On this page
USP18
ubiquitin specific peptidase 18
USP18 encodes a deubiquitinase that regulates type I interferon signalling, with pathogenic variants associated with neurological and immune phenotypes. The USP18 gene provides instructions for making a protein that acts as a negative regulator of type I interferon responses.
USP18 is located on the long (q) arm of chromosome 22, at band 22q11.21. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 22 in the library →Overview
USP18 is located on chromosome 22 and encodes ubiquitin specific peptidase 18, a member of the deubiquitinating enzyme family. The protein plays a critical role in dampening type I interferon signalling, a pathway central to antiviral immunity and inflammatory responses. When interferon signalling becomes dysregulated due to USP18 variants, individuals may develop neurological manifestations including intracerebral calcification, white matter abnormalities, and seizures, alongside immune dysfunction. The gene is included in multiple NHS Genomic Medicine Service panels for conditions ranging from early-onset epilepsy to primary immunodeficiency, reflecting its clinical importance in paediatric neurology and immunology.
What the gene does
The USP18 protein functions primarily as a negative feedback regulator of the type I interferon pathway. When interferon molecules bind to their receptors on cell surfaces, they typically trigger a cascade of immune responses. USP18 counteracts this signalling by directly interacting with IFNAR2, a component of the interferon receptor complex, and preventing prolonged activation. The protein also interacts with STAT2, a transcription factor involved in interferon-stimulated gene expression, further contributing to pathway downregulation. Through these mechanisms, USP18 helps maintain balanced immune responses and prevents tissue damage from chronic interferon activation. This regulatory role is particularly important in the developing brain, where excessive interferon signalling can impair neuronal development and cause inflammatory injury to white matter and other structures.
Video: Genetics 101
Chromosome location
USP18 is located at chromosomal band 22q11.21 on the long arm of chromosome 22. This region contains numerous genes involved in immune function and neurodevelopment. The precise genomic coordinates place USP18 within a segment that can be affected by larger structural rearrangements, though point mutations within the gene itself are the typical cause of associated conditions.
Protein structure
The USP18 protein comprises 372 amino acids organised into several functional regions. A disordered region spans amino acids 19-45, likely providing flexibility for protein interactions. Two regions mediate interaction with IFNAR2: amino acids 36-51 and 313-372, allowing the protein to bind the interferon receptor complex. The USP domain extends from amino acids 55-370 and represents the catalytic core characteristic of ubiquitin-specific proteases. Within this domain, amino acids 51-112 mediate interaction with STAT2, whilst a smaller region from amino acids 303-312 is essential for STAT2 binding and the negative regulation of type I interferon signalling. This domain architecture reflects USP18's dual function as both an enzyme and a signalling regulator.
Key variants
Pathogenic variants in USP18 follow an autosomal recessive inheritance pattern, meaning two altered copies are required for disease manifestation. Most documented pathogenic variants are loss-of-function alleles (nonsense, frameshift, or deletions) that eliminate USP18 protein function. Affected individuals typically carry two different pathogenic variants (compound heterozygotes) or, less commonly, two copies of the same variant. The resulting hyperactivation of the interferon pathway underlies the neurological and immune features observed in affected individuals.
Sample of pathogenic variants
5 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.772C>T | p.Arg258Ter | Pathogenic | ★☆☆☆ | Pseudo-TORCH syndrome 2 |
c.1073+1G>A | - | Pathogenic/Likely pathogenic | - | Pseudo-TORCH syndrome 2 |
USP18, 3-PRIME DEL | - | Pathogenic | - | Pseudo-TORCH syndrome 2 |
c.652C>T | p.Gln218Ter | Likely pathogenic | ★☆☆☆ | Pseudo-TORCH syndrome 2 |
c.891+1G>T | - | Likely pathogenic | ★☆☆☆ | Pseudo-TORCH syndrome 2 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in USP18 cause pseudo-TORCH syndrome (also called pseudo-TORCH syndrome 2, OMIM #617397), a serious condition that mimics the features of congenital infections (the TORCH group: toxoplasmosis, other infections such as syphilis, rubella, cytomegalovirus, and herpes) but occurs in the absence of any actual infection. The condition primarily affects the nervous system and immune function. Affected individuals may present with neurological features including intracerebral calcification (abnormal calcium deposits in brain tissue), white matter abnormalities visible on brain imaging, and seizures that may begin in infancy or early childhood. Additional features can include microcephaly (a smaller than expected head size), developmental delay, and signs of systemic inflammation. The excessive interferon signalling can also manifest as immune dysregulation, potentially contributing to inflammatory complications. The severity and specific combination of features can vary between individuals, reflecting differences in the underlying variants and modifying factors.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic USP18 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
USP18 appears on multiple NHS Genomic Medicine Service panels with green (high-evidence) status, reflecting its established clinical relevance. These include the Early Onset or Syndromic Epilepsy panel (R59), White Matter Disorders and Cerebral Calcification panel, Intracerebral Calcification Disorders panel, and Primary Immunodeficiency or Monogenic Inflammatory Bowel Disease panel (R15). The gene is also listed on the Fetal Anomalies panel (R21) and DDG2P, indicating its importance in prenatal and developmental contexts. USP18 has also been studied in broader interferon-related research contexts, given the central role of type I interferons in antiviral immunity.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does autosomal recessive inheritance mean for USP18?
Autosomal recessive inheritance means an individual must inherit two altered copies of USP18, one from each parent, to develop associated conditions. Parents who each carry one pathogenic variant are typically unaffected but have a 25% chance with each pregnancy of having a child with two altered copies.
Why does USP18 dysfunction cause brain calcification?
When USP18 cannot adequately regulate interferon signalling, chronic immune activation in the brain can trigger inflammatory processes that promote abnormal calcium deposition in brain tissue. This mechanism is similar to other interferonopathies where excessive immune responses damage neural structures.
Is USP18 testing available through the NHS?
Yes, USP18 is included on multiple NHS Genomic Medicine Service panels with green status, meaning testing is available for eligible individuals presenting with features such as early-onset epilepsy, white matter disorders, or intracerebral calcification. Clinical geneticists determine eligibility based on specific criteria for each panel.
What is pseudo-TORCH syndrome?
Pseudo-TORCH syndrome is the condition caused by biallelic pathogenic variants in USP18 (and a small number of other genes). It is named because its features - including brain calcification, white matter changes, and signs of inflammation present from birth - resemble those seen in congenital infections such as toxoplasmosis, rubella, cytomegalovirus, and herpes, even though no infection is present. In USP18-related cases it is sometimes called pseudo-TORCH syndrome 2.
What might families expect in terms of care and outlook?
Care is usually led by a multidisciplinary team and focuses on managing seizures, monitoring brain imaging and development, and supporting the immune system. Early developmental support such as physiotherapy and speech and language therapy is often part of the plan. The outlook varies considerably between individuals, with some severe early-onset presentations and a growing recognition of milder cases. A clinical genetics team can discuss what is known for a specific variant and offer genetic counselling.