Dominant Disease-Causing Effect of NOD2 Mutations in a Family with All Family Members Affected by Crohnʼs Disease

To the Editor: With great interest we read the recent review of Thompson and Lees1 on “Genetics in ulcerative colitis” in Inflammatory Bowel Diseases. A very recent meta-analysis of genome-wide association studies (GWAS) identified additional susceptibility genes for ulcerative colitis (UC).2 So far, there are at least 47 risk variants for UC and 71 susceptibility gene variants for Crohn's disease (CD), with a large overlap between CD and UC susceptibility genes.2,3 However, the majority of these risk genes has only a small effect on inflammatory bowel disease (IBD) risk, with odds ratios of well below 1.3. Therefore, the clinical importance of genotyping is currently discussed controversially. In contrast, we and others previously demonstrated a unique, severe disease phenotype of homozygous carriers of the p.Leu1007fsX1008 NOD2 mutation which leads to ileal stenosis requiring surgical intervention in almost all CD patients homozygous for this mutation.4,–7 Moreover, NOD2 is one of the very few genes with a strong disease-causing effect in CD.3