![]() Most IEIs are attributed to single-gene variants that cause abnormal immune function. From a counseling perspective, a genetic diagnosis can provide closure, clarify recurrence risk, and guide reproductive decision-making ( 11, 12). For instance, molecular diagnosis may lead to the initiation of mechanism-based precision therapies or escalation to hematopoietic stem cell transplant ( 5, 9– 11). A genetic diagnosis may impact management for roughly half of all patients diagnosed ( 5). Identifying the underlying genetic etiology of an IEI may have important implications for prognosis and treatment. While the symptoms of specific IEIs are wide-ranging, many IEIs have significant phenotypic overlap, making clinical diagnosis challenging ( 8). Patients may present with infections, autoimmunity, or risk of malignancy ( 2– 7). Inborn errors of immunity (IEI) include over 400 inherited disorders of the immune system with a wide spectrum of clinical manifestations ( 1). Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5% beyond ES alone.Ĭonclusion: Pairing ES and CMA can provide a comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Three (2.2%) participants had diagnostic molecular findings from both ES and CMA, including two compound heterozygotes and one participant with two distinct diagnoses. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novo changes. ![]() Of these, 116/134 (86.6%) were diagnosed by ES alone. Results: Of the 332 probands, 134 (40.4%) received molecular diagnoses. The analysis included primary, secondary, and incidental findings. Methods: We performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. We sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with IEI. Purpose: Though copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. 8National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States.7Division of Pulmonary Diseases and Critical Care Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.6National Eye Institute, National Institutes of Health, Bethesda, MD, United States.5Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.4Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States.3Baylor Genetics, Houston, TX, United States.2National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.1National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.Oler 1, Kathleen Jevtich 1, Yunting Yu 1, Haley Hullfish 1, Bibiana Bielekova 1, Pamela Frischmeyer-Guerrerio 1, An Dang Do 5, Laryssa A. Setzer 1, Colleen Jodarski 1, Rylee Duncan 1, Devin Hunt 1, Madison Mixer 1, Wenjia Cao 1, Weimin Bi 3,4, Daniel Veltri 1, Eric Karlins 1, Lingwen Zhang 1, Zhiwen Li 1, Andrew J. Seifert 1, Leila Jamal 2, Michael Kamen 1, Michael R.
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