Whole-exome sequencing in three children with sporadic Blau syndrome, one of them co-presenting with recurrent polyserositis

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.

Keywords:

• Rare inflammatory diseases
• Blau syndrome
• recurrent polyserositis
• whole-exome sequencing
• gain-of-function NOD2 variants

Acknowledgements

The authors thank the patients and their relatives who agreed to participate in this study. We also thank Flores-Contreras EA and Martínez-Carranco LE for their technical support.

Author contributions

C.C-F, M.M.R-S, and L.A.M-J designed and performed experiments and analysed genomic data; C.C-F, M.M.R-S, and L.E.B-S wrote the manuscript; C.C-F and J.E.G-O analysed all parts of the manuscript; L.E.B-S, C.A.A-V, J.A.T-P, A.A.H-O, and J.E.G-O provided samples, wrote the clinical part of the manuscript, and performed all clinical experiments and studies in patients. K.A.G-H and A.M.R-E contributed with the logistics, equipment, experiment design, experiments, and Sanger Data analysis for all individuals here assessed. C.C-F and J.E.G-O designed the study and critically reviewed the manuscript. All authors read and approved the final manuscript.

Disclosure statement

The authors have no conflicts of interest to declare.

Additional information

Funding

This work was supported by CONACYT [INFRA-2016-268123 and S0008-2014-1-233212] for C. C-F.