Rare variants in infection response protein pathways associated with sepsis in children

1 Abstract Sepsis is a major contributor to mortality in paediatric patients. We investigated the human genetic underpinnings of sepsis by analysing a large paediatric cohort with blood-culture confirmed sepsis through multi-tiered genomic assessments: single-case, single-variant, single-gene, and protein pathway analyses. We designed and applied novel analytical methods to automate for unbiased interpretation. We identified two pathways involved in susceptibility to sepsis, which contained 50 genes (42 and 8, respectively) including KIR2DL4, KIR3DL3, KLRD1, LILRA1, SIGLEC1, and SIRPG. These pathways are central to immune cell regulation, antigen processing, cellular signalling, and prevention of excessive inflammatory responses. A third enriched pathway of 22 genes was related to regulation of transcription. We additionally found 66 variants for inborn errors of immunity. Our findings highlight the influence of deleterious genomic variants on a shared immunological phenotype resulting in sepsis vulnerability in children. These insights lay a foundation for more personalised approaches to sepsis in children. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was funded by grants from the Swiss National Science Foundation (320030_201060 and 342730 153158/1), the Swiss Society of Intensive Care, the Bangerter Foundation, the Vinetum and Borer Foundation, and the Foundation for the Health of Children and Adolescents. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the respective ethics committees of all participating centers (Cantonal Ethics Committee Bern, approval number KEK-029/11) and the study was conducted in accordance with the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All summary statistic data are present within the work. Raw genomic data is controlled under restricted access according to ethical guidelines. All code is published.