AUTHOR=Elsink Kim , Huibers Manon M. H. , Hollink Iris H. I. M. , Simons Annet , Zonneveld-Huijssoon Evelien , van der Veken Lars T. , Leavis Helen L. , Henriet Stefanie S. V. , van Deuren Marcel , van de Veerdonk Frank L. , Potjewijd Judith , Berghuis Dagmar , Dalm Virgil A. S. H. , Vermont Clementien L. , van de Ven Annick A. J. M. , Lambeck Annechien J. A. , Abbott Kristin M. , van Hagen P. Martin , de Bree Godelieve J. , Kuijpers Taco W. , Frederix Geert W. J. , van Gijn Mariëlle E. , van Montfrans Joris M. , the Genetics First for Primary Immunodeficiency Disorders Consortium , KJ Aerde van, , J Altenburg, , W Armbrust , BH Barendregt, , JM Berg van den, , RGM Bredius, , EP Buddingh, , M Burg van der, , PM Ellerbroek, , RF Ernst, , PLA Fraaij, , M Hermans, , A Hoischen, , AH Hout van der, , MHA Jansen, , H Jolink, , RE Jonkers, , JAM Laar van, , K Leeuw de, , GE Legger, , EFA Leijten, , M Limper, , CA Lindemans, , J Oever ten, , M Pieterse, , SM Rombach, , AMC Rossum van, , A Rutgers, , GWE Santen, , EH Schölvinck, , A Simon, , K Stol, , RML Vervenne TITLE=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 JOURNAL=Frontiers in Immunology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.780134 DOI=10.3389/fimmu.2021.780134 ISSN=1664-3224 ABSTRACT=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.