A Mutation Outside the Dimerization Domain Causing Atypical STING-Associated Vasculopathy With Onset in Infancy

Area of Science:

• Genetics and Immunology
• Molecular Biology
• Pediatric Rheumatology

Background:

• Mutations in stimulator of interferon genes (STING) cause STING-associated vasculopathy with onset in infancy (SAVI), a type I interferon (IFN) related disease.
• SAVI patients typically present with cutaneous vasculopathy and interstitial lung disease, but not life-threatening infections.

Purpose of the Study:

• To investigate a child with an atypical presentation of an interferonopathy, including pulmonary hypertension.
• To determine the genetic basis and molecular mechanism of the child's condition.
• To evaluate the therapeutic response to JAK inhibition.

Main Methods:

• Whole genome sequencing (WGS) to identify genetic variants.
• Quantitative polymerase chain reaction (qPCR) to assess mRNA expression of IFN-stimulated genes and inflammatory cytokines.
• In vitro luciferase assays to model STING pathway activation.

Main Results:

• A de novo STING mutation (p.Arg284Ser) was identified, leading to constitutive IFN-gene activation and STING pathway activation in vitro.
• The patient presented with opportunistic infection, failure to thrive, developmental delay, livedo reticularis, and later, life-threatening pulmonary hypertension, without typical SAVI vasculitis.
• Treatment with corticosteroids and Ruxolitinib resulted in rapid clinical improvement and resolution of the IFN gene signature, although disease control was incomplete.

Conclusions:

• The p.Arg284Ser STING variant likely causes pathogenicity via a gain-of-function mechanism, potentially leading to atypical SAVI phenotypes.
• The case highlights that STING variants outside the dimerization domain may present atypically, including with opportunistic infections and pulmonary hypertension.
• JAK inhibition with Ruxolitinib demonstrated significant clinical efficacy in managing this interferonopathy.