USP18 – pseudo-TORCH syndrome 2

Pseudo-TORCH syndrome 2 is an ultra‐rare autosomal recessive disorder that phenotypically mimics congenital TORCH infections, presenting with microcephaly, ventriculomegaly, intracranial calcifications, and polymicrogyria. The condition arises from bi-allelic loss-of-function variants in USP18, a critical negative regulator of type I interferon (IFN) signaling. Early genetic diagnosis is essential for carrier screening, prenatal counseling, and guiding potential IFN-targeted therapies.

Genetic analyses have identified homozygous truncating USP18 alleles in affected individuals. A multi-patient cohort described five probands from two unrelated families harboring the recurrent nonsense variant c.652C>T (p.Gln218Ter), with parents as asymptomatic heterozygous carriers, consistent with autosomal recessive inheritance (PMID:27325888). A subsequent familial report from India detailed an additional kindred in which all affected offspring inherited a novel homozygous USP18 mutation, further corroborating the gene–disease link (PMID:36043132). Together, six patients across three families establish robust segregation.

The variant spectrum in USP18 associated with pseudo-TORCH syndrome 2 is dominated by early truncating alleles that abolish deISGylation activity and IFN-signal repression. The c.652C>T (p.Gln218Ter) change recurs in multiple kindreds, reflecting a loss-of-function mechanism critical for disease pathogenesis.

Functional characterization in patient fibroblasts demonstrates exaggerated and prolonged Jak/Stat activation and overexpression of IFN-stimulated genes upon type I IFN exposure. Lentiviral complementation with wild-type USP18 fully rescues these cellular phenotypes, confirming causality and the haploinsufficiency mechanism (PMID:27325888). Biochemical assays further solidify USP18 as the principal ISG15 deconjugase required to terminate IFN responses.

No conflicting reports have been published to dispute the USP18–pseudo-TORCH syndrome 2 association. The convergence of genetic segregation, recurrent loss-of-function alleles, and concordant functional rescue across multiple families provides strong clinical validity.

Key Take-home: Loss‐of‐function variants in USP18 cause autosomal recessive pseudo-TORCH syndrome 2, and molecular diagnosis enables targeted genetic counseling and informs potential IFN-modulatory therapies.

References

• Journal of reproduction & infertility • 2022 • A Novel Familial Case Report of Genetic Syndrome Mimicking Congenital TORCH infections; Pseudo-TORCH Syndrome 2. PMID:36043132
• The Journal of experimental medicine • 2016 • Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. PMID:27325888

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