ABSTRACT
Background D e novo variants (DNVs) are currently not routinely evaluated as part of diagnostic whole exome sequencing (WES) analysis in patients with suspected inborn errors of immunity (IEI). Methods This study explored the potential added value of systematic assessment of DNVs in a retrospective cohort of 123 patients with a suspected sporadic IEI who underwent patient-parent trio-based WES. Results A likely molecular diagnosis for (part) of the immunological phenotype was achieved in 12 patients with the diagnostic in silico IEI WES gene panel. Exome-wide evaluation of rare, non-synonymous DNVs affecting coding or splice site regions led to the identification of 14 candidate DNVs in genes with an annotated immune function. DNVs were identified in IEI genes ( NLRP3 and RELA ) and potentially novel candidate genes, including PSMB10 , DDX1 , KMT2C and FBXW11 . The FBXW11 canonical splice site DNV, in a patient with autoinflammatory disease, was shown to lead to defective RNA splicing, increased NF-κB p65 signalling, and elevated IL-1β production in primary immune cells. Conclusions This retrospective cohort study advocates the implementation of trio-based sequencing in routine diagnostics of patients with sporadic IEI. Furthermore, we have provided functional evidence supporting a causal role for FBXW11 loss-of-function mutations in autoinflammatory disease. Funding This research was supported by grants from the European Union, ZonMW and the Radboud Institute for Molecular Life Sciences.