Rare IFNAR1 variant in patient with autoinflammatory disorder and elevated type-1 interferon signaling

We present the case of a 30-year-old female with a history of chronic urticaria, fevers, mild hearing loss, and seronegative arthritis, who was found to have a rare variant in IFNAR1 and elevated type-1 interferon gene expression. She initially presented for evaluation of an autoinflammatory phenotype, and was found to have significantly elevated IL-18 (3473 pg/mL), IgG hypergammaglobulinemia (1680 mg/dL), and a variant of unknown significance in IFNAR1 (p.Ala424Thr). This variant is seen in 0.01% of East Asians in gnomAD. Further investigation revealed elevated expression of type-1 interferon stimulated genes (score 0.83, normal <–0.5). IFNAR1 codes for one subunit of the interferon alpha/beta receptor. Our patient’s rare variant in IFNAR1, in combination with her elevated type 1 interferon gene expression, is concerning for a gain-of-function variant in IFNAR1 leading to increased interferon pathway signaling. Gain-of-function variants in IFNAR1 have not been described previously. Further experiments are needed to validate whether this variant is gain of function. If so, she could benefit from inhibition of the type-1 interferon receptor signal, for example, with a JAK inhibitor such as baricitinib or with the monoclonal anifrolumab. This case demonstrates the utility of genetic testing in combination of functional assays to develop novel targeted therapies for patients in the field of clinical immunology.