Background/Purpose: Yao syndrome (YAOS, OMIM 617321) is formerly designated NOD2-associated autoinflammatory disease. A spectrum of NOD2 mutations have been associated with this disease. This study aimed to investigate the NOD2 genetic architecture in YAOS.

Methods: In this retrospective single center study, a large cohort of patients with systemic autoinflammatory diseases (SAIDs) was analyzed in relation to genotyping results. After extensive negative workup for systemic autoimmune and related diseases, genetic testing for periodic fever syndrome 6-gene panel and an extended autoinflammatory disease gene panel was performed at Commercial Diagnostic Molecular laboratories. YAOS was diagnosed based on our published criteria, i.e., the presence of characteristic phenotype and genotype with exclusion of related diseases.

Results: There were 207 patients who carried NOD2 mutations and nearly all were Caucasian with 82% being female. Mean age at diagnosis was 40.7±0.1 years and disease duration at diagnosis was 12.2±12.2 years. Of 207 patients, 179 (86.5%) were diagnosed with YAOS and the remaining were diagnosed with mixed NOD-like receptor associated autoinflammatory disease due to coexistence of mixed genotypes. The genetic profile of patients included in our study showed that patients with two or more NOD2 variants were 26.1% (54/207), rare variants 29.5% (61/207), NOD2 IVS8+158 17.4% (36/207), NOD2 V955I 7.7% (16/207), and combined NOD2 and other SAID gene variants 19.3% (40/207). Based on the Two-hit hypothesis that has been proven true, i.e., one germline mutation and one somatic mutation for monogenic (familial cancer) and some polygenic disorders and our result that approximately 50% of patients carried two or more mutational events, we propose “Two-hit like theory” for the role of NOD2 genetics in YAOS. That is two genetic mutations in the same NOD2 gene or separate genes could be required to cause disease. The combinations could be low frequency variants, low frequency and rare variants, or rare variants only. For a minority of patients with low frequency NOD2 variants only, we assume that another unidentified NOD2 or other SAID gene related variant could be present. The disease has been recently reclassified as the new category of genetically transitional disease (GTD) because of its association with low penetrance variants. GTD refers to disease or disease status straddling monogenic and polygenic, where mutation is necessary but not sufficient to cause disease. GTD highlights the influence of genetic background on disease in concert with environment.

Conclusion: Our study indicates that most patients with YAOS carry two or more gene variants, or rare variants, suggesting Two-hit like hypothesis could be applicable to some cases of autoinflammatory disease. Further study of a large cohort of patients is warranted.

References
Vijg J, et al. Pathogenic Mechanisms of somatic mutation and genome mosaicism in aging. Cell 2020; 182(1): 12-23.

Yao Q, et al. Genetically transitional disease: a new concept in genomic medicine. Trends Genet 2023; 39(2):98-108.

Yao Q, Shen B. A Systematic Analysis of Treatment and Outcomes of NOD2-Associated Autoinflammatory Disease. Am J Med. 2017;130(3):365 e13-365 e18.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/nod2-genotyping-landscape-in-yao-syndrome/