Systematic Review of Whole-Exome Sequencing in Severe Bacterial Infections
Overview
This systematic review analyzed 12 studies involving 694 previously healthy patients with severe bacterial infections (SBIs) who underwent whole-exome sequencing (WES). It found that 42% of these patients harbored putative disease-causing variants in genes related to inborn errors of immunity, supporting WES as a valuable diagnostic and research tool for uncovering genetic susceptibility to SBIs.
Background
Severe bacterial infections remain a significant cause of morbidity and mortality worldwide, particularly affecting children under five and the elderly. While some patients have known risk factors such as anatomical defects or acquired immunodeficiencies, many previously healthy individuals develop SBIs, suggesting a genetic predisposition. Inborn errors of immunity (IEI) are recognized contributors to infection susceptibility, but most genetic studies have used candidate-gene approaches, limiting discovery to known genes. Whole-exome sequencing offers an untargeted method to identify novel genetic variants associated with SBI susceptibility in patients without prior immune deficiencies.
Data Highlights
Twelve studies published between 2016 and 2024 included 694 patients with WES data. Across these studies, 42% of previously healthy patients with SBI were found to have putatively disease-causing variants in genes linked to inborn errors of immunity. The studies varied in methods for variant prioritization and infectious phenotypes analyzed, precluding meta-analysis but collectively supporting the diagnostic utility of WES in this population.
Key Findings
WES identified genetic variants associated with susceptibility to various severe bacterial infectious phenotypes in previously healthy patients.
42% of patients studied had putative disease-causing variants in genes implicated in inborn errors of immunity.
Studies used heterogeneous methods for variant prioritization, leading to identification of different genes and pathways.
WES proved to be a performant diagnostic tool for uncovering underlying genetic predispositions in SBI patients without known immune disorders.
Sample sizes were limited due to disease rarity, highlighting the need for collaborative large-scale studies.
Future research should adopt strict guidelines for variant prioritization to improve consistency and robustness of findings.
Clinical Implications
Whole-exome sequencing should be considered in previously healthy patients presenting with severe bacterial infections to identify underlying inborn errors of immunity. Early genetic diagnosis can inform personalized management strategies and guide preventive measures. Collaborative efforts and standardized variant analysis protocols are essential to enhance the clinical utility of WES in this context.
Conclusion
This review supports the integration of whole-exome sequencing into the diagnostic workup of severe bacterial infections in previously healthy individuals, revealing a substantial proportion with genetic predispositions. Larger, standardized studies are needed to further elucidate genetic factors and improve patient outcomes.
References
Systematic Review of Whole-Exome Sequencing for Discovering Genetic Factors Linked to Severe Bacterial Infections
