Abstract
ObjectiveInborn 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 DesignWe 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.ResultsFor 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.ConclusionIn 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.
Highlights
Inborn errors of immunity (IEI) are a heterogeneous group of inherited disorders affecting different components of the immune system [1, 2]
We separately collected the date of suspicion of inborn error of immunity (IEI), defined as date of first outpatient visit or first clinical consultation for IEI, and date of diagnosis, defined as the date of the genetic test result provided by the clinical laboratory geneticist
Patients were clustered according to their clinical presentations in one of 11 IEI categories based on the Immunological Societies (IUIS) classification [20]
Summary
Inborn errors of immunity (IEI) are a heterogeneous group of inherited disorders affecting different components of the immune system [1, 2]. Susceptibility to infections, failure to thrive, autoimmunity, autoinflammatory diseases, and/or malignancies. Severity of these manifestations and of disease related complications range from mild, with relatively little disease burden, to severe life-threatening complications. Other IEI include, for example, various types of (severe) combined immunodeficiency disorder (SCID or CID) and hemophagocytic lymphohistiocytosis (HLH), which require allogeneic hematopoietic stem cell transplantation (HSCT) or autologous hematopoietic stem cell based gene therapy. Diagnosis in IEI enables timely referral for diagnosis treatment and follow up, resulting in improved treatment outcome in several types of immune deficiencies. In the setting of SCID, early detection enables timely referral for HSCT, which was shown to improve treatment outcome and to reduce health care costs [17]
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