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Title: Whole-exome sequencing in three children with sporadic Blau syndrome, one of them co-presenting with recurrent polyserositis
Authors: Córdova Fletes, Carlos
Rangel Sosa, Martha M.
Martínez Jacobo, Lizeth A.
Becerra Solano, Luis Eduardo
Arellano Valdés, Carmen Araceli
Tlacuilo Parra, José Alberto
Galán Huerta, Kame Alberto
Rivas Estilla, Ana María
Hernandez Orozco, Angélica Alejandra
García Ortiz, José Elías
Keywords: rare inflammatory deseases
blau syndrome
recurrent polyserositis
whole-exome sequencing
gain-of-function NOD2 variants
Issue Date: Jun-2020
Publisher: Taylor and Francis Online
Citation: Carlos Córdova-Fletes, Martha M. Rangel-Sosa, Lizeth A. Martínez-Jacobo, Luis Eduardo Becerra-Solano, Carmen Araceli Arellano-Valdés, José Alberto Tlacuilo-Parra, Kame Alberto Galán-Huerta, Ana María Rivas-Estilla, Angélica Alejandra Hernandez-Orozco & José Elías García-Ortiz (2020) Whole-exome sequencing in three children with sporadic Blau syndrome, one of them co-presenting with recurrent polyserositis, Autoimmunity, 53:6, 344-352, DOI: 10.1080/08916934.2020.1786068
Series/Report no.: Autoimmunity;Vol 53: Issue 6, 344-352
Abstract: Abstract Blau syndrome (BS) is a rare, chronic autoinflammatory disease with onset before age 4 and mainly characterised by granulomatous arthritis, recurrent uveitis, and skin rash. Sporadic (also known as early-onset sarcoidosis) or familial BS is caused by gain-of-function mutations in the NOD2 gene, which encodes for a multi-task protein that plays a crucial role in the innate immune defense. We report on three Mexican patients clinically diagnosed with BS who exhibited a likely pathogenic variant in NOD2 as revealed by whole-exome sequencing (WES) and Sanger sequencing: two variants (c.1000 C > T/p.Arg334Trp and c.1538 T > C/p.Met513Thr) lie in the ATP/Mg2+ binding site, whereas the other (c.3019dupC/p.Leu1007ProfsTer2) introduces a premature stop codon disrupting the last LRR domain (LRR9) formation; all three variants are consistent with gain-of-function changes. Interestingly, all these patients presented concomitant likely pathogenic variants in other inflammatory disease-related genes, i.e. TLR10, PRR12, MEFV and/or SLC22A5. Although the clinical presentation in these patients included the BS diagnostic triad, overall it was rather heterogeneous. It is plausible that this clinical variability depends partly on the patients’ genetic background as suggested by our WES results. After this molecular diagnosis and given the absence of NOD2 mutations (demonstrated in two trios) and related symptoms in the respective parents (confirmed in all trios), patients 1 and 2 were considered to have sporadic BS, while patient 3, a sporadic BS-recurrent polyserositis compound phenotype. Altogether, our observations and findings underscore the overlapping among inflammatory diseases and the importance of determining the underlying genetic cause by high-throughput methods. Likewise, this study further reinforces a pathogenic link between the here found NOD2 variants and BS and envisages potential additive effects from other loci in these, and probably other patients.
Description: Artículo
ISSN: 1607-842X
Appears in Collections:2412 Artículos

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