Abstract

Prevalence and Clinical Features of Inflammatory Bowel Diseases Associated with Monogenic Variants, Identified by Whole-exome Sequencing in 1000 Children at a Single Center

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

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.

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

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

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

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

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

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

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

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.

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