The Genetics Involved
Last Updated: October 28th, 2025
Yao Syndrome is a systemic autoinflammatory disease associated with specific variants in the NOD2 gene.
Genetically Transitional Disease
A Genetically Transitional Disease (GTD) is a disease in which a gene mutation is necessary but not sufficient to cause disease alone.
The concept of GTDs is meant to accentuate how genetics and environment intertwine. It helps to fill the space in categorizing diseases that do not fall strictly into Monogenic or Complex/Polygenic and applies to diseases that can not be explained by classical Mendelian segregation or fully penetrant de novo variants.
Yao Syndrome is a Genetically Transitional Disease and is associated with NOD2 variants of low penetrance. These lower-penetrance variants have larger effects than the Genome-wide Association Study signals.
The NOD2 Gene
Nucleotide binding oligomerization domain containing 2; previously known as CARD15. The NOD2 gene is located on Chromosome 16.
The NOD2 gene plays an important role in the immune system. It is an intracellular pattern recognition receptor within the NLR family that is responsible for the recognition of pathogens and the activation of many biochemical processes within cells.
Health Conditions Related to NOD2:
Crohn's Disease, Blau Syndrome, and Yao Syndrome
NOD2 Variants in YAOS
Variants seen in Yao Syndrome include but are not limited to:
IVS8+158
1007fs
R702W
G908R
R703C
V955I
A755V
N852S
N289S
D154N
T189M
R373C
S431L
R684Q
R684W
A725G
E729D
R744W
R791Q
V793M
R830Q
E843K
A918D
D925G
c.-14C>T
Q902K
R311W
A110T
S127L
A661P
K818Q
A886V
R471C
A432V
A visiual look at the NOD2 Gene
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Note: R334W is a Blau Syndrome Variant
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.
Nomani H, Wu S, Saif A, Hwang F, Metzger J, Navetta-Modrov B, Gorevic PD, Aksentijevich I and Yao Q (2024) Comprehensive clinical phenotype, genotype and therapy in Yao syndrome. Front. Immunol. 15:1458118.
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