Whole-Exome Sequencing for the Identification of Genetic Factors Implicated in Severe Bacterial Infections: A...

Severe bacterial infections (SBIs) represent a major health issue worldwide. Many studies have explored patients' genetic predispositions to SBI, but most of them chose a candidate-gene design. Only few adopted a whole-exome sequencing (WES) approach. We aimed at reporting nontargeted WES studies describing genetic variants associated with SBI susceptibility in previously healthy patients without a known predisposition for infections.

We included studies using WES in previously healthy patients who had SBI. We excluded studies that included nonbacterial infections or patients with a known genetic or dysimmune disorders. We assessed certainty in the body of evidence and detected risk of bias. Studies were grouped according to the patients' infectious phenotype to present main common characteristics and compare results.

Twelve studies were included, gathering 694 patients with WES data. They described genetic associations with various infectious phenotypes, using heterogenous methods to prioritize genetic variants. This diversity led to the identification of different genes or pathways associated with infection susceptibility or severity, supporting WES use in patients with SBI. WES was also a performant diagnostic tool. In this review, 42% of previously healthy patients with SBI had putatively disease-causing variants in genes with inborn errors of immunity.

Overall, included studies supported the use of WES as they successfully diagnosed inborn errors of immunity in patients with SBI. Future studies should follow strict guidelines to correctly prioritize disease-causing variants. Because of the rarity of this disease, sample sizes are often limited. Collaboration between research teams should allow for large-scale studies with robust statistical results.