Sci Rep. 2021 Mar 10;11(1):5595. doi: 10.1038/s41598-021-84938-8.

Julie E Horowitz ¹, Neil Warner ^2 3, Jeffrey Staples ¹, Eileen Crowley ^2 3 4, Nehal Gosalia ¹, Ryan Murchie ^2 3, Cristopher Van Hout ¹, Karoline Fiedler ^2 3, Gabriel Welch ¹, Alejandra Klauer King ¹, Jeffrey G Reid ¹, John D Overton ¹, Aris Baras ¹, Alan R Shuldiner ¹, Anne Griffiths ², Omri Gottesman ¹, Aleixo M Muise ^5 6 7, Claudia Gonzaga-Jauregui ⁸

Author information

¹Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., 777 Saw Mill River Rd, Tarrytown, NY, USA.

²SickKids Inflammatory Bowel Disease Center, Hospital for Sick Children, 555 University Ave, Toronto, ON, M5G 1X8, Canada.

³Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.

⁴London Health Sciences Centre, Western University, London, ON, Canada.

⁵SickKids Inflammatory Bowel Disease Center, Hospital for Sick Children, 555 University Ave, Toronto, ON, M5G 1X8, Canada. aleixo.muise@utoronto.ca.

⁶Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada. aleixo.muise@utoronto.ca.

⁷Departments of Pediatrics and Biochemistry, University of Toronto, Toronto, ON, Canada. aleixo.muise@utoronto.ca.

⁸Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., 777 Saw Mill River Rd, Tarrytown, NY, USA. clau.gonzagajauregui@regeneron.com.

Abstract

Inflammatory bowel disease (IBD), clinically defined as Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0-18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn's Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7-10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn's Disease.