pseudo-TORCH syndrome 2

Summary

pseudo-TORCH syndrome 2 (MONDO:0018828) is a disease caused by USP18 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: USP18 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	pseudo-TORCH syndrome 2
Mondo ID	MONDO:0018828
OMIM	617397
Orphanet	481665
UMLS	C4479376
MedGen	1373355
GARD	0017875
Is cancer (heuristic)	no

Also known as: pseudo-TORCH syndrome 2 · PTORCH2

Data availability: 7 ClinVar variants · 5 GenCC gene-disease records.

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 › pseudo-TORCH syndrome › pseudo-TORCH syndrome 2

Related subtypes (2): pseudo-TORCH syndrome 1, pseudo-TORCH syndrome 3

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
3256725	NM_017414.4(USP18):c.772C>T (p.Arg258Ter)	USP18	Pathogenic	criteria provided, single submitter
417775	USP18, 3-PRIME DEL	USP18	Pathogenic	no assertion criteria provided
810842	NM_017414.4(USP18):c.1073+1G>A	USP18	Pathogenic/Likely pathogenic	no assertion criteria provided
2506027	NM_017414.4(USP18):c.891+1G>T	USP18	Likely pathogenic	criteria provided, single submitter
417774	NM_017414.4(USP18):c.652C>T (p.Gln218Ter)	USP18	Likely pathogenic	criteria provided, single submitter
2386333	NM_017414.4(USP18):c.907G>A (p.Glu303Lys)	USP18	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3767287	NM_017414.4(USP18):c.358C>T (p.Pro120Ser)	USP18	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
USP18	Definitive	Autosomal recessive	pseudo-TORCH syndrome 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
USP18	Orphanet:481665	Pseudo-TORCH syndrome type 2

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
USP18	HGNC:12616	ENSG00000184979	Q9UMW8	Ubl carboxyl-terminal hydrolase 18	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
USP18	Ubl carboxyl-terminal hydrolase 18	Interferon-induced ISG15-specific protease that plays a crucial role for maintaining a proper balance of ISG15-conjugated proteins in cells.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
USP18	Protease	yes		Peptidase_C19_UCH, USP_CS, USP

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
left testis	1
primordial germ cell in gonad	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
USP18	135	ubiquitous	marker	primordial germ cell in gonad, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
USP18	1,682

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
USP18	Q9UMW8	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Regulation of NF-kappa B signaling	1	634.4×	0.006	USP18
Regulation of IFNA/IFNB signaling	1	439.2×	0.006	USP18
TAK1-dependent IKK and NF-kappa-B activation	1	300.5×	0.006	USP18
ISG15 antiviral mechanism	1	150.3×	0.008	USP18
Ub-specific processing proteases	1	53.1×	0.019	USP18

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
response to stilbenoid	1	2808.7×	0.003	USP18
negative regulation of type I interferon-mediated signaling pathway	1	766.0×	0.005	USP18
antiviral innate immune response	1	227.7×	0.008	USP18
response to bacterium	1	193.7×	0.008	USP18
protein deubiquitination	1	177.4×	0.008	USP18
regulation of inflammatory response	1	168.5×	0.008	USP18
regulation of protein stability	1	125.8×	0.009	USP18
proteolysis	1	34.2×	0.029	USP18

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
USP18	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
USP18	4	Binding:4

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	1	USP18
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
USP18	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.