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A variety of Alu-mediated copy number variations can underlie IL-12Rβ1 deficiency

(2018) JOURNAL OF CLINICAL IMMUNOLOGY. 38(5). p.617-627
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Abstract
Inborn errors of IFN-gamma immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12R beta 1 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-12R beta 1-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-12R beta 1 deficiency due to CNVs. 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). We identified six new IL-12R beta 1-deficient patients with a complete loss of IL-12R beta 1 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%). The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12R beta 1 deficiency.
Keywords
IL-12R beta 1, Mycobacterium, Histoplasma, Salmonella, Copy number variation, Alu elements, RECEPTOR BETA-1 DEFICIENCY, MENDELIAN SUSCEPTIBILITY, SALMONELLA-ENTERITIDIS, MYCOBACTERIAL DISEASE, CLINICAL-FEATURES, CALMETTE-GUERIN, T-CELLS, CHILD, INFECTIONS, MUTATION

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Chicago
Rosain, Jérémie, Carmen Oleaga-Quintas, Caroline Deswarte, Hannah Verdin, Stéphane Marot, Garyfallia Syridou, Mahboubeh Mansouri, et al. 2018. “A Variety of Alu-mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency.” Journal of Clinical Immunology 38 (5): 617–627.
APA
Rosain, J., Oleaga-Quintas, C., Deswarte, C., Verdin, H., Marot, S., Syridou, G., Mansouri, M., et al. (2018). A variety of Alu-mediated copy number variations can underlie IL-12Rβ1 deficiency. JOURNAL OF CLINICAL IMMUNOLOGY, 38(5), 617–627.
Vancouver
1.
Rosain J, Oleaga-Quintas C, Deswarte C, Verdin H, Marot S, Syridou G, et al. A variety of Alu-mediated copy number variations can underlie IL-12Rβ1 deficiency. JOURNAL OF CLINICAL IMMUNOLOGY. 2018;38(5):617–27.
MLA
Rosain, Jérémie et al. “A Variety of Alu-mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency.” JOURNAL OF CLINICAL IMMUNOLOGY 38.5 (2018): 617–627. Print.
@article{8600867,
  abstract     = {Inborn errors of IFN-gamma immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12R beta 1 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-12R beta 1-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-12R beta 1 deficiency due to CNVs. 
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). 
We identified six new IL-12R beta 1-deficient patients with a complete loss of IL-12R beta 1 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%). 
The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12R beta 1 deficiency.},
  author       = {Rosain, Jérémie and Oleaga-Quintas, Carmen and Deswarte, Caroline and Verdin, Hannah and Marot, Stéphane and Syridou, Garyfallia and Mansouri, Mahboubeh and Mahdaviani, S Alireza and Venegas-Montoya, Edna and Tsolia, Maria and Mesdaghi, Mehrnaz and Chernyshova, Liudmyla and Stepanovskiy, Yuriy and Parvaneh, Nima and Mansouri, Davood and Pedraza-Sánchez, Sigifredo and Bondarenko, Anastasia and Espinosa-Padilla, Sara E and Yamazaki-Nakashimada, Marco A and Nieto-Patlán, Alejandro and Kerner, Gaspard and Lambert, Nathalie and Jacques, Corinne and Corvilain, Emilie and Migaud, Mélanie and Grandin, Virginie and Herrera, María T and Jabot-Hanin, Fabienne and Boisson-Dupuis, Stéphanie and Picard, Capucine and Nitschke, Patrick and Puel, Anne and Tores, Frederic and Abel, Laurent and Blancas-Galicia, Lizbeth and De Baere, Elfride and Bole-Feysot, Christine and Casanova, Jean-Laurent and Bustamante, Jacinta},
  issn         = {0271-9142},
  journal      = {JOURNAL OF CLINICAL IMMUNOLOGY},
  keywords     = {IL-12R beta 1,Mycobacterium,Histoplasma,Salmonella,Copy number variation,Alu elements,RECEPTOR BETA-1 DEFICIENCY,MENDELIAN SUSCEPTIBILITY,SALMONELLA-ENTERITIDIS,MYCOBACTERIAL DISEASE,CLINICAL-FEATURES,CALMETTE-GUERIN,T-CELLS,CHILD,INFECTIONS,MUTATION},
  language     = {eng},
  number       = {5},
  pages        = {617--627},
  title        = {A variety of Alu-mediated copy number variations can underlie IL-12Rβ1 deficiency},
  url          = {http://dx.doi.org/10.1007/s10875-018-0527-6},
  volume       = {38},
  year         = {2018},
}

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