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

Autor: 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
Rok vydání: 2018
Předmět:
Zdroj: Journal of Clinical Immunology. 38:617-627
ISSN: 1573-2592
0271-9142
DOI: 10.1007/s10875-018-0527-6
Popis: 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.
Databáze: OpenAIRE
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