Frontiers in Immunology (May 2023)
Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity
- Breanna J. Beers,
- Morgan N. Similuk,
- Rajarshi Ghosh,
- Bryce A. Seifert,
- Leila Jamal,
- Michael Kamen,
- Michael R. Setzer,
- Colleen Jodarski,
- Rylee Duncan,
- Devin Hunt,
- Madison Mixer,
- Wenjia Cao,
- Weimin Bi,
- Weimin Bi,
- Daniel Veltri,
- Eric Karlins,
- Lingwen Zhang,
- Zhiwen Li,
- Andrew J. Oler,
- Kathleen Jevtich,
- Yunting Yu,
- Haley Hullfish,
- Bibiana Bielekova,
- Pamela Frischmeyer-Guerrerio,
- An Dang Do,
- Laryssa A. Huryn,
- Kenneth N. Olivier,
- Helen C. Su,
- Jonathan J. Lyons,
- Christa S. Zerbe,
- V. Koneti Rao,
- Michael D. Keller,
- Alexandra F. Freeman,
- Steven M. Holland,
- Luis M. Franco,
- Magdalena A. Walkiewicz,
- Jia Yan
Affiliations
- Breanna J. Beers
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Morgan N. Similuk
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Rajarshi Ghosh
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Bryce A. Seifert
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Leila Jamal
- National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
- Michael Kamen
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Michael R. Setzer
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Colleen Jodarski
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Rylee Duncan
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Devin Hunt
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Madison Mixer
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Wenjia Cao
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Weimin Bi
- Baylor Genetics, Houston, TX, United States
- Weimin Bi
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
- Daniel Veltri
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Eric Karlins
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Lingwen Zhang
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Zhiwen Li
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Andrew J. Oler
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Kathleen Jevtich
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Yunting Yu
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Haley Hullfish
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Bibiana Bielekova
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Pamela Frischmeyer-Guerrerio
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- An Dang Do
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
- Laryssa A. Huryn
- National Eye Institute, National Institutes of Health, Bethesda, MD, United States
- Kenneth N. Olivier
- Division of Pulmonary Diseases and Critical Care Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Helen C. Su
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Jonathan J. Lyons
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Christa S. Zerbe
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- V. Koneti Rao
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Michael D. Keller
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Alexandra F. Freeman
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Steven M. Holland
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Luis M. Franco
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States
- Magdalena A. Walkiewicz
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Jia Yan
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- DOI
- https://doi.org/10.3389/fimmu.2023.1172004
- Journal volume & issue
-
Vol. 14
Abstract
PurposeThough 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. We sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with IEI.MethodsWe performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings.ResultsOf the 332 probands, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novo changes. Three (2.2%) participants had diagnostic molecular findings from both ES and CMA, including two compound heterozygotes and one participant with two distinct diagnoses. 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. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5% beyond ES alone.ConclusionPairing ES and CMA can provide a comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. 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.
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