TY - JOUR
T1 - Clinical exome sequencing data from patients with inborn errors of immunity
T2 - Cohort level diagnostic yield and the benefit of systematic reanalysis
AU - Vorsteveld, Emil E
AU - Van der Made, Caspar I
AU - Smeekens, Sanne P
AU - Schuurs-Hoeijmakers, Janneke H
AU - Astuti, Galuh
AU - Diepstra, Heleen
AU - Gilissen, Christian
AU - Hoenselaar, Evelien
AU - Janssen, Alice
AU - van Roozendaal, Kees
AU - Engelen, Jettie Sikkema-van
AU - Steyaert, Wouter
AU - Weiss, Marjan M
AU - Yntema, Helger G
AU - Mantere, Tuomo
AU - AlZahrani, Mofareh S
AU - van Aerde, Koen
AU - Derfalvi, Beata
AU - Faqeih, Eissa Ali
AU - Henriet, Stefanie S V
AU - van Hoof, Elise
AU - Idressi, Eman
AU - Issekutz, Thomas B
AU - Jongmans, Marjolijn C J
AU - Keski-Filppula, Riikka
AU - Krapels, Ingrid
AU - Te Loo, Maroeska
AU - Mulders-Manders, Catharina M
AU - Ten Oever, Jaap
AU - Potjewijd, Judith
AU - Sarhan, Nora Tarig
AU - Slot, Marjan C
AU - Terhal, Paulien A
AU - Thijs, Herman
AU - Vandersteen, Anthony
AU - Vanhoutte, Els K
AU - van de Veerdonk, Frank
AU - van Well, Gijs
AU - Netea, Mihai G
AU - Simons, Annet
AU - Hoischen, Alexander
AU - Arts, Rob J W
AU - Bijker, Else M
AU - Bruno, Mariolina
AU - Hobo, Willemijn
AU - Hoppenreijs, Esther
AU - de Jonge, Marien I
AU - van Laarhoven, Arjan
AU - Members of the Radboud University Medical Center multidisciplinary immune-disease board, Radboud University Medical Center multidisciplinary immune-disease board
PY - 2024/10/4
Y1 - 2024/10/4
N2 - 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.
AB - 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.
KW - Autoimmune disorders
KW - Autoinflammatory disorders
KW - Clinical exome sequencing
KW - Exome reanalysis
KW - Genomics
KW - Inborn errors of immunity
KW - Longitudinal follow-up
KW - NGS-based sequencing
KW - Primary immunodeficiencies
U2 - 10.1016/j.clim.2024.110375
DO - 10.1016/j.clim.2024.110375
M3 - Article
SN - 1521-6616
VL - 268
JO - Clinical Immunology
JF - Clinical Immunology
M1 - 110375
ER -