Back to Search Start Over

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

Authors :
Yuriy Stepanovskiy
Liudmyla Chernyshova
Elfride De Baere
Davood Mansouri
Nima Parvaneh
Mahboubeh Mansouri
María Teresa Herrera
S. Alireza Mahdaviani
Fabienne Jabot-Hanin
Jacinta Bustamante
Mélanie Migaud
Laurent Abel
Anne Puel
Jérémie Rosain
Alejandro Nieto-Patlán
Frédéric Tores
Mehrnaz Mesdaghi
Emilie Corvilain
Gaspard Kerner
Virginie Grandin
Edna Venegas-Montoya
Capucine Picard
Stéphanie Boisson-Dupuis
Patrick Nitschke
Sigifredo Pedraza-Sánchez
Carmen Oleaga-Quintas
Stéphane Marot
Caroline Deswarte
Jean-Laurent Casanova
Christine Bole-Feysot
Hannah Verdin
Anastasia Bondarenko
Garyfallia Syridou
Maria Tsolia
Sara Elva Espinosa-Padilla
Nathalie Lambert
Corinne Jacques
Lizbeth Blancas-Galicia
Marco Antonio Yamazaki-Nakashimada
Source :
Journal of Clinical Immunology. 38:617-627
Publication Year :
2018
Publisher :
Springer Science and Business Media LLC, 2018.

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 variation 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 PHA-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, in either 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.

Details

ISSN :
15732592 and 02719142
Volume :
38
Database :
OpenAIRE
Journal :
Journal of Clinical Immunology
Accession number :
edsair.doi.dedup.....f0d9835a10b58e963862dde90caf04ed
Full Text :
https://doi.org/10.1007/s10875-018-0527-6