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

Abstract

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.