Not getting the nod: The case against Yao syndrome

NOD2-associated autoinflammatory syndrome or Yao syndrome was first described in 2011 in seven patients who were heterozygous for the NOD2:c.2717+158C>T (previously IVS8+158) variant, several of whom were also heterozygous for a second variant, NOD2:c.2023C>T;p.Arg675Trp (previously R702W). Since then, over 30 papers have been published either about or including mention of Yao syndrome, with the rate of publication increasing over recent years. The largest case series now includes 152 individuals, almost all heterozygous for one or both of the two mentioned variants. However, to date, there is insufficient evidence to link the broad phenotypes described in Yao syndrome to variants in NOD2. Approximately one in five people is heterozygous for c.2717+158C>T in the gnomAD database, while one in 12 is heterozygous for p.Arg702Trp in gnomAD. Thus, while it is conceivable that there is an association between very common variants in NOD2 and the phenotypes referred to as Yao syndrome, this could only represent susceptibility with extremely low penetrance. Demonstrating such a link would require large-scale association studies, which have not been performed. As a result, given the current lack of evidence for the existence of Yao syndrome, this diagnosis should not be used.