Two Novel Compound heterozygous Loss-of-Function Mutations Cause Fetal IRAK-4 Deficiency presenting with Pseudomonas aeruginosa Sepsis

Abstract

Abstract Purpose To report a case of a five-month-old Chinese infant who died of IRAK-4 deficiency presenting with rapid and progressive Pseudomonas aeruginosa sepsis. Methods The genetic etiology of IRAK-4 deficiency was confirmed through Trio- whole-exome sequencing (Trio-WES) and Sanger sequencing. The detected novel mutations were further investigated by in vitro minigene splicing assays. Results Two novel compound heterozygous mutations, c.942-1G > A and c.644_651 + 6delTTGCAGCAGTAAGT in the IRAK4 gene, were identified in this infant, which separately originated from his symptom-free parents. The c.942-1G > A canonical splice-site variant demonstrated aberrant splicing with a deletion of exon 9 on an in vitro minigene assay and was predicted to result in a truncated protein by frameshift mutation, p. (Ser314ArgfsTer4). The c.644_651 + 6delTTGCAGCAGTAAGT demonstrated aberrant splicing with a complete or 86 bp deletion of exon 5 and was predicted to result in two truncated proteins by frameshift mutation, p. (Arg164HisfsTer3) and p. (Gly189AspfsTer3). Conclusions Our new finding not only broadens the mutation spectrum of IRAK4 but also functionally corroborates the pathogenic effects of splice-site variants. In addition, this case highlights the importance of considering an underlying inborn error of immunity while dealing with unusually overwhelming infections in previously healthy children and broadening the antimicrobial coverage when suspected.