Trichothiodystrophy 1, photosensitive

Summary

Trichothiodystrophy 1, photosensitive (MONDO:0011125) is a disease caused by variants in ERCC2 and ERCC3, with 5 cohort genes.

At a glance

• Causal genes: ERCC2 (GenCC Definitive), ERCC3 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 124

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	trichothiodystrophy 1, photosensitive
Mondo ID	MONDO:0011125
OMIM	601675
Orphanet	670
DOID	DOID:0111873
NCIT	C156433
UMLS	C1866504
MedGen	355730
GARD	0005270
Is cancer (heuristic)	no

Also known as: PIBIDS syndrome · trichothiodystrophy 1, photosensitive · TTD1

Data availability: 124 ClinVar variants · 5 GenCC gene-disease records · 33 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › ectodermal dysplasia syndrome › trichothiodystrophy › photosensitive trichothiodystrophy › trichothiodystrophy 1, photosensitive

Related subtypes (2): trichothiodystrophy 2, photosensitive, trichothiodystrophy 3, photosensitive

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

124 retrieved; paginated sample, class counts are floors:

36 uncertain significance, 29 pathogenic/likely pathogenic, 17 conflicting classifications of pathogenicity, 17 likely pathogenic, 13 pathogenic, 5 benign/likely benign, 4 benign, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3390959	NM_001354640.2(CIROP):c.988+1G>C	CIROP	Pathogenic	criteria provided, single submitter
1028729	NM_000400.4(ERCC2):c.2006_2007insA (p.Lys671fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1176084	NM_000400.4(ERCC2):c.139G>A (p.Gly47Arg)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1319436	NM_000400.4(ERCC2):c.1984C>T (p.Gln662Ter)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1319438	NM_000400.4(ERCC2):c.1759-2A>G	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1319444	NM_000400.4(ERCC2):c.1007dup (p.Leu337fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
134095	NM_000400.4(ERCC2):c.1703_1704del (p.Phe568fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
134102	NM_000400.4(ERCC2):c.2150C>G (p.Ala717Gly)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1346864	NM_000400.4(ERCC2):c.1480-2A>C	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1363277	NM_000400.4(ERCC2):c.1867dup (p.Val623fs)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1415975	NM_000400.4(ERCC2):c.1996C>T (p.Arg666Trp)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455083	NM_000400.4(ERCC2):c.1354C>T (p.Gln452Ter)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
16781	NM_000400.4(ERCC2):c.2173G>C (p.Ala725Pro)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16784	NM_000400.4(ERCC2):c.335G>A (p.Arg112His)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
16785	NM_000400.4(ERCC2):c.1972C>T (p.Arg658Cys)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16788	NM_000400.4(ERCC2):c.1846C>T (p.Arg616Trp)	ERCC2	Pathogenic/Likely 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
16793	NM_000400.4(ERCC2):c.2047C>T (p.Arg683Trp)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705082	NM_000400.4(ERCC2):c.2141_2148del (p.Val714fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705248	NM_000400.4(ERCC2):c.195_196delinsTT (p.Glu66Ter)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705268	NM_000400.4(ERCC2):c.2191-1G>A	ERCC2	Pathogenic	no assertion criteria provided
2169658	NM_000400.4(ERCC2):c.1017C>A (p.Tyr339Ter)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2573404	NM_000400.4(ERCC2):c.1802G>T (p.Arg601Leu)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
264679	NM_000400.4(ERCC2):c.2048G>A (p.Arg683Gln)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
2675039	NM_000400.4(ERCC2):c.361-1G>A	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675051	NM_000400.4(ERCC2):c.1852_1871dup (p.Tyr625fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2735179	NM_000400.4(ERCC2):c.849dup (p.Glu284fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2773219	NM_000400.4(ERCC2):c.1984_1985del (p.Gln662fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3023764	NM_000400.4(ERCC2):c.1847_1850del (p.Arg616fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3241396	NM_000400.4(ERCC2):c.570C>A (p.Cys190Ter)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 31 · Orphanet: 10 · 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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERCC2	Orphanet:1466	COFS syndrome
ERCC2	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC2	Orphanet:33364	Trichothiodystrophy
ERCC2	Orphanet:910	Xeroderma pigmentosum
ERCC3	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC3	Orphanet:33364	Trichothiodystrophy
ERCC3	Orphanet:910	Xeroderma pigmentosum
MPLKIP	Orphanet:33364	Trichothiodystrophy
CIROP	Orphanet:101063	Situs inversus totalis
CIROP	Orphanet:157769	Situs ambiguus

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
ERCC2	HGNC:3434	ENSG00000104884	P18074	General transcription and DNA repair factor IIH helicase subunit XPD	gencc,clinvar
ERCC3	HGNC:3435	ENSG00000163161	P19447	General transcription and DNA repair factor IIH helicase/translocase subunit XPB	gencc
MPLKIP	HGNC:16002	ENSG00000168303	Q8TAP9	M-phase-specific PLK1-interacting protein	clinvar
KLC3	HGNC:20717	ENSG00000104892	Q6P597	Kinesin light chain 3	clinvar
CIROP	HGNC:53647	ENSG00000283654	A0A1B0GTW7	Ciliated left-right organizer metallopeptidase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERCC2	General transcription and DNA repair factor IIH helicase subunit XPD	ATP-dependent 5’-3’ DNA helicase.
ERCC3	General transcription and DNA repair factor IIH helicase/translocase subunit XPB	ATP-dependent 3’-5’ DNA helicase/translocase.
MPLKIP	M-phase-specific PLK1-interacting protein	May play a role in maintenance of cell cycle integrity by regulating mitosis or cytokinesis.
KLC3	Kinesin light chain 3	Kinesin is a microtubule-associated force-producing protein that may play a role in organelle transport.
CIROP	Ciliated left-right organizer metallopeptidase	Putative metalloproteinase that plays a role in left-right patterning process.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.4

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
Protease	1	7.3×	0.388
Enzyme (other)	1	2.4×	0.530
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ERCC2	Enzyme (other)	yes	3.6.4.12	RAD3/XPD, DNA/RNA_helicase_DEAH_CS, Helicase-like_DEXD_c2
ERCC3	Other/Unknown	no		XPB/Ssl2, Helicase_C-like, Helicase/UvrB_N
MPLKIP	Other/Unknown	no		MPLKIP-like_vertebrate, TTDN1/SICKLE
KLC3	Other/Unknown	no		Kinesin_light, TPR-like_helical_dom_sf, TPR_rpt
CIROP	Protease	yes		Peptidase_M8

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
upper arm skin	2
left adrenal gland	1
right adrenal gland	1
stromal cell of endometrium	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
sural nerve	1
kidney epithelium	1
superior surface of tongue	1
skin of abdomen	1
skin of leg	1
C1 segment of cervical spinal cord	1
mucosa of stomach	1
primary visual cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERCC2	184	ubiquitous	marker	stromal cell of endometrium, right adrenal gland, left adrenal gland
ERCC3	277	ubiquitous	marker	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
MPLKIP	255	ubiquitous	marker	kidney epithelium, upper arm skin, superior surface of tongue
KLC3	189	broad	marker	upper arm skin, skin of abdomen, skin of leg
CIROP	49	tissue_specific	yes	mucosa of stomach, C1 segment of cervical spinal cord, primary visual cortex

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERCC3	3,219
ERCC2	2,746
KLC3	2,698
MPLKIP	652
CIROP	128

Intra-cohort edges

A	B	Sources
ERCC2	ERCC3	intact, string_interaction
ERCC3	MPLKIP	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERCC3	P19447	52
ERCC2	P18074	51

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KLC3	Q6P597	76.05
CIROP	A0A1B0GTW7	73.73
MPLKIP	Q8TAP9	57.39

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 46. 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
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	2	271.9×	1e-04	ERCC2, ERCC3
RNA Pol II CTD phosphorylation and interaction with CE	2	271.9×	1e-04	ERCC2, ERCC3
mRNA Capping	2	253.8×	1e-04	ERCC2, ERCC3
Formation of the Early Elongation Complex	2	223.9×	1e-04	ERCC2, ERCC3
Formation of the HIV-1 Early Elongation Complex	2	223.9×	1e-04	ERCC2, ERCC3
RNA Polymerase I Transcription Termination	2	217.5×	1e-04	ERCC2, ERCC3
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	2	177.1×	1e-04	ERCC2, ERCC3
Formation of HIV-1 elongation complex containing HIV-1 Tat	2	173.0×	1e-04	ERCC2, ERCC3
Tat-mediated elongation of the HIV-1 transcript	2	173.0×	1e-04	ERCC2, ERCC3
Dual Incision in GG-NER	2	173.0×	1e-04	ERCC2, ERCC3
Formation of Incision Complex in GG-NER	2	169.2×	1e-04	ERCC2, ERCC3
Formation of HIV elongation complex in the absence of HIV Tat	2	165.5×	1e-04	ERCC2, ERCC3
HIV Transcription Initiation	2	155.4×	1e-04	ERCC2, ERCC3
RNA Polymerase II HIV Promoter Escape	2	155.4×	1e-04	ERCC2, ERCC3
RNA Polymerase II Promoter Escape	2	155.4×	1e-04	ERCC2, ERCC3
RNA Polymerase II Transcription Pre-Initiation And Promoter Opening	2	155.4×	1e-04	ERCC2, ERCC3
RNA Polymerase II Transcription Initiation	2	155.4×	1e-04	ERCC2, ERCC3
RNA Polymerase II Transcription Initiation And Promoter Clearance	2	155.4×	1e-04	ERCC2, ERCC3
RNA Polymerase I Transcription Initiation	2	149.3×	1e-04	ERCC2, ERCC3
Formation of TC-NER Pre-Incision Complex	2	141.0×	2e-04	ERCC2, ERCC3
Formation of RNA Pol II elongation complex	2	129.0×	2e-04	ERCC2, ERCC3
RNA Polymerase II Transcription Elongation	2	129.0×	2e-04	ERCC2, ERCC3
TP53 Regulates Transcription of DNA Repair Genes	2	120.8×	2e-04	ERCC2, ERCC3
Gap-filling DNA repair synthesis and ligation in TC-NER	2	119.0×	2e-04	ERCC2, ERCC3
Transcription of the HIV genome	2	115.3×	2e-04	ERCC2, ERCC3
Dual incision in TC-NER	2	115.3×	2e-04	ERCC2, ERCC3
RNA Polymerase II Pre-transcription Events	2	91.7×	3e-04	ERCC2, ERCC3
RNA Polymerase I Promoter Escape	2	81.0×	3e-04	ERCC2, ERCC3
NoRC negatively regulates rRNA expression	2	69.8×	4e-04	ERCC2, ERCC3
RHO GTPases activate KTN1	1	346.1×	0.004	KLC3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hair cell differentiation	2	842.6×	7e-05	ERCC2, ERCC3
regulation of mitotic cell cycle phase transition	2	674.1×	7e-05	ERCC2, ERCC3
transcription-coupled nucleotide-excision repair	2	481.5×	7e-05	ERCC2, ERCC3
UV protection	2	481.5×	7e-05	ERCC2, ERCC3
embryonic organ development	2	192.6×	4e-04	ERCC2, ERCC3
nucleotide-excision repair	2	153.2×	5e-04	ERCC2, ERCC3
transcription initiation at RNA polymerase II promoter	2	149.8×	5e-04	ERCC2, ERCC3
positive regulation of mitotic recombination	1	1685.2×	0.003	ERCC2
response to oxidative stress	2	52.2×	0.003	ERCC2, ERCC3
axo-dendritic transport	1	842.6×	0.005	KLC3
central nervous system myelin formation	1	481.5×	0.007	ERCC2
transcription elongation by RNA polymerase I	1	421.3×	0.007	ERCC2
hair follicle maturation	1	421.3×	0.007	ERCC2
establishment of left/right asymmetry	1	421.3×	0.007	CIROP
sperm mitochondrial sheath assembly	1	421.3×	0.007	KLC3
transcription by RNA polymerase II	2	28.2×	0.007	ERCC2, ERCC3
DNA topological change	1	337.0×	0.008	ERCC3
embryonic cleavage	1	337.0×	0.008	ERCC2
erythrocyte maturation	1	168.5×	0.014	ERCC2
hematopoietic stem cell differentiation	1	153.2×	0.015	ERCC2
maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1	134.8×	0.016	ERCC2
hematopoietic stem cell proliferation	1	129.6×	0.016	ERCC2
intrinsic apoptotic signaling pathway by p53 class mediator	1	116.2×	0.017	ERCC2
spinal cord development	1	102.1×	0.018	ERCC2
insulin-like growth factor receptor signaling pathway	1	99.1×	0.018	ERCC2
transcription elongation by RNA polymerase II	1	88.7×	0.019	ERCC3
determination of adult lifespan	1	86.4×	0.019	ERCC2
apoptotic process	2	11.5×	0.019	ERCC2, ERCC3
response to UV	1	73.3×	0.022	ERCC3
microtubule-based movement	1	59.1×	0.026	KLC3

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERCC2	16	4
ERCC3	0	0
MPLKIP	0	0
KLC3	0	0
CIROP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SUNITINIB	4	ERCC2
DINACICLIB	3	ERCC2
DEFACTINIB	3	ERCC2
ALVOCIDIB	3	ERCC2
SELICICLIB	2	ERCC2
ZOTIRACICLIB	2	ERCC2
DANUSERTIB	2	ERCC2
MILCICLIB	2	ERCC2
PF-00562271	1	ERCC2
PHA-793887	1	ERCC2
KW-2449	1	ERCC2
BMS-387032	1	ERCC2
PF-03758309	1	ERCC2
TAK-901	1	ERCC2
RGB-286638	1	ERCC2
XL-228	1	ERCC2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ERCC2	3	Binding:3
ERCC3	1	ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ERCC2	3.6.4.12	DNA helicase

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

16 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
DINACICLIB	3	ERCC2
DEFACTINIB	3	ERCC2
ALVOCIDIB	3	ERCC2
SELICICLIB	2	ERCC2
ZOTIRACICLIB	2	ERCC2
DANUSERTIB	2	ERCC2
MILCICLIB	2	ERCC2
PF-00562271	1	ERCC2
PHA-793887	1	ERCC2
KW-2449	1	ERCC2
BMS-387032	1	ERCC2
PF-03758309	1	ERCC2
TAK-901	1	ERCC2
RGB-286638	1	ERCC2
XL-228	1	ERCC2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ERCC2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	CIROP
E	Difficult family or no structure, no drug	3	ERCC3, MPLKIP, KLC3

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)
ERCC3	1	ERCC2
MPLKIP	0	—
KLC3	0	—
CIROP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.