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
Frontiers in Immunology, vol. 12, pp. 780134
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.
Authors 23
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Utrecht University · University Medical Center Utrecht · Wilhelmina Children's Hospital
Affiliation as printed
Department of Pediatric Immunology and Infectious Diseases, Wilhelmina's Children Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
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Erasmus MC · Erasmus University Rotterdam
Affiliation as printed
Department of Clinical Genetics, Erasmus Medical Center, Erasmus University Rotterdam, Rotterdam, Netherlands
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Radboud University Nijmegen · Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Nijmegen Center for Molecular Life Sciences, Radboud University Medical Centre, Radboud University, Nijmegen, Netherlands
Radboud Institute for Oncology, Radboud University Medical Center, Radboud University, Nijmegen, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Amalia Kinderziekenhuis
Affiliation as printed
Department of Pediatric Infectious Diseases and Immunology, Amalia's Children Hospital, Radboud University Nijmegen Medical Centre, Radboud University, Nijmegen, Netherlands
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Radboud University Nijmegen · Radboud University Medical Center
Affiliation as printed
Department of Internal Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases, Nijmegen, Netherlands
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Radboud University Nijmegen · Radboud University Medical Center
Affiliation as printed
Department of Internal Medicine, Radboud University Medical Center, Radboud Center for Infectious Diseases, Nijmegen, Netherlands
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Maastricht University Medical Centre · Maastricht University
Affiliation as printed
Department of Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht University, Maastricht, Netherlands
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Leiden University Medical Center · Willem-Alexander Kinderziekenhuis
Affiliation as printed
Willem-Alexander Children's Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden University, Leiden, Netherlands
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Erasmus MC · Erasmus University Rotterdam
Affiliation as printed
Department of Internal Medicine, Division of Allergy & Clinical Immunology; Department of Immunology, Erasmus University Medical Center Rotterdam, Erasmus University Rotterdam, Rotterdam, Netherlands
Department of Immunology, Erasmus University Medical Center Rotterdam, Erasmus University Rotterdam, Rotterdam, Netherlands
Department of Internal Medicine, Division of Allergy & Clinical Immunology
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital · Erasmus University Rotterdam
Affiliation as printed
Department of Pediatric Infectious Diseases, Immunology and Rheumatology, Sophia Children's Hospital, Erasmus Medical Center, Erasmus University Rotterdam, Rotterdam, Netherlands
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University Medical Center Groningen
Affiliation as printed
Department of Internal Medicine and Allergology, Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
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Erasmus MC · Erasmus University Rotterdam
Affiliation as printed
Department of Internal Medicine, Division of Allergy & Clinical Immunology; Department of Immunology, Erasmus University Medical Center Rotterdam, Erasmus University Rotterdam, Rotterdam, Netherlands
Department of Immunology, Erasmus University Medical Center Rotterdam, Erasmus University Rotterdam, Rotterdam, Netherlands
Department of Internal Medicine, Division of Allergy & Clinical Immunology
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Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Department of Internal Medicine, Institute for Infection and Immunity, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
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Emma Kinderziekenhuis · Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, Netherlands
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Marielle E van Gijn corresponding
University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
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Utrecht University · University Medical Center Utrecht · Wilhelmina Children's Hospital
Affiliation as printed
Department of Pediatric Immunology and Infectious Diseases, Wilhelmina's Children Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
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