Compound heterozygous variants in IRAK4 cause IRAK4 deficiency characterized by recurrent bacterial infections, brain...

IRAK4 deficiency is a rare autosomal recessive inborn error of immunity caused by disruption of Toll-like receptor (TLR) signaling, and characterized by recurrent pyogenic bacterial infections and impaired inflammatory responses. Here, we reported an 11-year-old boy presenting with recurrent fever, rare severe brain calcification, and seizures. The persistently elevated C-reactive protein (CRP) levels suggested an underlying defect in innate immune signaling. Genetic analysis identified compound heterozygous variants in IRAK4, including a frameshift variant c.123dupA (p.Pro42Thrfs*4), and a missense variant c.543T>G (p.Asp181Glu). Functional analyses further demonstrated markedly reduced IRAK4 protein expression and impaired TLR-mediated signaling in the patient's peripheral blood and cells transfected with the variant sequences. Consistent with these findings, RNA-sequencing revealed dysregulation of innate immune pathways involved in cytokine and chemokine responses. Together, these results provide converging genetic, structural, and functional evidence supporting the pathogenicity of the identified IRAK4 variants. Our findings expand the variant and phenotype spectrum of IRAK4 deficiency, and underscore the essential role of IRAK4 in regulating innate immune signaling and host defense against bacterial infections.