Περίληψη:
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)orintrans (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. © �Springer Science+Business Media, LLC, part of Springer Nature 2018.
Συγγραφείς:
Rosain, J.
Oleaga-Quintas, C.
Deswarte, C.
Verdin, H.
Marot, S.
Syridou, G.
Mansouri, M.
Mahdaviani, S.A.
Venegas-Montoya, E.
Tsolia, M.
Mesdaghi, M.
Chernyshova, L.
Stepanovskiy, Y.
Parvaneh, N.
Mansouri, D.
Pedraza-Sánchez, S.
Bondarenko, A.
Espinosa-Padilla, S.E.
Yamazaki-Nakashimada, M.A.
Nieto-Patlán, A.
Kerner, G.
Lambert, N.
Jacques, C.
Corvilain, E.
Migaud, M.
Grandin, V.
Herrera, M.T.
Jabot-Hanin, F.
Boisson-Dupuis, S.
Picard, C.
Nitschke, P.
Puel, A.
Tores, F.
Abel, L.
Blancas-Galicia, L.
De Baere, E.
Bole-Feysot, C.
Casanova, J.-L.
Bustamante, J.
Λέξεις-κλειδιά:
gamma interferon; interleukin 12; interleukin 12 receptor beta1; interleukin 23; interleukin 12 receptor beta1, Alu sequence; Article; atypical mycobacteriosis; autosomal recessive disorder; B lymphocyte; BCG vaccination; clinical article; copy number variation; gene deletion; gene duplication; gene locus; hemagglutination; histoplasmosis; homozygosity; human; immune deficiency; indel mutation; infection sensitivity; interferon production; intron; lymphocyte transformation; mendelian susceptibility to mycobacterial disease; mucocutaneous candidiasis; next generation sequencing; pedigree analysis; priority journal; protein expression; salmonellosis; Sanger sequencing; single nucleotide polymorphism; T lymphocyte; allele; Alu repeat; case report; chromosomal mapping; female; gene expression; genetic association study; genetic predisposition; male; metabolism; mutation; mycobacteriosis; nucleotide sequence; pedigree; phenotype, Alleles; Alu Elements; Base Sequence; Chromosome Mapping; DNA Copy Number Variations; Female; Gene Expression; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Interferon-gamma; Interleukin-12 Receptor beta 1 Subunit; Male; Mutation; Mycobacterium Infections; Pedigree; Phenotype
