STING1 – STING-associated vasculopathy with onset in infancy

STING-associated vasculopathy with onset in infancy (SAVI) is an autosomal dominant autoinflammatory disorder caused by gain-of-function variants in STING1 (TMEM173), characterized by early-onset cutaneous vasculopathy, interstitial lung disease, systemic inflammation, and failure to thrive. Heterozygous pathogenic variants result in constitutive activation of the STING pathway, driving upregulation of type I interferon signaling and downstream inflammatory cascades. The mode of inheritance is autosomal dominant with both de novo and familial segregation documented.

Genetic evidence includes over 51 reported individuals with SAVI, of whom 17 had familial transmission of STING1 variants, and multiple independent de novo occurrences ([PMID:33425809]). Segregation of heterozygous mutations has been confirmed in kindreds spanning three generations ([PMID:32398023]) and in six unrelated cases with early-onset disease ([PMID:25029335]).

The variant spectrum comprises at least ten recurrent missense changes clustering in the ligand-binding and dimerization regions of STING1. The most prevalent is c.463G>A (p.Val155Met), reported in multiple unrelated patients and kindreds. Other pathogenic alleles include c.439G>A (p.Val147Met), c.461A>G (p.Asn154Ser), c.841C>T (p.Arg281Trp), and c.852G>C (p.Arg284Ser).

Functional studies demonstrate that SAVI-associated STING1 variants confer ligand-independent translocation to ER–Golgi compartments, elevated phosphorylation of TBK1 and STAT1, and spontaneous transcription of IFNB1 and interferon-stimulated genes ([PMID:25029335], [PMID:38953896]). In vitro assays using patient-derived cells and transfected HEK293T models confirm enhanced type I IFN signaling. Treatment with JAK inhibitors such as ruxolitinib and baricitinib partially normalizes interferon signatures and ameliorates pulmonary hypertension in some patients.

No convincing reports dispute the pathogenic association between STING1 gain-of-function variants and SAVI. However, phenotypic heterogeneity—ranging from isolated juvenile arthritis to adult-onset ANCA vasculitis—underscores the need for genotype-directed diagnosis and therapeutic stratification.

In summary, robust genetic and experimental data fulfill criteria for a definitive gene–disease relationship. Early recognition of SAVI through genetic testing of STING1 variants enables prompt consideration of JAK inhibition. Key take-home: Autosomal dominant STING1 gain-of-function variants cause SAVI, warranting early genetic testing in infants with cutaneous vasculopathy and interstitial lung disease to guide JAK inhibitor therapy.

References

• Frontiers in pediatrics • 2020 • Stimulator of Interferon Genes-Associated Vasculopathy With Onset in Infancy: A Systematic Review of Case Reports PMID:33425809
• Pediatric rheumatology online journal • 2020 • Type 1 interferonopathy presenting as juvenile idiopathic arthritis with interstitial lung disease: report of a new phenotype PMID:32398023
• The New England journal of medicine • 2014 • Activated STING in a vascular and pulmonary syndrome PMID:25029335
• The Journal of experimental medicine • 2024 • A novel STING variant triggers endothelial toxicity and SAVI disease PMID:38953896

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