title: Exome Sequencing Reveals Primary Immunodeficiencies in Children with Community-AcquiredPseudomonas aeruginosaSepsis.
abstract: One out of three pediatric sepsis deaths in high income countries occur in previously healthy children. Primary immunodeficiencies (PIDs) have been postulated to underlie fulminant sepsis, but this concept remains to be confirmed in clinical practice.Pseudomonas aeruginosa(P. aeruginosa) is a common bacterium mostly associated with health care-related infections in immunocompromised individuals. However, in rare cases, it can cause sepsis in previously healthy children. We used exome sequencing and bioinformatic analysis to systematically search for genetic factors underpinning severeP. aeruginosainfection in the pediatric population. We collected blood samples from 11 previously healthy children, with no family history of immunodeficiency, who presented with severe sepsis due to community-acquiredP. aeruginosabacteremia. Genomic DNA was extracted from blood or tissue samples obtained intravitam or postmortem. We obtained high-coverage exome sequencing data and searched for rare loss-of-function variants. After rigorous filtrations, 12 potentially causal variants were identified. Two out of eight (25%) fatal cases were found to carry novel pathogenic variants in PID genes, includingBTKandDNMT3B. This study demonstrates that exome sequencing allows to identify rare, deleterious human genetic variants responsible for fulminant sepsis in apparently healthy children. Diagnosing PIDs in such patients is of high relevance to 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 PIDs.
authors.affiliation: Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Samira
authors.initials: S
authors.lastname: Asgari
authors.affiliation: National HIV and Retrovirology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada; Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: McLaren
authors.affiliation: Lady Cilento Children's Hospital , Brisbane, QLD , Australia.
authors.forename: Jane
authors.initials: J
authors.lastname: Peake
authors.affiliation: Children's Hospital Westmead , Sydney, NSW , Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.affiliation: Pathology Queensland Central Laboratory, Royal Brisbane and Women's Hospital , Brisbane, QLD , Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Wong
authors.affiliation: Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Istvan
authors.initials: I
authors.lastname: Bartha
authors.affiliation: Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia; Royal Darwin Hospital, Darwin, NT, Australia.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Francis
authors.affiliation: Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Escuela de Medicina, Pontificia Universidad Católica de Chile , Santiago , Chile.
authors.forename: Katia
authors.initials: K
authors.lastname: Abarca
authors.affiliation: Sanquin Diagnostic Services , Amsterdam , Netherlands.
authors.forename: Kyra A
authors.initials: KA
authors.lastname: Gelderman
authors.affiliation: Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern , Bern , Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Agyeman
authors.affiliation: Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern , Bern , Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Aebi
authors.affiliation: University Children's Hospital Zurich , Zurich , Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Berger
authors.affiliation: Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Fellay
authors.affiliation: Lady Cilento Children's Hospital, Brisbane, QLD, Australia; Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Paediatric Critical Care Research Group (PCCRG), Mater Research, University of Queensland, Brisbane, QLD, Australia.
authors.forename: Luregn J
authors.initials: LJ
authors.lastname: Schlapbach
keywords: Pseudomonas; bacteremia; child; exome sequencing; primary immunodeficiency; sepsis