Whole-exome sequencing for the identification of rare variants in primary immunodeficiency genes in children with sepsis - a prospective population-based cohort study.
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
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: Multicenter population-based prospective study including previously healthy children ≥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: 176 children presenting with 185 sepsis episodes underwent WES (median age 52 months, IQR 15.4-126.4). 41 unique predicted pathogenic PID variants (1 homozygous, 5 hemizygous, and 35 heterozygous) were found in 35/176 (20%) patients, including 3/176 (2%) patients carrying variants which 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 one out of five children. Future studies need to investigate the functional relevance of these variants to determine whether variants in PID genes contribute to pediatric sepsis susceptibility.
Date Issued
2020-11-15
Date Acceptance
2020-02-25
Citation
Clinical Infectious Diseases, 2020, 71 (10), pp.e614-e623
ISSN
1058-4838
Publisher
Oxford University Press (OUP)
Start Page
e614
End Page
e623
Journal / Book Title
Clinical Infectious Diseases
Volume
71
Issue
10
Copyright Statement
© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
Sponsor
Imperial College Healthcare NHS Trust- BRC Funding
NIHR Imperial Biomedical Research Centre (BRC): Infection and AMR Theme
European Commission
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/32185379
PII: 5809292
Grant Number
RDA02
P76547
279185
Subjects
child
exome sequencing
genomics
immunodeficiency
sepsis
variant
variants of uncertain significance
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2020-03-18