Trichothiodystrophy

Summary

Trichothiodystrophy (MONDO:0018053) is a disease (an umbrella term covering 7 Mondo subtypes) caused by MARS1 (GenCC Strong), with 9 cohort genes and 2 clinical trials. The dominant Reactome pathway is HIV Transcription Initiation (4 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MARS1 (GenCC Strong)
• Umbrella term: 7 Mondo subtypes
• Cohort genes: 9
• ClinVar variants: 7
• Phenotypes (HPO): 91
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		201	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated
Prevalence at birth	1-9 / 1 000 000	0.12	Europe	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000133	Gonadal dysgenesis	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000278	Retrognathia	Occasional (5-29%)
HP:0000280	Coarse facial features	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000320	Bird-like facies	Occasional (5-29%)
HP:0000411	Protruding ear	Occasional (5-29%)
HP:0000482	Microcornea	Occasional (5-29%)
HP:0000483	Astigmatism	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000509	Conjunctivitis	Occasional (5-29%)
HP:0000519	Developmental cataract	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000546	Retinal degeneration	Occasional (5-29%)
HP:0000565	Esotropia	Occasional (5-29%)
HP:0000601	Hypotelorism	Occasional (5-29%)
HP:0000608	Macular degeneration	Occasional (5-29%)
HP:0000613	Photophobia	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000656	Ectropion	Occasional (5-29%)
HP:0000670	Carious teeth	Occasional (5-29%)
HP:0000938	Osteopenia	Occasional (5-29%)
HP:0000958	Dry skin	Occasional (5-29%)
HP:0000964	Eczematoid dermatitis	Occasional (5-29%)
HP:0000992	Cutaneous photosensitivity	Occasional (5-29%)
HP:0001097	Keratoconjunctivitis sicca	Occasional (5-29%)
HP:0001197	Abnormality of prenatal development or birth	Occasional (5-29%)
HP:0001217	Clubbing	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)
HP:0001338	Partial agenesis of the corpus callosum	Occasional (5-29%)
HP:0001363	Craniosynostosis	Occasional (5-29%)
HP:0001373	Joint dislocation	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001537	Umbilical hernia	Occasional (5-29%)
HP:0001598	Concave nail	Occasional (5-29%)
HP:0001618	Dysphonia	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0001807	Ridged nail	Occasional (5-29%)
HP:0001808	Fragile nails	Occasional (5-29%)
HP:0001809	Split nail	Occasional (5-29%)
HP:0001875	Decreased total neutrophil count	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	trichothiodystrophy
Mondo ID	MONDO:0018053
OMIM	601675
Orphanet	33364
DOID	DOID:0111866
ICD-11	1366758649
NCIT	C4924
SNOMED CT	723551003
UMLS	C1955934
MedGen	363064
GARD	0012109
MedDRA	10044628
NORD	1292
Is cancer (heuristic)	no

Also known as: trichothiodystrophy syndrome

Data availability: 7 ClinVar variants · 8 GenCC gene-disease records · 64 cell lines.

Disease family

An umbrella term covering 7 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › ectodermal dysplasia syndrome › trichothiodystrophy

Related subtypes (119): ADULT syndrome, autosomal dominant palmoplantar keratoderma and congenital alopecia, ameloonychohypohidrotic syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, anonychia with flexural pigmentation, Böök syndrome, blepharocheilodontic syndrome, Stern-Lubinsky-Durrie syndrome, dermatopathia pigmentosa reticularis, dermo-odonto dysplasia, Rapp-Hodgkin syndrome, Clouston syndrome, ectodermal dysplasia, trichoodontoonychial type, gingival fibromatosis-hypertrichosis syndrome, hypertrichosis cubiti-short stature syndrome, Johnson neuroectodermal syndrome, Marshall syndrome, Naegeli-Franceschetti-Jadassohn syndrome, oculodentodigital dysplasia, Cronkhite-Canada syndrome, scalp-ear-nipple syndrome, tooth and nail syndrome, tricho-dento-osseous syndrome, tricho-retino-dento-digital syndrome, acrofacial dysostosis, Weyers type, Ackerman syndrome, alopecia - contractures - dwarfism - intellectual disability syndrome, AREDYLD syndrome, Barber-Say syndrome, oculoosteocutaneous syndrome, cataract-hypertrichosis-intellectual disability syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, cerebellar ataxia-ectodermal dysplasia syndrome, cranioectodermal dysplasia, conductive deafness-ptosis-skeletal anomalies syndrome, dermatoosteolysis, Kirghizian type, Dubowitz syndrome, ectodermal dysplasia-sensorineural deafness syndrome, ectodermal dysplasia-intellectual disability-central nervous system malformation syndrome, hypohidrotic ectodermal dysplasia-hypothyroidism-ciliary dyskinesia syndrome, cleft lip/palate-ectodermal dysplasia syndrome, EEM syndrome, Ellis-van Creveld syndrome, amelocerebrohypohidrotic syndrome, GAPO syndrome, ichthyosis-alopecia-eclabion-ectropion-intellectual disability syndrome, Leukomelanoderma-infantilism-intellectual disability-hypodontia-hypotrichosis syndrome, Dahlberg-Borer-Newcomer syndrome, cartilage-hair hypoplasia, oculotrichodysplasia, pilodental dysplasia-refractive errors syndrome, Bartsocas-Papas syndrome 1, ectodermal dysplasia-blindness syndrome, Schinzel-Giedion syndrome, Teebi-Shaltout syndrome, taurodontia-absent teeth-sparse hair syndrome, odontotrichomelic syndrome, trichomegaly-retina pigmentary degeneration-dwarfism syndrome, trichoodontoonychial dysplasia, CHIME syndrome, anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome, Ito hypomelanosis, contractures-ectodermal dysplasia-cleft lip/palate syndrome, incontinentia pigmenti, Toriello-Lacassie-Droste syndrome, odontomicronychial dysplasia, ectodermal dysplasia with natal teeth, Turnpenny type, hidrotic ectodermal dysplasia, Christianson-Fourie type, trichodental syndrome, congenital hypotrichosis with juvenile macular dystrophy, tricho-oculo-dermo-vertebral syndrome, odonto-tricho-ungual-digito-palmar syndrome, Fried’s tooth and nail syndrome, limb-mammary syndrome, epidermolysis bullosa simplex due to plakophilin deficiency, arrhythmogenic cardiomyopathy with wooly hair and keratoderma, Curly hair - acral keratoderma - caries syndrome, hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma syndrome, Lelis syndrome, Fontaine progeroid syndrome, ectodermal dysplasia-syndactyly syndrome, ectodermal dysplasia 5, hair/nail type, nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome, ectodermal dysplasia 12, hypohidrotic/hair/tooth/nail type, cardiofaciocutaneous syndrome, choroidal atrophy-alopecia syndrome, dyskeratosis congenita, hidrotic ectodermal dysplasia, Halal type, hypertrichosis lanuginosa congenita, hypohidrotic ectodermal dysplasia, odonto-onycho dysplasia-alopecia syndrome, pili torti-onychodysplasia syndrome, chondroectodermal dysplasia with night blindness, trichorhinophalangeal syndrome, trichodermodysplasia-dental alterations syndrome, autosomal dominant trichoodontoonychodysplasia-syndactyly, focal facial dermal dysplasia, KID syndrome, pure hair and nail ectodermal dysplasia, circumscribed palmoplantar hypokeratosis, trichodysplasia-amelogenesis imperfecta syndrome, dermotrichic syndrome, alves Castelo dos Santos syndrome, Brunoni syndrome, ectodermal dysplasia Bartalos type, ectodermal dysplasia margarita type, ectodermal dysplasia alopecia preaxial polydactyly, ectodermal dysplasia arthrogryposis diabetes mellitus, ectodermal dysplasia blindness, ectodermal dysplasia neurosensory deafness, ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis, ectodermal dysplasia 15, hypohidrotic/hair type, linear hypopigmentation and craniofacial asymmetry with acral, ocular and brain anomalies, jones hersh yusk syndrome, ectodermal dysplasia 13, hair/tooth type, arthrogryposis-ectodermal dysplasia-other anomalies syndrome, ectodermal dysplasia WNT10A related, CTSC-related disorder, ectodermal dysplasia 17 with or without limb malformations

Subtypes (7): photosensitive trichothiodystrophy, trichothiodystrophy 5, nonphotosensitive, trichothiodystrophy 6, nonphotosensitive, trichothiodystrophy 4, nonphotosensitive, trichothiodystrophy 8, nonphotosensitive, trichothiodystrophy 9, nonphotosensitive, trichothiodystrophy 7, nonphotosensitive

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

7 retrieved; paginated sample, class counts are floors:

2 pathogenic, 2 uncertain significance, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1363277	NM_000400.4(ERCC2):c.1867dup (p.Val623fs)	ERCC2	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
2168783	NM_000400.4(ERCC2):c.1480-1G>C	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
634549	NM_000400.4(ERCC2):c.1636G>A (p.Glu546Lys)	ERCC2	Likely pathogenic	criteria provided, single submitter
1304777	NM_000400.4(ERCC2):c.2143C>T (p.Gln715Ter)	ERCC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3238864	NM_005030.6(PLK1):c.1316C>G (p.Ser439Ter)	PLK1	Uncertain significance	criteria provided, single submitter
3780692	NM_152295.5(TARS1):c.330-1G>T	TARS1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 69 · Orphanet: 15 · 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	trichothiodystrophy 1, photosensitive	19
ERCC3	Definitive	Autosomal recessive	trichothiodystrophy 2, photosensitive	12
GTF2H5	Definitive	Autosomal recessive	trichothiodystrophy 3, photosensitive	5
MPLKIP	Definitive	Autosomal recessive	trichothiodystrophy 4, nonphotosensitive	5
GTF2E2	Strong	Autosomal recessive	trichothiodystrophy 6, nonphotosensitive	6
MARS1	Strong	Autosomal recessive	trichothiodystrophy	12
RNF113A	Strong	X-linked	trichothiodystrophy 5, nonphotosensitive	7
TARS1	Moderate	Autosomal recessive	trichothiodystrophy 7, nonphotosensitive	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TARS1	Orphanet:33364	Trichothiodystrophy
ERCC2	Orphanet:1466	COFS syndrome
ERCC2	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC2	Orphanet:33364	Trichothiodystrophy
ERCC2	Orphanet:910	Xeroderma pigmentosum
RNF113A	Orphanet:33364	Trichothiodystrophy
MPLKIP	Orphanet:33364	Trichothiodystrophy
GTF2H5	Orphanet:33364	Trichothiodystrophy
ERCC3	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC3	Orphanet:33364	Trichothiodystrophy
ERCC3	Orphanet:910	Xeroderma pigmentosum
GTF2E2	Orphanet:33364	Trichothiodystrophy
MARS1	Orphanet:397735	Autosomal dominant Charcot-Marie-Tooth disease type 2U
MARS1	Orphanet:401835	Autosomal recessive spastic paraplegia type 70
MARS1	Orphanet:440427	Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TARS1	HGNC:11572	ENSG00000113407	P26639	Threonine–tRNA ligase 1, cytoplasmic	gencc,clinvar
ERCC2	HGNC:3434	ENSG00000104884	P18074	General transcription and DNA repair factor IIH helicase subunit XPD	gencc,clinvar
RNF113A	HGNC:12974	ENSG00000125352	O15541	E3 ubiquitin-protein ligase RNF113A	gencc
MPLKIP	HGNC:16002	ENSG00000168303	Q8TAP9	M-phase-specific PLK1-interacting protein	gencc
GTF2H5	HGNC:21157	ENSG00000272047	Q6ZYL4	General transcription factor IIH subunit 5	gencc
ERCC3	HGNC:3435	ENSG00000163161	P19447	General transcription and DNA repair factor IIH helicase/translocase subunit XPB	gencc
GTF2E2	HGNC:4651	ENSG00000197265	P29084	Transcription initiation factor IIE subunit beta	gencc
MARS1	HGNC:6898	ENSG00000166986	P56192	Methionine–tRNA ligase, cytoplasmic	gencc
PLK1	HGNC:9077	ENSG00000166851	P53350	Serine/threonine-protein kinase PLK1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TARS1	Threonine–tRNA ligase 1, cytoplasmic	Catalyzes the attachment of threonine to tRNA(Thr) in a two-step reaction: threonine is first activated by ATP to form Thr-AMP and then transferred to the acceptor end of tRNA(Thr).
ERCC2	General transcription and DNA repair factor IIH helicase subunit XPD	ATP-dependent 5’-3’ DNA helicase.
RNF113A	E3 ubiquitin-protein ligase RNF113A	Required for pre-mRNA splicing as component of the spliceosome.
MPLKIP	M-phase-specific PLK1-interacting protein	May play a role in maintenance of cell cycle integrity by regulating mitosis or cytokinesis.
GTF2H5	General transcription factor IIH subunit 5	Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription…
ERCC3	General transcription and DNA repair factor IIH helicase/translocase subunit XPB	ATP-dependent 3’-5’ DNA helicase/translocase.
GTF2E2	Transcription initiation factor IIE subunit beta	Recruits TFIIH to the initiation complex and stimulates the RNA polymerase II C-terminal domain kinase and DNA-dependent ATPase activities of TFIIH.
MARS1	Methionine–tRNA ligase, cytoplasmic	Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.
PLK1	Serine/threonine-protein kinase PLK1	Serine/threonine-protein kinase that performs several important functions throughout M phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inact…

Protein-family classification

Druggable: 4 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.44

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)	3	4.0×	0.133
Kinase	1	3.1×	0.563
Transcription factor	1	0.9×	0.847
Other/Unknown	4	0.8×	0.847

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TARS1	Enzyme (other)	yes	6.1.1.3	aa-tRNA-synt_IIb, Thr-tRNA-ligase_IIa, TGS
ERCC2	Enzyme (other)	yes	3.6.4.12	RAD3/XPD, DNA/RNA_helicase_DEAH_CS, Helicase-like_DEXD_c2
RNF113A	Transcription factor	no		Znf_CCCH, Znf_RING, Znf_RING/FYVE/PHD
MPLKIP	Other/Unknown	no		MPLKIP-like_vertebrate, TTDN1/SICKLE
GTF2H5	Other/Unknown	no		TFIIH_TTDA/Tfb5, TFB5-like_sf
ERCC3	Other/Unknown	no		XPB/Ssl2, Helicase_C-like, Helicase/UvrB_N
GTF2E2	Other/Unknown	no		TFIIE_bsu_DNA-bd, TFIIE-bsu, WH-like_DNA-bd_sf
MARS1	Enzyme (other)	yes	6.1.1.10	WHEP-TRS_dom, aa-tRNA-synth_I_CS, GST_C
PLK1	Kinase	yes	2.7.11.21	Prot_kinase_dom, POLO_box_dom, Ser/Thr_kinase_AS

Expression context

Cohort genes with no expression data: 0.

9 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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	2
sural nerve	2
superior surface of tongue	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
tongue squamous epithelium	1
left adrenal gland	1
right adrenal gland	1
stromal cell of endometrium	1
granulocyte	1
leukocyte	1
monocyte	1
kidney epithelium	1
upper arm skin	1
renal medulla	1
saphenous vein	1
body of pancreas	1
pancreas	1
cerebellar cortex	1
ganglionic eminence	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TARS1	296	ubiquitous	marker	sural nerve, adrenal tissue, tongue squamous epithelium
ERCC2	184	ubiquitous	marker	stromal cell of endometrium, right adrenal gland, left adrenal gland
RNF113A	240	ubiquitous	marker	granulocyte, leukocyte, monocyte
MPLKIP	255	ubiquitous	marker	kidney epithelium, upper arm skin, superior surface of tongue
GTF2H5	293	ubiquitous	marker	renal medulla, superior surface of tongue, saphenous vein
ERCC3	277	ubiquitous	marker	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
GTF2E2	274	ubiquitous	marker	adrenal tissue, body of pancreas, pancreas
MARS1	301	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PLK1	179	ubiquitous	marker	ventricular zone, primordial germ cell in gonad, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 11.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLK1	7,330
MARS1	5,727
ERCC3	3,219
TARS1	2,811
ERCC2	2,746
GTF2E2	2,377
RNF113A	2,007
GTF2H5	1,855
MPLKIP	652

Intra-cohort edges

A	B	Sources
ERCC2	ERCC3	intact, string_interaction
ERCC2	GTF2E2	intact, string_interaction
ERCC2	GTF2H5	biogrid_interaction, intact, string_interaction
ERCC3	GTF2E2	string_interaction
ERCC3	GTF2H5	biogrid_interaction, intact, string_interaction
ERCC3	MPLKIP	string_interaction
GTF2E2	MPLKIP	string_interaction
GTF2E2	RNF113A	string_interaction
GTF2H5	MPLKIP	string_interaction
MPLKIP	PLK1	biogrid_interaction, intact
MPLKIP	RNF113A	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLK1	P53350	85
GTF2H5	Q6ZYL4	53
ERCC3	P19447	52
ERCC2	P18074	51
GTF2E2	P29084	42
RNF113A	O15541	11
MARS1	P56192	7
TARS1	P26639	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MPLKIP	Q8TAP9	57.39

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 86. Enrichment computed across 9 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
HIV Transcription Initiation	4	116.5×	3e-07	ERCC2, GTF2H5, ERCC3, GTF2E2
RNA Polymerase II HIV Promoter Escape	4	116.5×	3e-07	ERCC2, GTF2H5, ERCC3, GTF2E2
RNA Polymerase II Promoter Escape	4	116.5×	3e-07	ERCC2, GTF2H5, ERCC3, GTF2E2
RNA Polymerase II Transcription Pre-Initiation And Promoter Opening	4	116.5×	3e-07	ERCC2, GTF2H5, ERCC3, GTF2E2
RNA Polymerase II Transcription Initiation	4	116.5×	3e-07	ERCC2, GTF2H5, ERCC3, GTF2E2
RNA Polymerase II Transcription Initiation And Promoter Clearance	4	116.5×	3e-07	ERCC2, GTF2H5, ERCC3, GTF2E2
Transcription of the HIV genome	4	86.5×	9e-07	ERCC2, GTF2H5, ERCC3, GTF2E2
RNA Polymerase II Pre-transcription Events	4	68.8×	2e-06	ERCC2, GTF2H5, ERCC3, GTF2E2
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	3	152.9×	6e-06	ERCC2, GTF2H5, ERCC3
RNA Pol II CTD phosphorylation and interaction with CE	3	152.9×	6e-06	ERCC2, GTF2H5, ERCC3
mRNA Capping	3	142.8×	7e-06	ERCC2, GTF2H5, ERCC3
Formation of the Early Elongation Complex	3	126.0×	9e-06	ERCC2, GTF2H5, ERCC3
Formation of the HIV-1 Early Elongation Complex	3	126.0×	9e-06	ERCC2, GTF2H5, ERCC3
RNA Polymerase I Transcription Termination	3	122.4×	9e-06	ERCC2, GTF2H5, ERCC3
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	3	99.6×	1e-05	ERCC2, GTF2H5, ERCC3
Formation of HIV-1 elongation complex containing HIV-1 Tat	3	97.3×	1e-05	ERCC2, GTF2H5, ERCC3
Tat-mediated elongation of the HIV-1 transcript	3	97.3×	1e-05	ERCC2, GTF2H5, ERCC3
Dual Incision in GG-NER	3	97.3×	1e-05	ERCC2, GTF2H5, ERCC3
Formation of Incision Complex in GG-NER	3	95.2×	1e-05	ERCC2, GTF2H5, ERCC3
Formation of HIV elongation complex in the absence of HIV Tat	3	93.1×	1e-05	ERCC2, GTF2H5, ERCC3
RNA Polymerase I Transcription Initiation	3	84.0×	2e-05	ERCC2, GTF2H5, ERCC3
Formation of TC-NER Pre-Incision Complex	3	79.3×	2e-05	ERCC2, GTF2H5, ERCC3
Formation of RNA Pol II elongation complex	3	72.6×	3e-05	ERCC2, GTF2H5, ERCC3
RNA Polymerase II Transcription Elongation	3	72.6×	3e-05	ERCC2, GTF2H5, ERCC3
TP53 Regulates Transcription of DNA Repair Genes	3	68.0×	3e-05	ERCC2, GTF2H5, ERCC3
Gap-filling DNA repair synthesis and ligation in TC-NER	3	66.9×	3e-05	ERCC2, GTF2H5, ERCC3
Dual incision in TC-NER	3	64.9×	3e-05	ERCC2, GTF2H5, ERCC3
RNA Polymerase I Promoter Escape	3	45.6×	9e-05	ERCC2, GTF2H5, ERCC3
NoRC negatively regulates rRNA expression	3	39.3×	1e-04	ERCC2, GTF2H5, ERCC3
Cytosolic tRNA aminoacylation	2	109.8×	4e-04	TARS1, MARS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
transcription initiation at RNA polymerase II promoter	4	166.4×	5e-07	ERCC2, GTF2H5, ERCC3, GTF2E2
regulation of mitotic cell cycle phase transition	3	561.7×	6e-07	ERCC2, ERCC3, PLK1
nucleotide-excision repair	3	127.7×	4e-05	ERCC2, GTF2H5, ERCC3
transcription by RNA polymerase II	4	31.3×	1e-04	ERCC2, GTF2H5, ERCC3, GTF2E2
transcription elongation by RNA polymerase I	2	468.1×	1e-04	ERCC2, GTF2H5
hair cell differentiation	2	468.1×	1e-04	ERCC2, ERCC3
transcription-coupled nucleotide-excision repair	2	267.5×	3e-04	ERCC2, ERCC3
UV protection	2	267.5×	3e-04	ERCC2, ERCC3
maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	2	149.8×	8e-04	ERCC2, GTF2H5
embryonic organ development	2	107.0×	0.001	ERCC2, ERCC3
nucleotide-excision repair, preincision complex assembly	1	1872.4×	0.004	GTF2H5
regulation of protein localization to cell cortex	1	1872.4×	0.004	PLK1
positive regulation of mitotic nuclear envelope disassembly	1	1872.4×	0.004	PLK1
methionyl-tRNA aminoacylation	1	936.2×	0.005	MARS1
snoRNA splicing	1	936.2×	0.005	RNF113A
positive regulation of mitotic recombination	1	936.2×	0.005	ERCC2
Golgi inheritance	1	936.2×	0.005	PLK1
synaptonemal complex disassembly	1	936.2×	0.005	PLK1
mitotic cleavage furrow formation	1	936.2×	0.005	PLK1
regulation of anaphase-promoting complex-dependent catabolic process	1	936.2×	0.005	PLK1
threonyl-tRNA aminoacylation	1	624.1×	0.007	TARS1
response to oxidative stress	2	29.0×	0.008	ERCC2, ERCC3
female meiosis chromosome segregation	1	468.1×	0.008	PLK1
homologous chromosome segregation	1	374.5×	0.010	PLK1
central nervous system myelin formation	1	267.5×	0.013	ERCC2
negative regulation of chemokine-mediated signaling pathway	1	267.5×	0.013	RNF113A
metaphase/anaphase transition of mitotic cell cycle	1	234.1×	0.014	PLK1
hair follicle maturation	1	234.1×	0.014	ERCC2
mitotic nuclear membrane disassembly	1	208.1×	0.015	PLK1
DNA topological change	1	187.2×	0.015	ERCC3

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 7

Druggability breadth: 6 of 9 evidence-associated genes (67%) 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
PLK1	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLK1	25	4
ERCC2	16	4
TARS1	0	0
RNF113A	0	0
MPLKIP	0	0
GTF2H5	0	0
ERCC3	0	0
GTF2E2	0	0
MARS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SUNITINIB	4	ERCC2
FEDRATINIB	4	PLK1
RUXOLITINIB	4	PLK1
BOSUTINIB	4	PLK1
BRIGATINIB	4	PLK1
VORINOSTAT	4	PLK1
DINACICLIB	3	ERCC2
DEFACTINIB	3	ERCC2
ALVOCIDIB	3	ERCC2
VOLASERTIB	3	PLK1
RIGOSERTIB	3	PLK1
RIGOSERTIB SODIUM	3	PLK1
QUERCETIN	3	PLK1
LESTAURTINIB	3	PLK1
SELICICLIB	2	ERCC2
ZOTIRACICLIB	2	ERCC2
DANUSERTIB	2	ERCC2, PLK1
MILCICLIB	2	ERCC2
SILMITASERTIB	2	PLK1
THYMOQUINONE	2	PLK1
ONVANSERTIB	2	PLK1
ADAVOSERTIB	2	PLK1
AZD-6482	2	PLK1
R-406	2	PLK1
BI-2536	2	PLK1
SOTRASTAURIN	2	PLK1
ELLAGIC ACID	2	PLK1
BAICALEIN	2	PLK1
PF-00562271	1	ERCC2
PHA-793887	1	ERCC2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PLK1	979	Binding:967, Functional:8, ADMET:4
TARS1	53	Binding:53
MARS1	26	Binding:26
ERCC2	3	Binding:3
ERCC3	1	ADMET:1
GTF2E2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TARS1	6.1.1.3	threonine-tRNA ligase
ERCC2	3.6.4.12	DNA helicase
MARS1	6.1.1.10	methionine-tRNA ligase
PLK1	2.7.11.21	polo kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PLK1	979

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 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
FEDRATINIB	4	PLK1
RUXOLITINIB	4	PLK1
BOSUTINIB	4	PLK1
BRIGATINIB	4	PLK1
VORINOSTAT	4	PLK1
DINACICLIB	3	ERCC2
DEFACTINIB	3	ERCC2
ALVOCIDIB	3	ERCC2
VOLASERTIB	3	PLK1
RIGOSERTIB	3	PLK1
RIGOSERTIB SODIUM	3	PLK1
QUERCETIN	3	PLK1
LESTAURTINIB	3	PLK1
SELICICLIB	2	ERCC2
ZOTIRACICLIB	2	ERCC2
DANUSERTIB	2	ERCC2, PLK1
MILCICLIB	2	ERCC2
SILMITASERTIB	2	PLK1
THYMOQUINONE	2	PLK1
ONVANSERTIB	2	PLK1
ADAVOSERTIB	2	PLK1
AZD-6482	2	PLK1
R-406	2	PLK1
BI-2536	2	PLK1
SOTRASTAURIN	2	PLK1
ELLAGIC ACID	2	PLK1
BAICALEIN	2	PLK1
PF-00562271	1	ERCC2
PHA-793887	1	ERCC2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	ERCC2, PLK1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	TARS1, MARS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	RNF113A, MPLKIP, GTF2H5, ERCC3, GTF2E2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GTF2H5	0	ERCC2
ERCC3	1	ERCC2
TARS1	53	—
RNF113A	0	—
MPLKIP	0	—
GTF2E2	1	—
MARS1	26	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05484570	Not specified	RECRUITING	Natural History Study for DNA Repair Disorders
NCT00001813	Not specified	COMPLETED	Examination of Clinical and Laboratory Abnormalities in Patients With Defective DNA Repair: Xeroderma Pigmentosum, Cockayne Syndrome, or Trichothiodystrophy