Loss of function mutation inELF4causes autoinflammatory and immunodeficiency disease in human

Monogenic autoinflammatory diseases (mAIDs) are a heterogeneous group of diseases affecting primarily innate immunity, with various specific genetic causes. Genetic diagnosis of mAIDs can assist in the patient’s management and therapy. However, a large number of sporadic and familial cases remain genetically uncharacterized. Here, we described a pediatric patient suffering from recurrent viral and bacterial respiratory infection, refractory oral ulcer and constipation, who was clinically diagnosed of inborn errors of immunity (IEI). In an effort to establish genetic diagnosis, no known causative genes were identified by whole-exome sequencing. However, manually going through bioinformatically predicted candidate genes, we suspected and prioritized ELF4 (chrX:129205133 A>G, c.691T>C, p.W231R) as the genetic cause for our patient. We then evaluated the pathogenicity of this mutation by both various bioinformatic methods and preliminary but definitive experimental approach. Our data suggested that W231R mutant ELF4 is a “loss of function” mutation causing decreased protein stability and decreased trans-activation activity. Thus, we identified a novel mAID, which we termed “X-linked autoinflammatory and immunodeficiency disease associated with ELF4, X-AIDE”.