Clinical exome sequencing data from patients with inborn errors of immunity: Cohort level diagnostic yield and the benefit of systematic reanalysis
Vorsteveld, Emil E; Van der Made, Caspar I; Smeekens, Sanne P; Schuurs-Hoeijmakers, Janneke H; Astuti, Galuh; Diepstra, Heleen; Gilissen, Christian; Hoenselaar, Evelien; Janssen, Alice; van Roozendaal, Kees; Engelen, Jettie Sikkema-van; Steyaert, Wouter; Weiss, Marjan M; Yntema, Helger G; Mantere, Tuomo; AlZahrani, Mofareh S; van Aerde, Koen; Derfalvi, Beata; Faqeih, Eissa Ali; Henriet, Stefanie S V; van Hoof, Elise; Idressi, Eman; Issekutz, Thomas B; Jongmans, Marjolijn C J; Keski-Filppula, Riikka; Krapels, Ingrid; Te Loo, Maroeska; Mulders-Manders, Catharina M; Ten Oever, Jaap; Potjewijd, Judith; Sarhan, Nora Tarig; Slot, Marjan C; Terhal, Paulien A; Thijs, Herman; Vandersteen, Anthony; Vanhoutte, Els K; van de Veerdonk, Frank; van Well, Gijs; Netea, Mihai G; on behalf of all members of the Radboud University Medical Center multidisciplinary immune-disease board; Simons, Annet; Hoischen, Alexander (2024-10-05)
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, 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, Annet Simons, Alexander Hoischen, Clinical exome sequencing data from patients with inborn errors of immunity: Cohort level diagnostic yield and the benefit of systematic reanalysis, Clinical Immunology, Volume 268, 2024, 110375, ISSN 1521-6616, https://doi.org/10.1016/j.clim.2024.110375
© 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
https://creativecommons.org/licenses/by/4.0/
https://urn.fi/URN:NBN:fi:oulu-202410186381
Tiivistelmä
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.
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