Utilization of the All of Us Research Program in a study of genetics in Yao syndrome

Background: Yao syndrome (OMIM 617321) is a chronic and recurring inflammatory disease linked to specific variants in the nucleotide-binding oligomerization domain containing protein 2 (NOD2) gene. Objective: This study aimed to further dissect the genetic mechanisms of the disease. Methods: A total of 405 patients suspected of having systemic autoinflammatory diseases were included. Molecular testing was performed using an autoinflammatory disease gene panel to aid diagnosis. To compare the frequencies of commonly encountered individual and combined NOD2 variants, whole genome sequencing data from the All of Us Research Program, consisting of 128,196 participants of European ancestry, was interrogated. Results: Commonly encountered NOD2 variants and combinations were compared to the All of Us Research Program genomic data. We found that NOD2 variant IVS8 + 158 (JW1) was significantly more prevalent in the patient population (odds ratio [OR] = 1.32, P =. 006). Similarly, NOD2 variants p.Leu1007Profs∗2 and p.Arg703Cys were significantly higher in the patient population (OR = 1.61, P =. 018; OR = 2.66, P =. 004, respectively). Linkage disequilibrium analysis demonstrated a haplotype configuration for IVS8 + 158 and p.Arg702Trp or IVS8 + 158 (JW1) and p.Leu1007Profs∗2. Additionally, NOD2 IVS8 + 158 (JW1) and p.Val955Ile was found to be significantly more frequent in the patient group (OR = 1.63, P =. 038). These findings confirm and further expand the association of these individual and combined NOD2 variants with Yao syndrome. Conclusion: This large case–control study of population genetics provides valuable insights into the genetic mechanisms of Yao syndrome and has important implications for ordering genetic tests, interpretation of the results, genomic diagnosis, and genetic counseling.