Department of Human Genetics, Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, Netherlands
Annet Simons
Department of Human Genetics, Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, Netherlands
Janneke HM Schuurs-Hoeijmakers
Department of Human Genetics, Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, Netherlands
Hans JPM Koenen
Department of Laboratory Medicine, Laboratory for Medical Immunology, Radboud University Medical Center, Nijmegen, Netherlands
Evelien Zonneveld-Huijssoon
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
Stefanie SV Henriet
Department of Pediatric Infectious Diseases and Immunology, Amalia Children’s Hospital, Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands
Ellen JH Schatorjé
Department of Pediatric Rheumatology and Immunology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands
Esther PAH Hoppenreijs
Department of Pediatric Rheumatology and Immunology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands
Erika KSM Leenders
Department of Human Genetics, Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, Netherlands
Etienne JM Janssen
Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, Netherlands
Gijs WE Santen
Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
Sonja A de Munnik
Department of Human Genetics, Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, Netherlands
Simon V van Reijmersdal
Department of Human Genetics, Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, Netherlands
Esther van Rijssen
Department of Laboratory Medicine, Laboratory for Medical Immunology, Radboud University Medical Center, Nijmegen, Netherlands
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands; Department for Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
Ruben L Smeets
Department of Laboratory Medicine, Laboratory for Medical Immunology, Radboud University Medical Center, Nijmegen, Netherlands; Department of Laboratory Medicine, Laboratory for Diagnostics, Radboud University Medical Center, Nijmegen, Netherlands
Department of Human Genetics, Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, Netherlands; Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands
Department of Human Genetics, Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, Netherlands; Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands
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.
