Kantonsspital St.Gallen

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

Alessandro Borghesi, Johannes Trück, Samira Asgari, Vanessa Sancho-Shimizu, Philipp K A Agyeman, Evangelos Bellos, Eric Giannoni, Martin Stocker, Klara M Posfay-Barbe, Ulrich Heininger, Sara Bernhard-Stirnemann, Anita Niederer-Loher, Christian R. Kahlert, Giancardlo Natalucci, Christa Relly, Thomas Riedel, Claudia E Kuehni, Christian W Thorball, Nimisha Chaturvedi, Federico Martinon-Torres, Taco W Kuijpers, Lachlan Coin, Victoria Wright, Jethro Herberg, Michael Levin, Christoph Aebi, Christoph Berger, Jacques Fellay, Luregn J Schlapbach & EUCLIDS Consortium And The Swiss Paediatric Sepsis Study


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.

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.

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.

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.
citation Borghesi A, Trück J, Asgari S, Sancho-Shimizu V, Agyeman P K A, Bellos E, Giannoni E, Stocker M, Posfay-Barbe K M, Heininger U, Bernhard-Stirnemann S, Niederer-Loher A, Kahlert C R, Natalucci G, Relly C, Riedel T, Kuehni C E, Thorball C W, Chaturvedi N, Martinon-Torres F, Kuijpers T W, Coin L, Wright V, Herberg J, Levin M, Aebi C, Berger C, Fellay J, Schlapbach L J, EUCLIDS consortium and the Swiss Paediatric Sepsis Study . Whole-exome sequencing for the identification of rare variants in primary immunodeficiency genes in children with sepsis - a prospective population-based cohort study. Clin Infect Dis 2020;.
type journal paper/review (English)
date of publishing 18-03-2020
journal title Clin Infect Dis
ISSN electronic 1537-6591
PubMed 32185379
DOI 10.1093/cid/ciaa290