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A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency

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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.

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Acknowledgments

We thank the patients and their families for their collaboration, both branches of the Laboratory of Human Genetics of Infectious Diseases for their helpful discussions and support, and Yelena Nemirovskaya, Catherine Heitz, Céline Desvallées, Cécile Patissier, and Dominick Papandrea for their administrative support.

Funding

The Laboratory of Human Genetics of Infectious Diseases is supported by the National Institute of Allergy and Infectious Diseases (grant number 5R37AI095983), the Rockefeller University, the St. Giles Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), and the French National Research Agency under the “Investments for the future” program (grant number ANR-10-IAHU-01), ANR-GENMSMD (ANR-16-CE17-0005-01 for J.B.), and ANR-HGDIFD (ANR-14-CE15-006-01 for A.P.). C.O.-Q. is supported by ANR-14-CE15-006-01. A.N.-P. was supported by CONACYT National PhD Fellowship Program. This study was supported by a Ghent University Special Research Fund (BOF15/GOA/011) grant to E.D.B. H.V. is a Research Foundation Flanders post-doctoral fellow (12R3415N), and E.D.B. is a Research Foundation Flanders senior clinical investigator (1802215N).

Author information

Author notes

  1. Carmen Oleaga-Quintas and Caroline Deswarte contributed equally to this work; Hannah Verdin, Stéphane Marot, Garyfallia Syridou, Mahboubeh Mansouri, Seyed A. Mahdaviani, Maria Tsolia, Mehrnaz Mesdaghi, Liudmyla Chernyshova, Yuriy Stepanovskiy, Nima Parvaneh, Davood Mansouri, Sigifredo Pedraza-Sánchez, Anastasia Bondarenko, Sara E. Espinosa-Padilla and Marco A. Yamazaki-Nakashimada contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Hospital for Sick Children, Paris, France

    Jérémie Rosain, Carmen Oleaga-Quintas, Caroline Deswarte, Alejandro Nieto-Patlán, Gaspard Kerner, Emilie Corvilain, Mélanie Migaud, Fabienne Jabot-Hanin, Stéphanie Boisson-Dupuis, Anne Puel, Laurent Abel, Jean-Laurent Casanova & Jacinta Bustamante

  2. Imagine Institute, Paris Descartes University, Paris, France

    Jérémie Rosain, Carmen Oleaga-Quintas, Caroline Deswarte, Alejandro Nieto-Patlán, Gaspard Kerner, Emilie Corvilain, Mélanie Migaud, Fabienne Jabot-Hanin, Stéphanie Boisson-Dupuis, Capucine Picard, Anne Puel, Laurent Abel, Jean-Laurent Casanova & Jacinta Bustamante

  3. Study Center for Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France

    Jérémie Rosain, Stéphane Marot, Nathalie Lambert, Corinne Jacques, Virginie Grandin, Capucine Picard & Jacinta Bustamante

  4. Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium

    Hannah Verdin & Elfride De Baere

  5. Pediatric Infectious Diseases, Thriasio Hospital, Athens, Greece

    Garyfallia Syridou

  6. Department of Allergy and Clinical Immunology, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mahboubeh Mansouri & Mehrnaz Mesdaghi

  7. Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran

    S. Alireza Mahdaviani

  8. The Immunodeficiencies Research Unit, National Institute of Pediatrics, Mexico City, Mexico

    Edna Venegas-Montoya, Sara E. Espinosa-Padilla & Lizbeth Blancas-Galicia

  9. Second Department of Pediatrics, P. and A. Kyriakou Children’s Hospital, National and Kapodistrian University of Athens (NKUA), Athens, Greece

    Maria Tsolia

  10. Department of Pediatric Infectious Diseases and Immunology, Shupyk National Medical Academy for Postgraduate Education, Kiev, Ukraine

    Liudmyla Chernyshova, Yuriy Stepanovskiy & Anastasia Bondarenko

  11. Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

    Nima Parvaneh

  12. Department of Internal Medicine, Division of Infectious Disease and Clinical Immunology, NRITLD, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Davood Mansouri

  13. Clinical Tuberculosis and Epidemiology Research Center, NRITLD, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Davood Mansouri

  14. Unit of Biochemistry, National Institute for Medical Sciences and Nutrition Salvador Zubiran (INCMNSZ), Mexico City, Mexico

    Sigifredo Pedraza-Sánchez

  15. Department of Clinical Immunology, National Institute of Pediatrics, Mexico City, Mexico

    Marco A. Yamazaki-Nakashimada

  16. Free University of Brussels, Brussels, Belgium

    Emilie Corvilain

  17. Department of Microbiology Research, National Institute of Respiratory Diseases (INER), Mexico City, Mexico

    María T. Herrera

  18. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA

    Stéphanie Boisson-Dupuis, Anne Puel, Laurent Abel, Jean-Laurent Casanova & Jacinta Bustamante

  19. Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France

    Capucine Picard & Jean-Laurent Casanova

  20. Bioinformatics Core Facility, Imagine Institute, SFR-Necker, INSERM UMR1163 and INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, Paris, France

    Patrick Nitschke & Frederic Tores

  21. Genomic Core Facility, INSERM UMR1163, SFR-Necker, Imagine Institute, Paris, France

    Christine Bole-Feysot

  22. INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, Paris, France

    Christine Bole-Feysot

  23. Howard Hughes Medical Institute, New York, NY, USA

    Jean-Laurent Casanova

Authors
  1. Jérémie Rosain
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  2. Carmen Oleaga-Quintas
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  3. Caroline Deswarte
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  4. Hannah Verdin
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  5. Stéphane Marot
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  6. Garyfallia Syridou
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  7. Mahboubeh Mansouri
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  8. S. Alireza Mahdaviani
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Corresponding author

Correspondence to Jacinta Bustamante.

Ethics declarations

Research Involving Human Participants

Informed consent for participation in this study was obtained in accordance with local regulations, with approval from the IRB. The experiments described here were performed in France, in accordance with local regulations, and with the approval of the IRB of Necker Hospital for Sick Children, France.

Informed Consent

Written informed consent was obtained from the guardians of the patients.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Rosain, J., Oleaga-Quintas, C., Deswarte, C. et al. A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency. J Clin Immunol 38, 617–627 (2018). https://doi.org/10.1007/s10875-018-0527-6

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  • DOI: https://doi.org/10.1007/s10875-018-0527-6

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