Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity
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)...
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1172004/full |
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| author | 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 |
| author_facet | 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 |
| author_sort | Breanna J. Beers |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T14:17:19Z |
| format | Article |
| id | doaj.art-5a9a5d2c1d2843bb9d22ca82e9ec744f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-09T14:17:19Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5a9a5d2c1d2843bb9d22ca82e9ec744f2023-05-05T05:57:00ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-05-011410.3389/fimmu.2023.11720041172004Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunityBreanna J. Beers0Morgan N. Similuk1Rajarshi Ghosh2Bryce A. Seifert3Leila Jamal4Michael Kamen5Michael R. Setzer6Colleen Jodarski7Rylee Duncan8Devin Hunt9Madison Mixer10Wenjia Cao11Weimin Bi12Weimin Bi13Daniel Veltri14Eric Karlins15Lingwen Zhang16Zhiwen Li17Andrew J. Oler18Kathleen Jevtich19Yunting Yu20Haley Hullfish21Bibiana Bielekova22Pamela Frischmeyer-Guerrerio23An Dang Do24Laryssa A. Huryn25Kenneth N. Olivier26Helen C. Su27Jonathan J. Lyons28Christa S. Zerbe29V. Koneti Rao30Michael D. Keller31Alexandra F. Freeman32Steven M. Holland33Luis M. Franco34Magdalena A. Walkiewicz35Jia Yan36National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Cancer Institute, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesBaylor Genetics, Houston, TX, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United StatesNational Eye Institute, National Institutes of Health, Bethesda, MD, United StatesDivision of Pulmonary Diseases and Critical Care Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United StatesPurposeThough 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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1172004/fullgeneticcopy numberimmunitysequencingmicroarraydiagnosis |
| spellingShingle | 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 Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity Frontiers in Immunology genetic copy number immunity sequencing microarray diagnosis |
| title | Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity |
| title_full | Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity |
| title_fullStr | Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity |
| title_full_unstemmed | Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity |
| title_short | Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity |
| title_sort | chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity |
| topic | genetic copy number immunity sequencing microarray diagnosis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1172004/full |
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