Crowley E¹, Warner N², Pan J², Khalouei S³, Elkadri A⁴, Fiedler K², Foong J³, Turinsky AL³, Bronte-Tinkew D², Zhang S², Hu J², Tian D², Li D⁵; Regeneron Genetics Center, Horowitz J⁶, Siddiqui I⁷, Upton J⁸, Roifman CM⁸, Church PC², Wall DA⁹, Ramani AK³, Kotlarz D¹⁰, Klein C¹⁰, Uhlig H¹¹, Snapper SB¹², Gonzaga-Jauregui C⁶, Paterson A¹³, McGovern DP⁵, Brudno M¹⁴, Walters TD², Griffiths AM², Muise AM¹⁵. Gastroenterology. 2020 Feb 18. pii: S0016-5085(20)30233-X. doi: 10.1053/j.gastro.2020.02.023. [Epub ahead of print]

Author information

1 SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, ON, Canada; School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland; Division of Pediatric Gastroenterology, Western University, Children's Hospital, London Health Sciences Centre, London, ON, Canada.

2 SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, ON, Canada.

3 Centre for Computational Medicine, The Hospital for Sick Children, Toronto, ON, Canada.

4 SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, ON, Canada; Division of Pediatric Gastroenterology, Medical College of Wisconsin, Milwaukee, WI, USA.

5 F. Widjaja Foundation Inflammatory Bowel Disease Center and Immunobiology Research Institute at Cedars-Sinai Medical Center, Los Angeles, CA, USA.

6 Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA.

7 Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada.

8 Division of Immunology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada.

9 Blood and Marrow Transplant/Cellular Therapy, Haematology/Oncology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada.

10 Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany.

11 Translational Gastroenterology Unit, University of Oxford, UK, Department of Pediatrics, University of Oxford, UK.

12 Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School; Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.

13 Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.

14 Centre for Computational Medicine, The Hospital for Sick Children, Toronto, ON, Canada; Department of Computer Science, University of Toronto, Toronto, ON, Canada.

15 SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, ON, Canada; Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, Institute of Medical Science and Biochemistry, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address: aleixo.muise@utoronto.ca.

Abstract

BACKGROUND & AIMS: A proportion of infants and young children with inflammatory bowel diseases (IBD) have subtypes associated with a single gene variant (monogenic IBD). We aimed to determine the prevalence of monogenic disease in a cohort of pediatric patients with IBD.

METHODS: We performed whole-exome sequencing analyses of blood samples from an unselected cohort of 1005 children with IBD, 0-18 y old (median age at diagnosis, 11.96 y) at a single center in Canada and their family members (2305 samples total). Variants believed to cause IBD were validated using Sanger sequencing. Biopsies from patients were analyzed by immunofluorescence and histochemical analyses.

RESULTS: We identified 40 rare variants associated with 21 monogenic genes among 31 of the 1005 children with IBD (including 5 variants in XIAP, 3 in DOCK8, and 2 each in FOXP3, GUCY2C, and LRBA). These variants occurred in 7.8% of children younger than 6 y and 2.3% of children 6-18 y old. Of the 17 patients with monogenic Crohn's disease, 35% had abdominal pain, 24% had non-bloody loose stool, 18% had vomiting, 18% had weight loss, and 5% had intermittent bloody loose stool. The 14 patients with monogenic ulcerative colitis or IBD unclassified received their diagnosis at a younger age, and their most predominant feature was bloody loose stool (78%). Features associated with monogenic IBD, compared to cases of IBD not associated with a single variant, were age of onset younger than 2 y (odds ratio [OR], 6.30; P=.020), family history of autoimmune disease (OR, 5.12; P=.002), extra-intestinal manifestations (OR, 15.36; P<.0001), and surgery (OR, 3.42; P=.042). Seventeen patients had variants in genes that could be corrected with allogeneic hematopoietic stem cell transplantation.

CONCLUSIONS: In whole-exome sequencing analyses of more than 1000 children with IBD at a single center, we found that 3% had rare variants in genes previously associated with pediatric IBD. These were associated with different IBD phenotypes, and 1% of the patients had variants that could be potentially corrected with allogeneic hematopoietic stem cell transplantation. Monogenic IBD is rare but should be considered in analysis of all patients with pediatric onset of IBD.