Clinical exome sequencing data from patients with inborn errors of immunity: Cohort level diagnostic yield and the benefit of systematic reanalysis
Emil E. Vorsteveld, Caspar I. van der Made, Sanne P. Smeekens, Janneke 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 AlZahrani, Koen van Aerde, Beáta Dérfalvi, Eissa Faqeih, Stefanie Henriet, Elise van Hoof, Eman Idressi, Thomas B. Issekutz, Marjolijn C.J. Jongmans, Riikka Keski-Filppula, Ingrid P.C. Krapels, D. Maroeska W. M. 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 L. van de Veerdonk, Gijs 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 G. van der Molen, Manon S. Oud, Ellen J. H. Schatorjé, Ruben L. Smeets, Evelien G. G. Sprenkeler, Kim Stol, Lilly M. Verhagen, Evelien Zonneveld‐Huijssoon, Annet Simons, Alexander Hoischen
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.