Clinical exome sequencing data from patients with inborn errors of immunity: cohort level meta-analysis and the benefit of systematic reanalysis

While next generation sequencing has expanded the scientific understanding of Inborn Errors of Immunity (IEI), the clinical use of exome sequencing is still emerging. We performed a cohort level meta-analysis by revisiting clinical exome data from 1,300 IEI patients using an updated in-silico gene panel for IEI. Variants were classified and curated through expert review. The molecular diagnostic yield after standard exome analysis was 11.8%. A systematic reanalysis resulted in the identification of variants of interest in 5.2% of undiagnosed patients, of which 75.4% were (candidate) disease-causing, increasing the molecular diagnostic yield to 15.2%. We find a high degree of actionability in IEI patients with a genetic diagnosis (76.4%). Despite the modest absolute diagnostic gain, these data support the benefit of iterative exome reanalysis in patients with IEI conveying the notion that our current understanding of genes and variants involved in IEI is by far not saturated. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement MGN was supported by an ERC Advanced Grant (#833247) and a Spinoza Grant of the Netherlands Organization for Scientific Research. AH was supported by the Solve-RD project, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 779257. ### 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: Patients and their parents (encountered in Genome Diagnostics at the Department of Human Genetics in the Radboud University Medical Center (RUMC)) provided written informed consent for in silico IEI WES gene panel analysis with or without exome-wide variant analysis in line with the diagnostic procedure and clinical question, as approved by the local ethics committee (medisch-ethische toetsingscommissie Oost-Nederland). This research is in compliance with the principles of 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I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 The datasets supporting the conclusions of this article are included within the article and supplementary files. All raw data was generated within the diagnostic procedure and analysis. This does not allow public data sharing as these data can be identifiable information, for which the patients or their families did not provide consent. All identifiable information has been redacted. Patient IDs used within the study are only known within the research group.