TY - JOUR
T1 - Implementation of Early Next-Generation Sequencing for Inborn Errors of Immunity
T2 - A Prospective Observational Cohort Study of Diagnostic Yield and Clinical Implications in Dutch Genome Diagnostic Centers
AU - the Genetics First for Primary Immunodeficiency Disorders Consortium
AU - Elsink, Kim
AU - Huibers, Manon M.H.
AU - Hollink, Iris H.I.M.
AU - Simons, Annet
AU - Zonneveld-Huijssoon, Evelien
AU - van der Veken, Lars T.
AU - Leavis, Helen L.
AU - Henriet, Stefanie S.V.
AU - van Deuren, Marcel
AU - van de Veerdonk, Frank L.
AU - Potjewijd, Judith
AU - Berghuis, Dagmar
AU - Dalm, Virgil A.S.H.
AU - Vermont, Clementien L.
AU - van de Ven, Annick A.J.M.
AU - Lambeck, Annechien J.A.
AU - Abbott, Kristin M.
AU - van Hagen, P. Martin
AU - de Bree, Godelieve J.
AU - Kuijpers, Taco W.
AU - Frederix, Geert W.J.
AU - van Gijn, Mariëlle E.
AU - van Montfrans, Joris M.
N1 - Funding Information:
This publication and the underlying study have been made possible partly on the basis of the data that Hartwig Medical Foundation and Central Genome Analysis Laboratory-UMC St Radboud have generated for the study. We thank our colleagues Walter de Valk from the Erasmus Medical Center and Genomics Coordination Centre-UMC Groningen for their support regarding bioinformatics.
Publisher Copyright:
Copyright © 2021 Elsink, Huibers, Hollink, Simons, Zonneveld-Huijssoon, van der Veken, Leavis, Henriet, van Deuren, van de Veerdonk, Potjewijd, Berghuis, Dalm, Vermont, van de Ven, Lambeck, Abbott, van Hagen, de Bree, Kuijpers, Frederix, van Gijn, van Montfrans and the Genetics First for Primary Immunodeficiency Disorders Consortium.
PY - 2021/12/21
Y1 - 2021/12/21
N2 - 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.
AB - 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.
KW - clinical implication
KW - diagnostic yield
KW - gene panel
KW - inborn errors of immunity
KW - next-generation sequencing
U2 - 10.3389/fimmu.2021.780134
DO - 10.3389/fimmu.2021.780134
M3 - Article
AN - SCOPUS:85122204889
SN - 1664-3224
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 780134
ER -