Whole-exome Sequencing for the Identification of Rare Variants in Primary Immunodeficiency Genes in Children With Sepsis: A Prospective, Population-based Cohort Study.

Adolescent Child Cohort Studies Humans Middle Aged Primary Immunodeficiency Diseases Prospective Studies Sepsis / genetics Exome Sequencing
child exome sequencing genomics immunodeficiency sepsis variant variants of uncertain significance

Journal

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
ISSN: 1537-6591
Titre abrégé: Clin Infect Dis
Pays: United States
ID NLM: 9203213

Informations de publication

Date de publication:
17 12 2020
Historique:
received: 29 03 2019
accepted: 15 03 2020
pubmed: 19 3 2020
medline: 29 4 2021
entrez: 19 3 2020
Statut: ppublish

Résumé

The role of primary immunodeficiencies (PID) in susceptibility to sepsis remains unknown. It is unclear whether children with sepsis benefit from genetic investigations. We hypothesized that sepsis may represent the first manifestation of underlying PID. We applied whole-exome sequencing (WES) to a national cohort of children with sepsis to identify rare, predicted pathogenic variants in PID genes. We conducted a multicenter, population-based, prospective study including previously healthy children aged ≥28 days and <17 years admitted with blood culture-proven sepsis. Using a stringent variant filtering procedure, analysis of WES data was restricted to rare, predicted pathogenic variants in 240 PID genes for which increased susceptibility to bacterial infection has been reported. There were 176 children presenting with 185 sepsis episodes who underwent WES (median age, 52 months; interquartile range, 15.4-126.4). There were 41 unique predicted pathogenic PID variants (1 homozygous, 5 hemizygous, and 35 heterozygous) found in 35/176 (20%) patients, including 3/176 (2%) patients carrying variants that were previously reported to lead to PID. The variants occurred in PID genes across all 8 PID categories, as defined by the International Union of Immunological Societies. We did not observe a significant correlation between clinical or laboratory characteristics of patients and the presence or absence of PID variants. Applying WES to a population-based cohort of previously healthy children with bacterial sepsis detected variants of uncertain significance in PID genes in 1 out of 5 children. Future studies need to investigate the functional relevance of these variants to determine whether variants in PID genes contribute to pediatric sepsis susceptibility.

Sections du résumé

BACKGROUND
The role of primary immunodeficiencies (PID) in susceptibility to sepsis remains unknown. It is unclear whether children with sepsis benefit from genetic investigations. We hypothesized that sepsis may represent the first manifestation of underlying PID. We applied whole-exome sequencing (WES) to a national cohort of children with sepsis to identify rare, predicted pathogenic variants in PID genes.
METHODS
We conducted a multicenter, population-based, prospective study including previously healthy children aged ≥28 days and <17 years admitted with blood culture-proven sepsis. Using a stringent variant filtering procedure, analysis of WES data was restricted to rare, predicted pathogenic variants in 240 PID genes for which increased susceptibility to bacterial infection has been reported.
RESULTS
There were 176 children presenting with 185 sepsis episodes who underwent WES (median age, 52 months; interquartile range, 15.4-126.4). There were 41 unique predicted pathogenic PID variants (1 homozygous, 5 hemizygous, and 35 heterozygous) found in 35/176 (20%) patients, including 3/176 (2%) patients carrying variants that were previously reported to lead to PID. The variants occurred in PID genes across all 8 PID categories, as defined by the International Union of Immunological Societies. We did not observe a significant correlation between clinical or laboratory characteristics of patients and the presence or absence of PID variants.
CONCLUSIONS
Applying WES to a population-based cohort of previously healthy children with bacterial sepsis detected variants of uncertain significance in PID genes in 1 out of 5 children. Future studies need to investigate the functional relevance of these variants to determine whether variants in PID genes contribute to pediatric sepsis susceptibility.

Identifiants

DOI: 10.1093/cid/ciaa290 PMID: 32185379 PMC: PMC7744985
pubmed: 32185379
pii: 5809292
doi: 10.1093/cid/ciaa290
pmc: PMC7744985
doi:

Types de publication

Journal Article Multicenter Study Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e614-e623

Subventions

Organisme : Medical Research Council
ID : MR/S032304/1
Pays : United Kingdom
Organisme : MRF
ID : MRF_C0483
Pays : United Kingdom

Informations de copyright

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.

Auteurs

Alessandro Borghesi (A)

Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Neonatal Intensive Care Unit, Fondazione Institute for Research, Hospitalization and Health Care (IRCCS) Policlinico San Matteo, Pavia, Italy.

Johannes Trück (J)

University Children's Hospital Zurich and the Children's Research Center, Zurich, Switzerland.
University of Zurich, Zurich, Switzerland.

Samira Asgari (S)

Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Division of Genetics and Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

Vanessa Sancho-Shimizu (V)

Section of Paediatrics, Imperial College London, London, United Kingdom.
Section of Virology, Imperial College London, London, United Kingdom.

Philipp K A Agyeman (PKA)

Department of Paediatrics, Bern University Hospital, Inselspital, University of Bern, Bern, Switzerland.

Evangelos Bellos (E)

Section of Paediatrics, Imperial College London, London, United Kingdom.

Eric Giannoni (E)

Service of Neonatology, Department Woman-Mother-Child, and Infectious Diseases Service, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.

Martin Stocker (M)

Department of Paediatrics, Children's Hospital Lucerne, Lucerne, Switzerland.

Klara M Posfay-Barbe (KM)

Paediatric Infectious Diseases Unit, Children's Hospital of Geneva, University Hospitals of Geneva, Geneva, Switzerland.

Ulrich Heininger (U)

Infectious Diseases and Vaccinology, University of Basel Children's Hospital, Basel, Switzerland.

Sara Bernhard-Stirnemann (S)

Children's Hospital Aarau, Aarau, Switzerland.

Anita Niederer-Loher (A)

Children's Hospital of Eastern Switzerland St. Gallen, St. Gallen, Switzerland.

Christian R Kahlert (CR)

Department of Neonatology, University Hospital Zurich, Zurich, Switzerland.

Giancarlo Natalucci (G)

Department of Neonatology, University Hospital Zurich, Zurich, Switzerland.

Christa Relly (C)

University Children's Hospital Zurich and the Children's Research Center, Zurich, Switzerland.

Thomas Riedel (T)

Department of Paediatrics, Cantonal Hospital Graubuenden, Chur, Switzerland.

Claudia E Kuehni (CE)

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

Christian W Thorball (CW)

Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

Nimisha Chaturvedi (N)

Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

Federico Martinon-Torres (F)

Translational Paediatrics and Infectious Diseases Section, Paediatrics Department, Santiago de Compostela, Spain.
Instituto de Investigación Sanitaria de Santiago, Genetics, Vaccines, Infectious Diseases and Paediatrics Research Group, Santiago de Compostela, Spain.

Taco W Kuijpers (TW)

Academic Medical Center, Emma Children's Hospital, University of Amsterdam, Amsterdam, The Netherlands.

Lachlan Coin (L)

Institute of Molecular Biosciences, The University of Queensland, Brisbane, Australia.

Victoria Wright (V)

Section of Paediatrics, Imperial College London, London, United Kingdom.

Jethro Herberg (J)

Section of Paediatrics, Imperial College London, London, United Kingdom.

Michael Levin (M)

Section of Paediatrics, Imperial College London, London, United Kingdom.

Christoph Aebi (C)

Department of Paediatrics, Bern University Hospital, Inselspital, University of Bern, Bern, Switzerland.

Christoph Berger (C)

University Children's Hospital Zurich and the Children's Research Center, Zurich, Switzerland.

Jacques Fellay (J)

Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Precision Medicine Unit, Lausanne University Hospital, Lausanne, Switzerland.

Luregn J Schlapbach (LJ)

University Children's Hospital Zurich and the Children's Research Center, Zurich, Switzerland.
Paediatric Critical Care Research Group, Child Health Research Centre, The University of Queensland, Brisbane, Australia.
Paediatric Intensive Care Unit, Queensland Children's Hospital, Children's Health Queensland, Brisbane, Australia.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adolescent › Whole-exome Sequencing for the Identification...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Whole-exome Sequencing for the Identification...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Whole-exome Sequencing for the Identification...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Whole-exome Sequencing for the Identification...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Whole-exome Sequencing for the Identification...
questionsmedicales.fr › Maladies du système immunitaire › Déficits immunitaires › Maladies d'immunodéficience primaire › Whole-exome Sequencing for the Identification...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études prospectives › Whole-exome Sequencing for the Identification...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › Sepsie › Whole-exome Sequencing for the Identification...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ADN › Séquençage du génome entier › Séquençage de l'exome › Whole-exome Sequencing for the Identification...