Clinical exome sequencing data from patients with inborn errors of immunity: cohort level meta-analysis and the benefit of systematic reanalysis
Author:
Vorsteveld Emil E.ORCID, Van der Made Caspar I.ORCID, Smeekens Sanne P., Schuurs-Hoeijmakers Janneke H., Astuti Galuh, Diepstra Heleen, Gilissen ChristianORCID, Hoenselaar Evelien, Janssen Alice, van Roozendaal Kees, Sikkema-van Engelen Jettie, 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 FrankORCID, van Well GijsORCID, Netea Mihai G.ORCID, Simons Annet, Hoischen AlexanderORCID
Abstract
AbstractWhile next generation sequencing has expanded the scientific understanding of Inborn Errors of Immunity (IEI), the clinical use of exome sequencing is still emerging. We performed a cohort level meta-analysis by revisiting clinical exome data from 1,300 IEI patients using an updatedin-silicogene panel for IEI. Variants were classified and curated through expert review. The molecular diagnostic yield after standard exome analysis was 11.8%. A systematic reanalysis resulted in the identification of variants of interest in 5.2% of undiagnosed patients, of which 75.4% were (candidate) disease-causing, increasing the molecular diagnostic yield to 15.2%. We find a high degree of actionability in IEI patients with a genetic diagnosis (76.4%). Despite the modest absolute diagnostic gain, these data support the benefit of iterative exome reanalysis in patients with IEI conveying the notion that our current understanding of genes and variants involved in IEI is by far not saturated.
Publisher
Cold Spring Harbor Laboratory
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