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Clinical exome sequencing data from patients with inborn errors of immunity: Cohort level diagnostic yield and the benefit of systematic reanalysis.

Clinical immunology (Orlando, Fla.)

Authors: Emil E Vorsteveld, Caspar I Van der Made, Sanne P Smeekens, Janneke H Schuurs-Hoeijmakers, Galuh Astuti, Heleen Diepstra, Christian Gilissen, Evelien Hoenselaar, Alice Janssen, Kees van Roozendaal, Jettie Sikkema-van Engelen, Wouter Steyaert, Marjan M Weiss, Helger G Yntema, Tuomo Mantere, Mofareh S AlZahrani, Koen van Aerde, Beata Derfalvi, Eissa Ali Faqeih, Stefanie S V Henriet, Elise van Hoof, Eman Idressi, Thomas B Issekutz, Marjolijn C J Jongmans, Riikka Keski-Filppula, Ingrid Krapels, Maroeska Te Loo, Catharina M Mulders-Manders, Jaap Ten Oever, Judith Potjewijd, Nora Tarig Sarhan, Marjan C Slot, Paulien A Terhal, Herman Thijs, Anthony Vandersteen, Els K Vanhoutte, Frank van de Veerdonk, Gijs van Well, Mihai G Netea, Annet Simons, Alexander Hoischen, Rob J W Arts, Else M Bijker, Mariolina Bruno, Willemijn Hobo, Esther Hoppenreijs, Marien I de Jonge, Arjan van Laarhoven, Renate van der Molen, Manon Oud, Ellen J H Schatorje, Ruben Smeets, Evelien G G Sprenkeler, Kim Stol, Lilly M Verhagen, Evelien Zonneveld-Huijssoon

While next generation sequencing has expanded the scientific understanding of Inborn Errors of Immunity (IEI), the clinical use and re-use of exome sequencing is still emerging. We revisited clinical exome data from 1300 IEI patients using an updated in silico IEI gene panel. Variants were classified and curated through expert review. The molecular diagnostic yield after standard exome analysis was 11.8 %. Through systematic reanalysis, we identified variants of interest in 5.2 % of undiagnosed patients, with 76.7 % being (candidate) disease-causing, providing a (candidate) diagnosis in 15.2 % of our cohort. We find a 1.7 percentage point increase in conclusive molecular diagnoses. We find a high degree of actionability in patients with a genetic diagnosis (76.4 %). Despite the modest absolute diagnostic gain, these data support the benefit of iterative exome reanalysis in IEI patients, conveying the notion that our current understanding of genes and variants involved in IEI is by far not saturated.

Copyright © 2024. Published by Elsevier Inc.

PMID: 39369972

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