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

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 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.

Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis

“…In a recent report, Borghesi et al used WES to identify immunodeficiency variants in 20% of previously healthy children with positive blood cultures, predominantly described as variants of uncertain significance [ 8 ]. While these study participants had bacteremia, only 38% were admitted to ICU, and less than half had organ dysfunction, a necessary criterion for diagnosis of severe sepsis.…”

“…Inborn errors of immunity (IEI) are hypothesized to underlie vulnerability to life-threatening infection, not just in primary immunodeficiencies, but also in sporadic cases of severe sepsis [ 2 ]. While links have been explored in individual cases and pathogens such as influenza [ 3 ], invasive pneumococcus [ 4 ], Pseudomonas [ 5 ], SARS-CoV-2 [ 6 , 7 ], and previously healthy children with bacteremia [ 8 ], systematic investigation of IEI in pediatric sepsis is limited.…”

Screening for Immunodeficiencies in Children With Invasive Pneumococcal Disease: Six-year Experience From a UK Children’s Hospital

“…21 The high proportion of potentially pathogenic variants found by whole exome sequencing in children presenting with sepsis, suggests that when applying commonly used tests, such as immunoglobulin levels, vaccine responses, lymphocyte subsets and complement function, a considerable proportion of children with IEI might be missed. 22 Genetic testing of children presenting with IPD through an IEI gene panel of WGS is important to identify IEIs that are not necessarily detected through functional testing. Whether or not to apply genetic testing for an individual patient currently depends on local resources and availability.…”

Editorial: The Immunology of Sepsis—Understanding Host Susceptibility, Pathogenesis of Disease, and Avenues for Future Treatment

“…Considering how few patients develop sepsis in comparison to the exposed population, there is biological plausibility and epidemiologic evidence for underlying genetic mechanisms affecting susceptibility to sepsis (9,10). These may affect both very rare variants associated with extreme phenotypes (11) and common variants that may be of relevance at the populational level (12).…”