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Journal of Clinical Immunology
Published in: Journal of Clinical Immunology 5/2018

01-07-2018 | Original Article

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

Authors: Jérémie Rosain, Carmen Oleaga-Quintas, Caroline Deswarte, Hannah Verdin, Stéphane Marot, Garyfallia Syridou, Mahboubeh Mansouri, S. Alireza Mahdaviani, Edna Venegas-Montoya, Maria Tsolia, Mehrnaz Mesdaghi, Liudmyla Chernyshova, Yuriy Stepanovskiy, Nima Parvaneh, Davood Mansouri, Sigifredo Pedraza-Sánchez, Anastasia Bondarenko, Sara E. Espinosa-Padilla, Marco A. Yamazaki-Nakashimada, Alejandro Nieto-Patlán, Gaspard Kerner, Nathalie Lambert, Corinne Jacques, Emilie Corvilain, Mélanie Migaud, Virginie Grandin, María T. Herrera, Fabienne Jabot-Hanin, Stéphanie Boisson-Dupuis, Capucine Picard, Patrick Nitschke, Anne Puel, Frederic Tores, Laurent Abel, Lizbeth Blancas-Galicia, Elfride De Baere, Christine Bole-Feysot, Jean-Laurent Casanova, Jacinta Bustamante

Published in: Journal of Clinical Immunology | Issue 5/2018

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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.
Appendix
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Metadata
Title
A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency
Authors
Jérémie Rosain
Carmen Oleaga-Quintas
Caroline Deswarte
Hannah Verdin
Stéphane Marot
Garyfallia Syridou
Mahboubeh Mansouri
S. Alireza Mahdaviani
Edna Venegas-Montoya
Maria Tsolia
Mehrnaz Mesdaghi
Liudmyla Chernyshova
Yuriy Stepanovskiy
Nima Parvaneh
Davood Mansouri
Sigifredo Pedraza-Sánchez
Anastasia Bondarenko
Sara E. Espinosa-Padilla
Marco A. Yamazaki-Nakashimada
Alejandro Nieto-Patlán
Gaspard Kerner
Nathalie Lambert
Corinne Jacques
Emilie Corvilain
Mélanie Migaud
Virginie Grandin
María T. Herrera
Fabienne Jabot-Hanin
Stéphanie Boisson-Dupuis
Capucine Picard
Patrick Nitschke
Anne Puel
Frederic Tores
Laurent Abel
Lizbeth Blancas-Galicia
Elfride De Baere
Christine Bole-Feysot
Jean-Laurent Casanova
Jacinta Bustamante
Publication date
01-07-2018
Publisher
Springer US
Published in
Journal of Clinical Immunology / Issue 5/2018
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-018-0527-6

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