Exome sequencing reveals underlying primary immunodeficiencies in children with fulminant community-acquired pseudomonas aeruginosa sepsis

Abstract

Introduction: One out of three paediatric sepsis deaths occur in previously healthy children. Primary immunodeficiencies (PID) have been postulated to underlie fulminant sepsis, but this concept remains to be confirmed in clinical practice. Pseudomonas aeruginosa is a rare cause of sepsis in children without comorbidities, but carries a very high mortality. We hypothesized that P. aeruginosa sepsis in apparently healthy children may be the first manifestation of a PID. Study Objectives: To search for rare genetic variants conferring susceptibility to sepsis in children with P. aeruginosa bacteremia using exome sequencing. Methods: We extracted genomic DNA from blood or tissue samples obtained intravitam or postmortem from previously healthy children who developed severe sepsis due to community-acquired P. aeruginosa bacteremia. We obtained high-coverage exome sequencing data and searched for rare lossof- function variants. Results: Eleven patients were included, of which 8 (73%) had a fatal outcome. PID was identified in three patients. We found a novel frame-shift indel in exon 7 of the BTK gene, a known cause of X-linked agammaglobulinemia. Functional follow up confirmed absence of immunoglobulins. A novel 6 base-pair deletion was found in exon 21 of DNMT3B, compatible with ICF immunodeficiency syndrome. Plasma immunoglobulin levels were significantly decreased. Complement C9 deficiency due to a known heterozygous stop-gain mutation was identified in one patient in the second exon of complement C9 gene. Further investigations for novel PID in the other cases are ongoing. Conclusions: This study provides proof of concept that exome sequencing allows to identify rare, deleterious human genetic variants responsible for fulminant sepsis in apparently healthy children. We were able to diagnose PID in several cases, with a significant impact for survivors and affected families. We propose that unusually severe and fatal sepsis cases in previously healthy children should be considered for exome/genome sequencing to search for underlying PID.L723256902016-07-23 <br />