Adult-onset STING-associated vasculopathy.

Area of Science:

• Genetics
• Immunology
• Rheumatology

Background:

• Genetic factors in systemic autoimmunity are traditionally viewed as more influential in pediatric cases.
• Adult-onset autoimmune diseases often lack clear genetic diagnoses.
• A STING-associated vasculopathy with onset in infancy (SAVI) mutation was found in an adult patient with relapsing polychondritis and lupus erythematosus.

Purpose of the Study:

• To investigate the hypothesis that STING gain-of-function mutations contribute to a wider range of adult autoimmune diseases.
• To identify adult patients with STING gain-of-function mutations and associated autoimmune conditions.

Main Methods:

• Systematic screening of 43,731 exomes from the Penn Medicine Biobank.
• Genetic analysis to identify STING gain-of-function mutations.
• Clinical evaluation of patients with identified mutations.

Main Results:

• Five additional unrelated adults with SAVI-associated STING gain-of-function mutations were identified.
• Some patients presented with clinical features of SAVI.
• Asymptomatic individuals with type I interferon signatures were also found.
• The term adult-onset STING-associated vasculopathy (AO-SAVI) is proposed.

Conclusions:

• STING gain-of-function mutations are implicated in adult-onset autoimmune diseases, broadening the known spectrum of SAVI.
• Findings challenge traditional symptom-based diagnostics, advocating for molecular classification.
• Molecular classification can reveal shared genetic underpinnings across diverse autoimmune conditions.