Whole-exome sequencing in three children with sporadic Blau syndrome, one of them co-presenting with recurrent polyserositis
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, whic...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-08-01
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| Series: | Autoimmunity |
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| Online Access: | http://dx.doi.org/10.1080/08916934.2020.1786068 |
| _version_ | 1797684735766429696 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Carlos Córdova-Fletes |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T00:34:05Z |
| format | Article |
| id | doaj.art-5c4fe4ace2d449838d137292af66f5e0 |
| institution | Directory Open Access Journal |
| issn | 0891-6934 1607-842X |
| language | English |
| last_indexed | 2024-03-12T00:34:05Z |
| publishDate | 2020-08-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Autoimmunity |
| spelling | doaj.art-5c4fe4ace2d449838d137292af66f5e02023-09-15T10:01:09ZengTaylor & Francis GroupAutoimmunity0891-69341607-842X2020-08-0153634435210.1080/08916934.2020.17860681786068Whole-exome sequencing in three children with sporadic Blau syndrome, one of them co-presenting with recurrent polyserositisCarlos Córdova-Fletes0Martha M. Rangel-Sosa1Lizeth A. Martínez-Jacobo2Luis Eduardo Becerra-Solano3Carmen Araceli Arellano-Valdés4José Alberto Tlacuilo-Parra5Kame Alberto Galán-Huerta6Ana María Rivas-Estilla7Angélica Alejandra Hernandez-Orozco8José Elías García-Ortiz9Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo LeónVicerrectoría de Ciencias de la Salud, Departamento de Ciencias Básicas, Universidad de MonterreyVicerrectoría de Ciencias de la Salud, Departamento de Ciencias Básicas, Universidad de MonterreyUnidad de Investigación Médica en Medicina ReproductivaDepartamento de Medicina Interna y Reumatología pediátrica, UMAE pediatría, CMNO, IMSSDepartamento de Medicina Interna y Reumatología pediátrica, UMAE pediatría, CMNO, IMSSDepartamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo LeónDepartamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo LeónDivisión de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro SocialDivisión de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro SocialBlau 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.http://dx.doi.org/10.1080/08916934.2020.1786068rare inflammatory diseasesblau syndromerecurrent polyserositiswhole-exome sequencinggain-of-function nod2 variants |
| spellingShingle | 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 Whole-exome sequencing in three children with sporadic Blau syndrome, one of them co-presenting with recurrent polyserositis Autoimmunity rare inflammatory diseases blau syndrome recurrent polyserositis whole-exome sequencing gain-of-function nod2 variants |
| title | Whole-exome sequencing in three children with sporadic Blau syndrome, one of them co-presenting with recurrent polyserositis |
| title_full | Whole-exome sequencing in three children with sporadic Blau syndrome, one of them co-presenting with recurrent polyserositis |
| title_fullStr | Whole-exome sequencing in three children with sporadic Blau syndrome, one of them co-presenting with recurrent polyserositis |
| title_full_unstemmed | Whole-exome sequencing in three children with sporadic Blau syndrome, one of them co-presenting with recurrent polyserositis |
| title_short | Whole-exome sequencing in three children with sporadic Blau syndrome, one of them co-presenting with recurrent polyserositis |
| title_sort | whole exome sequencing in three children with sporadic blau syndrome one of them co presenting with recurrent polyserositis |
| topic | rare inflammatory diseases blau syndrome recurrent polyserositis whole-exome sequencing gain-of-function nod2 variants |
| url | http://dx.doi.org/10.1080/08916934.2020.1786068 |
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