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

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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Publication Details

Journal
Clinical Immunology
Published
2024-10-05
DOI
https://doi.org/10.1016/j.clim.2024.110375
Citations
15
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
Field-Weighted Citation Impact
3.61

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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

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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

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

Abstract

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.

Clinical ImmunologyVol. 268
Dalhousie University (CA), University Medical Center Groningen (NL), Radboud University Nijmegen (NL), University of Groningen (NL), Oulu University Hospital (FI), Maastricht University Medical Centre (NL), Izaak Walton Killam Health Centre (CA), Gelre Hospitals (NL), Nova Scotia Health Authority (CA), Radboud University Medical Center (NL), University Medical Center Utrecht (NL), Maastricht University (NL), Radboud Institute for Molecular Life Sciences (NL), Amalia Kinderziekenhuis (NL), Princess Máxima Center (NL), University of Oulu (FI)
Radboud Universiteit, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Radboud Universitair Medisch Centrum, European Research Council, Horizon 2020
Zero hunger
Openalex Percentile: Top 6%
Immunodeficiency and Autoimmune Disorders
3.61
DOIOpen Access PDFOpenAlex
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