Intellectual disability
Gene: USP18

USP18 (ubiquitin specific peptidase 18)
EnsemblGeneIds (GRCh38): ENSG00000184979
EnsemblGeneIds (GRCh37): ENSG00000184979
OMIM: 607057, Gene2Phenotype
USP18 is in 9 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

Phenotypes
Pseudo-TORCH syndrome 2, 617397

Publications

Created: 8 Oct 2020, 3:12 p.m.
Last Modified: 8 Oct 2020, 3:12 p.m.
Panel version: 3.400

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

Phenotypes
Pseudo-TORCH syndrome 2, OMIM #617397

Publications

Created: 2 Mar 2020, 5:09 a.m.
Last Modified: 2 Mar 2020, 5:09 a.m.
Panel version: 3.3

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Red
Victorian Clinical Genetics Services

Phenotypes

Pseudo-TORCH syndrome 2, 617397

Tags

treatable

OMIM

607057

Clinvar variants

Variants in USP18

Penetrance

None

Publications

Panels with this gene