Inflammatory Bowel Disease 1 (Crohn Disease), Susceptibility to
In 112 Ashkenazi Jewish patients with Crohn disease (IBD1; 266600), Sugimura et al. (2003) found a novel disease-predisposing variant in the NOD2 gene, IVS8+158, which is a C-to-T mutation in the palindrome sequence in the intron 8 splicing region. The IVS8+158 variant, which the authors designated 'JW1,' occurred on a specific haplotype with a 268S variant, and this combination exhibited a further increased risk (odds ratio = 5.75, p = 0.0005) and the highest population-attributable risk (15.1%) for Crohn disease (CD) among reported disease-predisposing mutations in Jews. However, no association was found between the 268S-JW1 haplotype and disease in 166 non-Jewish white CD patients. Sugimura et al. (2003) concluded that in Ashkenazi Jews, unrecognized population-specific predisposing factor(s) for CD exist on the 268S-JW1 haplotype at the IBD1 locus.
In a study of 193 Jewish Israeli CD patients, Karban and Eliakim (2004) failed to replicate the association of the S268P variant or S268P-IVS+158 combination with Crohn disease.
Tukel et al. (2004) assessed the haplotypes and allele frequencies of the common NOD2 mutations and variants in 219 members of 50 Ashkenazi Jewish and 53 members of 10 Sephardi/Oriental Jewish multiplex families with CD, in 36 Ashkenazi Jewish patients with sporadic CD, and in 246 Ashkenazi and 82 Sephardi/Oriental Jewish controls, and found no evidence for increased risk associated with the IVS8+158 variant.
Blau Syndrome
In a 9-month-old Caucasian boy with Blau syndrome (BLAUS; 186580), Borzutzky et al. (2010) identified heterozygosity for the IVS8+158 variant in the NOD2 gene. Borzutzky et al. (2010) stated that this was the first reported case of gastrointestinal granulomas in a patient with early-onset sarcoidosis.
Yao Syndrome, Susceptibility to
In 7 unrelated patients with multisystem autoinflammatory disease (YAOS; 617321), Yao et al. (2011) identified heterozygosity for the IVS8+158 variant in the NOD2 gene. Four of the patients also carried the R702W mutation in NOD2 (605956.0003). Yao et al. (2011) stated that the clinical relevance of these gene mutations remained to be determined, and that this disease might be genetically complex rather than mendelian.
In 22 patients with autoinflammatory disease, including the 7 patients previously studied by Yao et al. (2011), Yao et al. (2013) screened the NOD2 gene and found that all carried at least 1 variant: 21 had the IVS8+158 variant, and 8 had the R702W variant. Yao et al. (2013) noted that the allele frequency of the IVS8+158 variant in the healthy white population had been estimated to be approximately 15% by Sugimura et al. (2003), whereas in an aggregated cohort of 41 patients tested by Yao et al. (2013) for IVS8+158, the variant was detected in approximately 55% of patients (p less than 0.001), all of whom were non-Jewish.
Yao et al. (2015) genotyped 143 patients with symptoms suggestive of Yao syndrome for NOD2 variants and identified 54 patients who fulfilled criteria for the disorder, including the presence of NOD2 variants. The IVS8+158 variant was detected in 46 of the 54 patients, including 30 who carried only IVS8+158 and 18 who also carried other known variants, including R702W, 3020insC (605956.0001), and G908R (605956.0002). In addition, 9 other rare NOD2 variants were detected in 13 of the patients. Yao et al. (2015) noted that it remained unclear whether these variants were causative or served as markers indirectly associated with the disease.
