Whole-exome sequencing for the identification of rare variants in primary immunodeficiency genes in children with sepsis - a prospective population-based cohort study.

Borghesi, Alessandro; Trück, Johannes; Asgari, Samira; Sancho-Shimizu, Vanessa; Agyeman, Philipp KA; Bellos, Evangelos; Giannoni, Eric; Stocker, Martin; Posfay-Barbe, Klara M; Heininger, Ulrich; Bernhard-Stirnemann, Sara; Niederer-Loher, Anita; Kahlert, Christian R; Natalucci, Giancardlo; Relly, Christa; Riedel, Thomas; Kuehni, Claudia E; Thorball, Christian W; Chaturvedi, Nimisha; Martinon-Torres, Federico; ... (2020). Whole-exome sequencing for the identification of rare variants in primary immunodeficiency genes in children with sepsis - a prospective population-based cohort study. (In Press). Clinical infectious diseases The University of Chicago Press 10.1093/cid/ciaa290

Borghesi ClinInfectDis 2020_epub.pdf - Accepted Version
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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.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Social and Preventive Medicine (ISPM)
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine

UniBE Contributor:

Agyeman, Philipp; Kühni, Claudia; Aebi, Christoph and Schlapbach, Luregn Jan


600 Technology > 610 Medicine & health
300 Social sciences, sociology & anthropology > 360 Social problems & social services




The University of Chicago Press


[4] Swiss National Science Foundation




Andrea Flükiger-Flückiger

Date Deposited:

07 Apr 2020 16:39

Last Modified:

16 Apr 2020 15:52

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

child exome sequencing genomics immunodeficiency sepsis variant variants of uncertain significance





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