Whole exome sequencing for the identification of primary immunodeficiencies in a national cohort of children with bacterial sepsis

Abstract

Background: Many primary immunodeficiencies (PIDs) are associated with an increased susceptibility to bacterial infection. However, the presence of underlying PIDs among pediatric sepsis cases has not been systematically evaluated. We hypothesized that community-acquired sepsis may represent the first manifestation of an underlying PID and performed whole exome sequencing (WES) of samples collected from a national cohort of children with bacterial sepsis. Methods: Eligible children were previously healthy children admitted to the ten largest children's hospitals in Switzerland between 01.09.2011 and 31.12.2015 with community-acquired sepsis caused by S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, or E. coli. Analysis of WES data was restricted to rare variants (<1% and <0.1% MAF for homozygous/hemizygous and heterozygous variants, respectively) in 182 PID genes for which an association with increased susceptibility to bacterial infection has been described in the literature. Results: A total of 23 rare homozygous/hemizygous variants were found in 23/154 patients (15%). There was a larger number of very rare monoallelic variants in genes for which heterozygous mutations have previously been associated with immunodeficiency and susceptibility to bacterial infection. No major differences between infections caused by the different pathogens or sepsis severity and the likelihood of detecting mutations in PID genes were seen. Conclusion: WES allowed to detect potentially pathogenic variants in previously reported PID genes. While functional confirmation of these variants is pending, the findings suggest that PIDs might be more common than previously thought among apparently healthy children experiencing a first sepsis episode. WES represents a promising approach to diagnose PID in children with sepsis.L6270245092019-04-05 <br />