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Intellectual disability

Gene: USP18

Red List (low evidence)

USP18 (ubiquitin specific peptidase 18)
EnsemblGeneIds (GRCh38): ENSG00000184979
EnsemblGeneIds (GRCh37): ENSG00000184979
OMIM: 607057, Gene2Phenotype
USP18 is in 10 panels

2 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: DD reported in one surviving patient. However, this only became apparent following treatment which was administered after genetic diagnosis was already achieved. DD is therefore unlikely represent the clinical indication to prompt testing in the neonatal period.

Therefore keeping rating Red on the ID panel. USP18 is Green on other relevant panels (White matter disorders and cerebral calcification, PID) which should be adequate for detecting these cases.
Created: 8 Oct 2020, 3:58 p.m. | Last Modified: 8 Oct 2020, 3:58 p.m.
Panel Version: 3.401
Added 'treatable' tag as clinical remission was achieved in a patient following rapid genetic diagnosis and subsequent treatment with the JAK inhibitor ruxolitinib
Created: 8 Oct 2020, 3:37 p.m. | Last Modified: 8 Oct 2020, 3:37 p.m.
Panel Version: 3.400
- PMID: 27325888 (2016) - Three sibs from a consanguineous Turkish family with a homozygous variant (c.652C>T, p.Q218X) in USP18. Antenatal presentation in one sib led to termination of pregnancy at 22 wk of gestation, and in the remaining two children presentation was neonatal and resulted in death within 2 weeks of life. In the latter two individuals manifestations included severe intracerebral haemorrhages, liver dysfunction, ascites, and lactic acidosis. One sib additionally had severe thrombocytopenia with petechiae, while the other developed seizures.

Two German sibs, previously reported in PMID: 12833411 (2013), were found to be compound het for the same p.Q218X variant and a cryptic 3-prime deletion of the USP18 gene. They presented thrombocytopenia, petechiae, ascites, hepatomegaly, and systemic calcifications. Within the first days of life, they developed seizures and died from severe cerebral haemorrhage.

Haplotype analysis of the region containing the Q218X mutation suggested a common ancestor between the 2 families and a founder effect.

- PMID: 31940699 (2020) - One Saudi Arabian boy with a homozygous splice-site variant (c.1073+1G>A) in USP18, presented hydrocephalus with seizures, intraventricular haemorrhage, brain calcifications, necrotizing cellulitis, systemic inflammation, multiple organ failure, and respiratory failure. This was the only patient to survive beyond the perinatal period owing to supportive care and prompt treatment with ruxolitinib. At the time of publication, the child was 3-years-old and was in full remission of clinical manifestations while continuing to receive oral ruxolitinib. He continues to grow normally, however authors note delay in developmental milestones.
Created: 8 Oct 2020, 3:12 p.m. | Last Modified: 8 Oct 2020, 3:12 p.m.
Panel Version: 3.397

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Pseudo-TORCH syndrome 2, 617397


Zornitza Stark (Australian Genomics)

Green List (high evidence)

Total 3 families, 6 patients, with functional evidence.

Family 1: 3 sibs with homozygous truncating mutation in the USP18 gene, segregated with the disorder in the family.
Family 2: 2 sibs with compound heterozygous mutations.
Cells from patients in both families showed complete absence of the USP18 protein. Patient fibroblasts showed enhanced induction of IFN-stimulated transcripts after stimulation with alpha-IFN compared to controls, and transduction of patient cells with wildtype USP18 rescued these effects at the mRNA and protein level. The findings indicated that the disorder results from an aberrant response to type I IFN, rather than an increase in expression of IFN itself.

Family 3: 1 patient with homozygous splice site variant in the USP18 gene This patient had stable mRNA (with skipping of exon 10), and functional studies showed that the mechanism of the mutation was not USP18 deficiency but lack of its ability to stabilize ISG15 (147571) and thereby suppress interferon signaling.
Created: 2 Mar 2020, 5:09 a.m. | Last Modified: 2 Mar 2020, 5:09 a.m.
Panel Version: 3.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Pseudo-TORCH syndrome 2, OMIM #617397



Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
  • Expert Review Red
  • Victorian Clinical Genetics Services
  • Pseudo-TORCH syndrome 2, 617397
Clinvar variants
Variants in USP18
Panels with this gene

History Filter Activity

8 Oct 2020, Gel status: 1

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: usp18 has been classified as Red List (Low Evidence).

8 Oct 2020, Gel status: 1

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag treatable tag was added to gene: USP18.

8 Oct 2020, Gel status: 1

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: USP18 were set to

8 Oct 2020, Gel status: 1

Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

Mode of inheritance for gene: USP18 was changed from to BIALLELIC, autosomal or pseudoautosomal

8 Oct 2020, Gel status: 1

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: USP18 were changed from to Pseudo-TORCH syndrome 2, 617397

29 Sep 2018, Gel status: 1

Created, Added New Source, Set mode of inheritance

Louise Daugherty (Genomics England Curator)

gene: USP18 was added gene: USP18 was added to Intellectual disability. Sources: Victorian Clinical Genetics Services Mode of inheritance for gene: USP18 was set to