TY - JOUR TI - Trio-based whole exome sequencing in patients with suspected sporadic inborn errors of immunity: A retrospective cohort study AU - Hebert, Anne AU - Simons, Annet AU - Schuurs-Hoeijmakers, Janneke HM AU - Koenen, Hans JPM AU - Zonneveld-Huijssoon, Evelien AU - Henriet, Stefanie SV AU - Schatorjé, Ellen JH AU - Hoppenreijs, Esther PAH AU - Leenders, Erika KSM AU - Janssen, Etienne JM AU - Santen, Gijs WE AU - de Munnik, Sonja A AU - van Reijmersdal, Simon V AU - van Rijssen, Esther AU - Kersten, Simone AU - Netea, Mihai G AU - Smeets, Ruben L AU - van de Veerdonk, Frank L AU - Hoischen, Alexander AU - van der Made, Caspar I A2 - Yuen, Tony A2 - Zaidi, Mone VL - 11 PY - 2022 DA - 2022/10/17 SP - e78469 C1 - eLife 2022;11:e78469 DO - 10.7554/eLife.78469 UR - https://doi.org/10.7554/eLife.78469 AB - Background:. De 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 that 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. Systematic evaluation of rare, non-synonymous DNVs in coding or splice site regions led to the identification of 14 candidate DNVs in genes with an annotated immune function. DNVs were found in IEI genes (NLRP3 and RELA) and in potentially novel candidate genes, including PSMB10, DDX1, KMT2C, and FBXW11. The FBXW11 canonical splice site DNV was shown to lead to defective RNA splicing, increased NF-κB p65 signalling, and elevated IL-1β production in primary immune cells extracted from the patient with autoinflammatory disease. Conclusions:. Our findings in this retrospective cohort study advocate the implementation of trio-based sequencing in routine diagnostics of patients with sporadic IEI. Furthermore, we provide 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. KW - trio-based whole exome sequencing KW - de novo variants KW - inborn errors of immunity KW - primary immunodeficiencies JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -