	criteria provided, single submitter
2952742	NM_005236.3(ERCC4):c.1402del (p.Arg468fs)	ERCC4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3243523	NC_000016.9:g.(?14028029)(14031735_?)del	ERCC4	Pathogenic	criteria provided, single submitter
3602651	NM_005236.3(ERCC4):c.1417dup (p.Gln473fs)	ERCC4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3748773	NM_005236.3(ERCC4):c.891T>G (p.Tyr297Ter)	ERCC4	Pathogenic	criteria provided, single submitter
4783059	NM_005236.3(ERCC4):c.2314C>T (p.Arg772Ter)	ERCC4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4783221	NM_005236.3(ERCC4):c.2074C>T (p.Arg692Ter)	ERCC4	Pathogenic	criteria provided, single submitter
4788501	NM_005236.3(ERCC4):c.2241dup (p.Met748fs)	ERCC4	Pathogenic	criteria provided, single submitter
1322833	NM_000124.4(ERCC6):c.39_49delinsA (p.Glu14fs)	ERCC6	Pathogenic/Likely 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
190147	NM_000124.4(ERCC6):c.1526+1G>T	ERCC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 15 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERCC1	Orphanet:1466	COFS syndrome
ERCC1	Orphanet:90322	Cockayne syndrome type 2
ERCC4	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC4	Orphanet:84	Fanconi anemia
ERCC4	Orphanet:90321	Cockayne syndrome type 1
ERCC4	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
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

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ERCC1	HGNC:3433	ENSG00000012061	P07992	DNA excision repair protein ERCC-1	clinvar
ERCC4	HGNC:3436	ENSG00000175595	Q92889	DNA repair endonuclease XPF	clinvar
ERCC6	HGNC:3438	ENSG00000225830	P0DP91	Chimeric ERCC6-PGBD3 protein	clinvar
ERCC8	HGNC:3439	ENSG00000049167	Q13216	DNA excision repair protein ERCC-8	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
ERCC4	DNA repair endonuclease XPF	Catalytic component of a structure-specific DNA repair endonuclease responsible for the 5-prime incision during DNA repair, and which is essential for nucleotide excision repair (NER) and interstrand cross-link (ICL) repair.
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.
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: 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	1	4.3×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ERCC1	Other/Unknown	no		ERCC1/RAD10/SWI10, RuvA_2-like, Restrct_endonuc-II-like
ERCC4	Other/Unknown	no		ERCC4_domain, XPF, RuvA_2-like
ERCC6	Other/Unknown	no		PGBD, PiggyBac_TE-derived, CC_ERCC-6_N
ERCC8	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS

Expression context

Cohort genes with no expression data: 0.

3 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	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	2
male germ line stem cell (sensu Vertebrata) in testis	2
apex of heart	1
parotid gland	1
right atrium auricular region	1
sperm	1
oocyte	1
secondary oocyte	1
primordial germ cell in gonad	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERCC1	285	ubiquitous	marker	apex of heart, parotid gland, right atrium auricular region
ERCC4	242	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue, sperm
ERCC6	257	ubiquitous	marker	oocyte, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis
ERCC8	218	ubiquitous	yes	adrenal tissue, ventricular zone, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERCC4	2,102
ERCC1	2,085
ERCC8	1,550
ERCC6	13

Intra-cohort edges

A	B	Sources
ERCC1	ERCC4	biogrid_interaction, intact, string_interaction
ERCC1	ERCC8	string_interaction
ERCC4	ERCC8	string_interaction
ERCC6	ERCC8	biogrid_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERCC8	Q13216	16
ERCC1	P07992	14
ERCC4	Q92889	13
ERCC6	P0DP91	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 4 evidence-associated genes (4 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 4 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	4	173.0×	1e-08	ERCC1, ERCC4, ERCC6, ERCC8
HDR through Single Strand Annealing (SSA)	2	146.4×	2e-04	ERCC1, ERCC4
Fanconi Anemia Pathway	2	139.3×	2e-04	ERCC1, ERCC4
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	2	132.8×	2e-04	ERCC6, ERCC8
Dual Incision in GG-NER	2	129.8×	2e-04	ERCC1, ERCC4
Formation of Incision Complex in GG-NER	2	126.9×	2e-04	ERCC1, ERCC4
Formation of TC-NER Pre-Incision Complex	2	105.7×	2e-04	ERCC6, ERCC8
Gap-filling DNA repair synthesis and ligation in TC-NER	2	89.2×	3e-04	ERCC6, ERCC8
RNA Polymerase I Transcription Initiation	1	56.0×	0.024	ERCC6
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	1	38.1×	0.031	ERCC6
B-WICH complex positively regulates rRNA expression	1	30.4×	0.035	ERCC6
Neddylation	1	11.8×	0.082	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 4 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	665.2×	4e-07	ERCC1, ERCC6, ERCC8
telomeric DNA-containing double minutes formation	2	2106.5×	6e-06	ERCC1, ERCC4
negative regulation of protection from non-homologous end joining at telomere	2	2106.5×	6e-06	ERCC1, ERCC4
negative regulation of telomere maintenance	2	1404.3×	1e-05	ERCC1, ERCC4
double-strand break repair via classical nonhomologous end joining	2	842.6×	2e-05	ERCC6, ERCC8
response to oxidative stress	3	98.0×	2e-05	ERCC1, ERCC6, ERCC8
single strand break repair	2	702.2×	3e-05	ERCC6, ERCC8
transcription-coupled nucleotide-excision repair	2	601.9×	3e-05	ERCC6, ERCC8
UV protection	2	601.9×	3e-05	ERCC1, ERCC4
DNA repair	3	47.9×	1e-04	ERCC1, ERCC4, ERCC6
double-strand break repair via nonhomologous end joining	2	210.7×	2e-04	ERCC1, ERCC4
nucleotide-excision repair	2	191.5×	2e-04	ERCC1, ERCC4
response to UV	2	183.2×	2e-04	ERCC4, ERCC8
positive regulation of DNA repair	2	179.3×	2e-04	ERCC6, ERCC8
positive regulation of transcription initiation by RNA polymerase II	2	135.9×	4e-04	ERCC1, ERCC6
regulation of transcription-coupled nucleotide-excision repair	1	4213.0×	0.001	ERCC8
multicellular organism growth	2	68.5×	0.001	ERCC1, ERCC6
positive regulation of peptidyl-serine phosphorylation of STAT protein	1	2106.5×	0.002	ERCC6
nucleotide-excision repair involved in interstrand cross-link repair	1	1404.3×	0.003	ERCC4
pyrimidine dimer repair by nucleotide-excision repair	1	1053.2×	0.003	ERCC1
pyrimidine dimer repair	1	1053.2×	0.003	ERCC6
obsolete syncytium formation	1	1053.2×	0.003	ERCC1
positive regulation of t-circle formation	1	1053.2×	0.003	ERCC1
response to superoxide	1	842.6×	0.004	ERCC6
mitotic recombination	1	702.2×	0.004	ERCC1
regulation of DNA-templated transcription elongation	1	702.2×	0.004	ERCC6
post-embryonic hemopoiesis	1	702.2×	0.004	ERCC1
DNA protection	1	702.2×	0.004	ERCC6
transcription elongation by RNA polymerase I	1	526.6×	0.005	ERCC6
negative regulation of double-strand break repair via nonhomologous end joining	1	526.6×	0.005	ERCC6

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERCC1	0	0
ERCC4	0	0
ERCC6	0	0
ERCC8	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
ERCC4	28	Binding:28

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	4	ERCC1, ERCC4, ERCC6, ERCC8

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ERCC1	28	—
ERCC4	28	—
ERCC6	0	—
ERCC8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01142154	PHASE1/PHASE2	COMPLETED	Pharmacokinetics and Safety Study of Single and Multiple Oral Doses Prodarsan™ in Patients With Cockayne Syndrome
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT05484570	Not specified	RECRUITING	Natural History Study for DNA Repair Disorders
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT00001813	Not specified	COMPLETED	Examination of Clinical and Laboratory Abnormalities in Patients With Defective DNA Repair: Xeroderma Pigmentosum, Cockayne Syndrome, or Trichothiodystrophy
NCT00985413	Not specified	TERMINATED	Observational Study to Assess Natural History in Cockayne Syndrome Patients
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03044210	Not specified	TERMINATED	Metabolic Study of Cockayne Syndrome