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Trio-based whole exome sequencing in patients with suspected sporadic inborn errors of immunity: A retrospective cohort study.

eLife

Authors: Anne Hebert, Annet Simons, Janneke H M Schuurs-Hoeijmakers, Hans J P M Koenen, Evelien Zonneveld-Huijssoon, Stefanie S V Henriet, Ellen J H Schatorjé, Esther P A H Hoppenreijs, Erika K S M Leenders, Etienne J M Janssen, Gijs W E Santen, Sonja A de Munnik, Simon V van Reijmersdal, Esther van Rijssen, Simone Kersten, Mihai G Netea, Ruben L Smeets, Frank L van de Veerdonk, Alexander Hoischen, Caspar I van der Made

BACKGROUND: 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 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 ( and ) and in potentially novel candidate genes, including , , and . The 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 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.

© 2022, Hebert et al.

PMID: 36250618

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