White matter disorders and cerebral calcification - narrow panel

Gene: USP18

Green List (high evidence)

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, 4:05 p.m. | Last Modified: 8 Oct 2020, 4:05 p.m.

Panel Version: 1.18

- 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, 4:05 p.m. | Last Modified: 8 Oct 2020, 4:05 p.m.

Panel Version: 1.18

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Pseudo-TORCH syndrome 2, 617397

Publications

• 12833411
• 27325888
• 31940699