Implementation of Early Next-Generation Sequencing for Inborn Errors of Immunity: A Prospective Observational Cohort Study of Diagnostic Yield and Clinical Implications in Dutch Genome Diagnostic Centers

Kim Elsink, Manon M.H. Huibers, the Genetics First for Primary Immunodeficiency Disorders Consortium, Iris H.I.M. Hollink, Annet Simons, Evelien Zonneveld-Huijssoon, Lars T. van der Veken, Helen L. Leavis, Stefanie S.V. Henriet, Marcel van Deuren, Frank L. van de Veerdonk, Judith Potjewijd, Dagmar Berghuis, Virgil A.S.H. Dalm, Clementien L. Vermont, Annick A.J.M. van de Ven, Annechien J.A. Lambeck, Kristin M. Abbott, P. Martin van Hagen, Godelieve J. de BreeTaco W. Kuijpers, Geert W.J. Frederix, Mariëlle E. van Gijn*, Joris M. van Montfrans

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Objective: Inborn errors of immunity (IEI) are a heterogeneous group of disorders, affecting different components of the immune system. Over 450 IEI related genes have been identified, with new genes continually being recognized. This makes the early application of next-generation sequencing (NGS) as a diagnostic method in the evaluation of IEI a promising development. We aimed to provide an overview of the diagnostic yield and time to diagnosis in a cohort of patients suspected of IEI and evaluated by an NGS based IEI panel early in the diagnostic trajectory in a multicenter setting in the Netherlands.

Study Design: We performed a prospective observational cohort study. We collected data of 165 patients with a clinical suspicion of IEI without prior NGS based panel evaluation that were referred for early NGS using a uniform IEI gene panel. The diagnostic yield was assessed in terms of definitive genetic diagnoses, inconclusive diagnoses and patients without abnormalities in the IEI gene panel. We also assessed time to diagnosis and clinical implications.

Results: For children, the median time from first consultation to diagnosis was 119 days versus 124 days for adult patients (U=2323; p=0.644). The median turn-around time (TAT) of genetic testing was 56 days in pediatric patients and 60 days in adult patients (U=1892; p=0.191). A definitive molecular diagnosis was made in 25/65 (24.6%) of pediatric patients and 9/100 (9%) of adults. Most diagnosed disorders were identified in the categories of immune dysregulation (n=10/25; 40%), antibody deficiencies (n=5/25; 20%), and phagocyte diseases (n=5/25; 20%). Inconclusive outcomes were found in 76/165 (46.1%) patients. Within the patient group with a genetic diagnosis, a change in disease management occurred in 76% of patients.

Conclusion: In this cohort, the highest yields of NGS based evaluation for IEI early in the diagnostic trajectory were found in pediatric patients, and in the disease categories immune dysregulation and phagocyte diseases. In cases where a definitive diagnosis was made, this led to important disease management implications in a large majority of patients. More research is needed to establish a uniform diagnostic pathway for cases with inconclusive diagnoses, including variants of unknown significance.
Original languageEnglish
Article number780134
JournalFrontiers in Immunology
Publication statusPublished - 21 Dec 2021

Bibliographical note

This study is part of the Genetics First: next-generation sequencing for cost-effective PID diagnostics project. This project is funded by ZonMw (grant number 846002001).


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