Jérémie Rosain1,2,3, Carmen Oleaga-Quintas1,2, Caroline Deswarte1,2, Hannah Verdin4, Stéphane Marot3, Garyfallia Syridou5, Mahboubeh Mansouri6, S Alireza Mahdaviani7, Edna Venegas-Montoya8, Maria Tsolia9, Mehrnaz Mesdaghi6, Liudmyla Chernyshova10, Yuriy Stepanovskiy10, Nima Parvaneh11, Davood Mansouri12,13, Sigifredo Pedraza-Sánchez14, Anastasia Bondarenko10, Sara E Espinosa-Padilla8, Marco A Yamazaki-Nakashimada15, Alejandro Nieto-Patlán1,2, Gaspard Kerner1,2, Nathalie Lambert3, Corinne Jacques3, Emilie Corvilain1,2,16, Mélanie Migaud1,2, Virginie Grandin3, María T Herrera17, Fabienne Jabot-Hanin1,2, Stéphanie Boisson-Dupuis1,2,18, Capucine Picard2,3,19, Patrick Nitschke20, Anne Puel1,2,18, Frederic Tores20, Laurent Abel1,2,18, Lizbeth Blancas-Galicia8, Elfride De Baere4, Christine Bole-Feysot21,22, Jean-Laurent Casanova1,2,18,19,23, Jacinta Bustamante24,25,26,27. 1. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Hospital for Sick Children, Paris, France. 2. Imagine Institute, Paris Descartes University, Paris, France. 3. Study Center for Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France. 4. Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium. 5. Pediatric Infectious Diseases, Thriasio Hospital, Athens, Greece. 6. Department of Allergy and Clinical Immunology, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 7. Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. 8. The Immunodeficiencies Research Unit, National Institute of Pediatrics, Mexico City, Mexico. 9. Second Department of Pediatrics, P. and A. Kyriakou Children's Hospital, National and Kapodistrian University of Athens (NKUA), Athens, Greece. 10. Department of Pediatric Infectious Diseases and Immunology, Shupyk National Medical Academy for Postgraduate Education, Kiev, Ukraine. 11. Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. 12. Department of Internal Medicine, Division of Infectious Disease and Clinical Immunology, NRITLD, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 13. Clinical Tuberculosis and Epidemiology Research Center, NRITLD, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 14. Unit of Biochemistry, National Institute for Medical Sciences and Nutrition Salvador Zubiran (INCMNSZ), Mexico City, Mexico. 15. Department of Clinical Immunology, National Institute of Pediatrics, Mexico City, Mexico. 16. Free University of Brussels, Brussels, Belgium. 17. Department of Microbiology Research, National Institute of Respiratory Diseases (INER), Mexico City, Mexico. 18. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA. 19. Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France. 20. Bioinformatics Core Facility, Imagine Institute, SFR-Necker, INSERM UMR1163 and INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, Paris, France. 21. Genomic Core Facility, INSERM UMR1163, SFR-Necker, Imagine Institute, Paris, France. 22. INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, Paris, France. 23. Howard Hughes Medical Institute, New York, NY, USA. 24. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Hospital for Sick Children, Paris, France. jacinta.bustamante@inserm.fr. 25. Imagine Institute, Paris Descartes University, Paris, France. jacinta.bustamante@inserm.fr. 26. Study Center for Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France. jacinta.bustamante@inserm.fr. 27. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA. jacinta.bustamante@inserm.fr.
Abstract
PURPOSE: Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rβ1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy number variations (CNVs), identified in two of the 213 IL-12Rβ1-deficient patients and two of the 164 kindreds reported. These two CNVs are large deletions found in the heterozygous or homozygous state. We searched for novel families with IL-12Rβ1 deficiency due to CNVs. METHODS: We studied six MSMD patients from five unrelated kindreds displaying adverse reactions to BCG vaccination. Three of the patients also presented systemic salmonellosis, two had mucocutaneous candidiasis, and one had disseminated histoplasmosis. We searched for CNVs and other variations by IL12RB1-targeted next-generation sequencing (NGS). RESULTS: We identified six new IL-12Rβ1-deficient patients with a complete loss of IL-12Rβ1 expression on phytohemagglutinin-activated T cells and/or EBV-transformed B cells. The cells of these patients did not respond to IL-12 and IL-23. Five different CNVs encompassing IL12RB1 (four deletions and one duplication) were identified in these patients by NGS coverage analysis, either in the homozygous state (n = 1) or in trans (n = 4) with a single-nucleotide variation (n = 3) or a small indel (n = 1). Seven of the nine mutations are novel. Interestingly, four of the five CNVs were predicted to be driven by nearby Alu elements, as well as the two previously reported large deletions. The IL12RB1 locus is actually enriched in Alu elements (44.7%), when compared with the rest of the genome (10.5%). CONCLUSION: The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12Rβ1 deficiency.
PURPOSE: Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rβ1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy number variations (CNVs), identified in two of the 213 IL-12Rβ1-deficient patients and two of the 164 kindreds reported. These two CNVs are large deletions found in the heterozygous or homozygous state. We searched for novel families with IL-12Rβ1 deficiency due to CNVs. METHODS: We studied six MSMD patients from five unrelated kindreds displaying adverse reactions to BCG vaccination. Three of the patients also presented systemic salmonellosis, two had mucocutaneous candidiasis, and one had disseminated histoplasmosis. We searched for CNVs and other variations by IL12RB1-targeted next-generation sequencing (NGS). RESULTS: We identified six new IL-12Rβ1-deficient patients with a complete loss of IL-12Rβ1 expression on phytohemagglutinin-activated T cells and/or EBV-transformed B cells. The cells of these patients did not respond to IL-12 and IL-23. Five different CNVs encompassing IL12RB1 (four deletions and one duplication) were identified in these patients by NGS coverage analysis, either in the homozygous state (n = 1) or in trans (n = 4) with a single-nucleotide variation (n = 3) or a small indel (n = 1). Seven of the nine mutations are novel. Interestingly, four of the five CNVs were predicted to be driven by nearby Alu elements, as well as the two previously reported large deletions. The IL12RB1 locus is actually enriched in Alu elements (44.7%), when compared with the rest of the genome (10.5%). CONCLUSION: The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12Rβ1 deficiency.
Entities:
Keywords:
Alu elements; Copy number variation; Histoplasma; IL-12Rβ1; Mycobacterium; Salmonella
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