Trichothiodystrophy 2, photosensitive

Summary

Trichothiodystrophy 2, photosensitive (MONDO:0014615) is a disease caused by ERCC3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ERCC3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 40

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	trichothiodystrophy 2, photosensitive
Mondo ID	MONDO:0014615
OMIM	616390
DOID	DOID:0111869
NCIT	C173103
UMLS	C4225344
MedGen	905904
GARD	0016100
Is cancer (heuristic)	no

Also known as: trichothiodystrophy 2, photosensitive · TTD2

Data availability: 40 ClinVar variants · 3 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › ectodermal dysplasia syndrome › trichothiodystrophy › photosensitive trichothiodystrophy › trichothiodystrophy 2, photosensitive

Related subtypes (2): trichothiodystrophy 1, 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

40 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 11 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity, 4 likely pathogenic, 3 pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070632	NM_000122.2(ERCC3):c.1757del (p.Gln586fs)	ERCC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1319556	NM_000122.2(ERCC3):c.1162C>T (p.Gln388Ter)	ERCC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1335950	NM_000122.2(ERCC3):c.1115_1120dup (p.Trp374Ter)	ERCC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
134130	NM_000122.2(ERCC3):c.1421dup (p.Asp474fs)	ERCC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1405507	NM_000122.2(ERCC3):c.1720C>T (p.Arg574Ter)	ERCC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458593	NM_000122.2(ERCC3):c.2131C>T (p.Gln711Ter)	ERCC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16583	NM_000122.2(ERCC3):c.296T>C (p.Phe99Ser)	ERCC3	Pathogenic	criteria provided, single submitter
16584	NM_000122.2(ERCC3):c.355A>C (p.Thr119Pro)	ERCC3	Pathogenic	no assertion criteria provided
16585	NM_000122.2(ERCC3):c.1273C>T (p.Arg425Ter)	ERCC3	Pathogenic	criteria provided, multiple submitters, no conflicts
1805744	NM_000122.2(ERCC3):c.1300G>T (p.Glu434Ter)	ERCC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265515	NM_000122.2(ERCC3):c.325C>T (p.Arg109Ter)	ERCC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632330	NM_000122.2(ERCC3):c.1757_1758del (p.Gln586fs)	ERCC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
808798	NM_000122.2(ERCC3):c.1588C>T (p.Arg530Ter)	ERCC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
995893	NM_000122.2(ERCC3):c.1354C>T (p.Arg452Ter)	ERCC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1469975	NM_000122.2(ERCC3):c.657+1G>A	ERCC3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1928310	NM_000122.2(ERCC3):c.1828-1G>C	ERCC3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3584365	NM_000122.2(ERCC3):c.1832del (p.Gly611fs)	ERCC3	Likely pathogenic	criteria provided, single submitter
3584367	NM_000122.2(ERCC3):c.1114del (p.Glu372fs)	ERCC3	Likely pathogenic	criteria provided, single submitter
134128	NM_000122.2(ERCC3):c.847C>T (p.Arg283Cys)	ERCC3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331076	NM_000122.2(ERCC3):c.2080G>A (p.Ala694Thr)	ERCC3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
721411	NM_000122.2(ERCC3):c.417C>T (p.Tyr139=)	ERCC3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
870690	NM_000122.2(ERCC3):c.1762dup (p.Glu588fs)	ERCC3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1319554	NM_000122.2(ERCC3):c.1549G>A (p.Glu517Lys)	ERCC3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1327109	NM_000122.2(ERCC3):c.1457C>T (p.Pro486Leu)	ERCC3	Uncertain significance	criteria provided, single submitter
134119	NM_000122.2(ERCC3):c.1996G>A (p.Asp666Asn)	ERCC3	Uncertain significance	criteria provided, multiple submitters, no conflicts
134126	NM_000122.2(ERCC3):c.350A>G (p.Lys117Arg)	ERCC3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1361081	NM_000122.2(ERCC3):c.2089G>A (p.Glu697Lys)	ERCC3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1366666	NM_000122.2(ERCC3):c.701G>A (p.Arg234Gln)	ERCC3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1394743	NM_000122.2(ERCC3):c.1348A>G (p.Met450Val)	ERCC3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1972912	NM_000122.2(ERCC3):c.518A>G (p.Asn173Ser)	ERCC3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 3 · 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
ERCC3	Definitive	Autosomal recessive	trichothiodystrophy 2, photosensitive	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERCC3	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC3	Orphanet:33364	Trichothiodystrophy
ERCC3	Orphanet:910	Xeroderma pigmentosum

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ERCC3	HGNC:3435	ENSG00000163161	P19447	General transcription and DNA repair factor IIH helicase/translocase subunit XPB	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERCC3	General transcription and DNA repair factor IIH helicase/translocase subunit XPB	ATP-dependent 3’-5’ DNA helicase/translocase.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ERCC3	Other/Unknown	no		XPB/Ssl2, Helicase_C-like, Helicase/UvrB_N

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	1
right hemisphere of cerebellum	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERCC3	277	ubiquitous	marker	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERCC3	3,219

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERCC3	P19447	52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 1 evidence-associated genes (1 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 1 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	1	407.9×	0.006	ERCC3
RNA Pol II CTD phosphorylation and interaction with CE	1	407.9×	0.006	ERCC3
mRNA Capping	1	380.7×	0.006	ERCC3
Formation of the Early Elongation Complex	1	335.9×	0.006	ERCC3
Formation of the HIV-1 Early Elongation Complex	1	335.9×	0.006	ERCC3
RNA Polymerase I Transcription Termination	1	326.3×	0.006	ERCC3
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1	265.6×	0.006	ERCC3
Formation of HIV-1 elongation complex containing HIV-1 Tat	1	259.6×	0.006	ERCC3
Tat-mediated elongation of the HIV-1 transcript	1	259.6×	0.006	ERCC3
Dual Incision in GG-NER	1	259.6×	0.006	ERCC3
Formation of Incision Complex in GG-NER	1	253.8×	0.006	ERCC3
Formation of HIV elongation complex in the absence of HIV Tat	1	248.3×	0.006	ERCC3
HIV Transcription Initiation	1	233.1×	0.006	ERCC3
RNA Polymerase II HIV Promoter Escape	1	233.1×	0.006	ERCC3
RNA Polymerase II Promoter Escape	1	233.1×	0.006	ERCC3
RNA Polymerase II Transcription Pre-Initiation And Promoter Opening	1	233.1×	0.006	ERCC3
RNA Polymerase II Transcription Initiation	1	233.1×	0.006	ERCC3
RNA Polymerase II Transcription Initiation And Promoter Clearance	1	233.1×	0.006	ERCC3
RNA Polymerase I Transcription Initiation	1	223.9×	0.006	ERCC3
Formation of TC-NER Pre-Incision Complex	1	211.5×	0.006	ERCC3
Formation of RNA Pol II elongation complex	1	193.6×	0.006	ERCC3
RNA Polymerase II Transcription Elongation	1	193.6×	0.006	ERCC3
TP53 Regulates Transcription of DNA Repair Genes	1	181.3×	0.006	ERCC3
Gap-filling DNA repair synthesis and ligation in TC-NER	1	178.4×	0.006	ERCC3
Transcription of the HIV genome	1	173.0×	0.006	ERCC3
Dual incision in TC-NER	1	173.0×	0.006	ERCC3
RNA Polymerase II Pre-transcription Events	1	137.6×	0.008	ERCC3
RNA Polymerase I Promoter Escape	1	121.5×	0.009	ERCC3
NoRC negatively regulates rRNA expression	1	104.8×	0.010	ERCC3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 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	1	2106.5×	0.003	ERCC3
DNA topological change	1	1685.2×	0.003	ERCC3
regulation of mitotic cell cycle phase transition	1	1685.2×	0.003	ERCC3
transcription-coupled nucleotide-excision repair	1	1203.7×	0.003	ERCC3
UV protection	1	1203.7×	0.003	ERCC3
embryonic organ development	1	481.5×	0.004	ERCC3
transcription elongation by RNA polymerase II	1	443.5×	0.004	ERCC3
nucleotide-excision repair	1	383.0×	0.004	ERCC3
transcription initiation at RNA polymerase II promoter	1	374.5×	0.004	ERCC3
response to UV	1	366.4×	0.004	ERCC3
response to oxidative stress	1	130.6×	0.011	ERCC3
intracellular protein localization	1	104.7×	0.013	ERCC3
transcription by RNA polymerase II	1	70.5×	0.017	ERCC3
DNA repair	1	63.8×	0.018	ERCC3
positive regulation of apoptotic process	1	56.7×	0.019	ERCC3
apoptotic process	1	28.7×	0.035	ERCC3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERCC3	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
ERCC3	1	ADMET:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	ERCC3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ERCC3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.