Comprehensive clinical phenotype, genotype and therapy in Yao syndrome

Abstract

Objective: Yao syndrome (YAOS) is formerly called nucleotide-binding oligomerization domain containing 2 (NOD2)-associated autoinflammatory disease.We report a large cohort of YAOS.

Methods: We conducted a retrospective analysis of a cohort of adult patients with systemic autoinflammatory diseases (SAIDs). All patients underwent testing for a periodic fever syndrome gene panel.

Results: A total of 194 patients carried NOD2 variants, 152 patients were diagnosed with YAOS, and 42 had mixed autoinflammatory diseases with combined variants in NOD2 and other SAID-associated genes. Demographic, clinical and molecular data were summaried. In sub-group analysis of the 194 patients, individual patients were often identified to carry two or more variants that usually included IVS8 + 158/R702W, IVS8 + 158/L1007fs, IVS8 + 158/V955I, IVS8 + 158/other, or NOD2/variants in other SAID genes. Ninety-nine patients carried single variants. Taken together, these variants contribute to the disease in combination or individually.

Conclusion: This largest cohort has provided comprehensive clinical and genotyping data in YAOS. Variants in the NOD2 gene can give rise to a spectrum from inflammatory bowel disease to autoinflammatory disease.This report further raises awareness of the underdiagnosed disease in the medical community.

Keywords: Blau syndrome; NOD2; Yao syndrome; autoinflammatory disease; genetically transitional disease; genotype; inflammatory bowel disease; phenotype.

Figure 1

Cutaneous presentations in three representative patients. Upper panel: patchy erythema on cheeks, anterior neck and upper chest (A), eyelid redness and mild puffiness (B), erythematous rash on the thigh and knee with swelling (C). This patient carries heterozygous NOD2 IVS8 + 158 only and had a good response to IL-1 inhibitor therapy. Middle panel: diffuse redness on the chin, anterior neck and chest (A), bilateral eyelid swelling with discoloration (B), redness on the right upper cheek, temple and external ear (C). This patient carries heterozygous NOD2 V955I only and had a good response to IL-1 inhibitor therapy. Lower panel: erythematous patches on the face, forehead and bilateral eyelid swelling with discoloration(A), large patchy erythema on the left cheek (B), swollen ankle and foot (C, D), erythematous patches on the arm (E). This patient carries heterozygous and compound NOD2 IVS8 + 158/1007fs/V955I and had a good response to IL-1 inhibitor therapy.

Figure 2

A schematic representation of NOD2 gene and protein. There are 12 exons in the NOD2 gene as indicated in vertical lines. NOD2 protein is composed of 1040 amino acids and is divided into three regions: the leucin-rich repeats (LRRs), nucleotide-binding domain (NBD) and caspase recruitment domains (CARDs). They are responsible for bacterial recognition, NOD2 self-oligomerization and down steam signal transduction, respectively. Three main variants in red, 1007fs, Q908R, R702W, are identified in -40% patients with Crohn’s disease. These three NOD2 variants, IVS8 + 158, V955I or other variants are linked to Yao syndrome (YAOS). Most YAOS-associated variants are within the region encoding LRRs and are detected often in combination in individual patients. In a minority of YAOS patients, variants in exon 4(non-Blau syndrome associated variants) and between the exon 4 and the region encoding the LRRs are identified; these are usually rare variants and were detected singly or in combination with the LRR variants. Blau syndrome-associated variants are within exon 4 and are of high penetrance.

Figure 3

Genotyping distribution in disease (piechart).