Background: Yao syndrome (YAOS, OMIM #617321) is a chronic and recurring inflammatory disease associated with specific Nucleotide-binding Oligomerization Domain containing protein 2 (NOD2) variants. YAOS is classified as a genetically transitional disease. It is more common than initially thought.

Objectives: This study aimed to further dissect the genetic mechanisms of the disease.

Methods: A total of 405 patients with suspicion of systemic autoinflammatory diseases (SAID) were included. Molecular testing using an autoinflammatory disease gene panel was carried out for diagnosis. To compare the frequencies of commonly encountered individual and combined NOD2 variants, the All of Us Research Program (All of Us) whole genome sequencing data of 128,196 participants of European ancestry was interrogated.

Results: In total, 345/405 (85.2%) patients were found to have positive genotypes, and 60 were negative. 269/405 (66.4%) carried NOD2 variants. The commonly encountered NOD2 variants and combinations were compared with the All of Us genomic data. We found that the NOD2 variant, IVS8 + 158, most commonly identified in YAOS, was significantly more frequent in the patient population than the All of Us control (OR = 1.32, p value = 0.006). Similarly, NOD2 L1007fs and R703C were significantly higher in the patient population (OR = 1.61, p value = 0.018; OR=2.66, p value =0.004). Since the compound NOD2 variants, IVS8 + 158/R702W and IVS8 + 158/L1007fs are commonly observed in YAOS patients, linkage disequilibrium haplotype analysis of the All of Us genomic data demonstrates a coinheritance in cis configuration. NOD2 IVS8 + 158/V955I was significantly more frequent in the patient group (OR = 1.63, p value = 0.038). These data confirm and expand the association of these individual and combined NOD2 variants with YAOS.

Conclusion: This largest cohort of patients with SAID phenotypes compared with genomic data of the All of Us database has allowed us to delve into the intricate genetic mechanisms of YAOS. These data are significant and important for genetic testing ordering, interpretation, diagnosis and counselling for patients.

REFERENCES: [1] Niewold, T. B., Aksentijevich, I., Gorevic, P. D., Gibson, G. & Yao, Q. Genetically transitional disease: conceptual understanding and applicability to rheumatic disease. Nat Rev Rheumatol (2024). https://doi.org:10.1038/s41584-024-01086-9 .

[2] Nomani H, Wu S, Saif A, Hwang F, Metzger J, Navetta-Modrov B, Gorevic P, Aksentijivich, Yao Q. Comprehensive clinical phenotype, genotype and therapy in Yao syndrome. Front Immunol. Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1458118.

[3] Yao, Q. & Shen, B. A Systematic Analysis of Treatment and Outcomes of NOD2-Associated Autoinflammatory Disease. Am J Med 130 , 365 e313-365 e318 (2017).

Acknowledgements: The authors are grateful to the All of Us Research Program.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.