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Copy Number Analysis in a Large Cohort Suggestive of Inborn Errors of Immunity Indicates a Wide Spectrum of Relevant Chromosomal Losses and Gains Publisher Pubmed



Wan R1 ; Schieck M1, 2 ; Caballerooteyza A3 ; Hofmann W1 ; Cochino AV4 ; Shcherbina A5 ; Sherkat R6 ; Wachemainier C7 ; Fernandez A7 ; Sultan M7 ; Illig T1, 2, 8 ; Grimbacher B2, 3, 9, 10, 11 ; Proietti M2, 3, 12 ; Steinemann D1, 2
Authors
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Authors Affiliations
  1. 1. Department of Human Genetics, Hannover Medical School, Hannover, Germany
  2. 2. RESIST-Cluster of Excellence 2155, Hannover Medical School, Hannover, Germany
  3. 3. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany
  4. 4. Institute for Mother and Child Health, Bucharest, Romania
  5. 5. Dmitry Rogachev National Medical and Research Center for Pediatric Hematology, Oncology, Immunology, Moscow, Russian Federation
  6. 6. Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
  7. 7. Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland
  8. 8. Hannover Unified Biobank, Hannover Medical School, Hannover, Germany
  9. 9. Clinic for Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany
  10. 10. DZIF – German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany
  11. 11. CIBSS – Centre for Integrative Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany
  12. 12. Department of Rheumatology and Clinical Immunology, Hannover Medical School, Hannover, Germany

Source: Journal of Clinical Immunology Published:2022


Abstract

Inborn errors of immunity (IEI) are genetically driven disorders. With the advancement of sequencing technologies, a rapidly increasing number of gene defects has been identified, thereby mirroring the high heterogeneity in immunological and clinical presentations observed in patients. However, for a large majority of patients, no causative single nucleotide variant (SNV) or small indel can be identified using next-generation sequencing. First studies have shown that also copy number variants (CNVs) can cause IEI. Unfortunately, CNVs are not well examined in many routine diagnostic settings and the aim of this study was to assess the number of clinically relevant chromosomal losses and gains in a large cohort. We identified a total of 20 CNVs using whole exome sequencing data of a cohort of 191 patients with a suspected IEI. A definite molecular diagnosis could be made in five patients (2.6%), including pathogenic deletions affecting ICOS, TNFAIP3, and 22q11.2. CNVs of uncertain significance were observed in fifteen patients (7.9%), including deletions of 11q22.1q22.3 and 16p11.2 but also duplications affecting entire or parts of genes previously associated with IEI. Importantly, five patients carrying a CNV of uncertain significance also carried pathogenic or likely pathogenic SNVs (PIK3R1, NFKB1, NLRC4, DOCK2), or SNVs of unknown significance (NFKB2). This cooccurrence of SNVs and CNVs suggests modifying effects in some patients, and functional follow-up is warranted now in order to better understand phenotypic heterogeneity. In summary, the diagnostic yield of IEI can be increased substantially by evaluating CNVs, which allows an improved therapeutic management in those patients. © 2022, The Author(s).
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