Eileen Crowley1, Neil Warner2, Jie Pan2, Sam Khalouei3, Abdul Elkadri4, Karoline Fiedler2, Justin Foong3, Andrei L Turinsky3, Dana Bronte-Tinkew2, Shiqi Zhang2, Jamie Hu2, David Tian2, Dalin Li5, Julie Horowitz6, Iram Siddiqui7, Julia Upton8, Chaim M Roifman8, Peter C Church2, Donna A Wall9, Arun K Ramani3, Daniel Kotlarz10, Christoph Klein10, Holm Uhlig11, Scott B Snapper12, Claudia Gonzaga-Jauregui6, Andrew D Paterson13, Dermot P B McGovern5, Michael Brudno14, Thomas D Walters2, Anne M Griffiths2, Aleixo M Muise15. 1. SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, Ontario, 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, Ontario, Canada. 2. SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, Ontario, Canada. 3. Centre for Computational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada. 4. SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Pediatric Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin. 5. F. Widjaja Foundation Inflammatory Bowel Disease Center and Immunobiology Research Institute at Cedars-Sinai Medical Center, Los Angeles, California. 6. Regeneron Genetics Center, Regeneron Pharmaceuticals Inc, Tarrytown, New York. 7. Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada. 8. Division of Immunology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada. 9. Blood and Marrow Transplant/Cellular Therapy, Haematology/Oncology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada. 10. Dr von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig Maximilian University of 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, Boston, Massachusetts; Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts. 13. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. 14. Centre for Computational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. 15. SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, Ontario, Canada; Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, Institute of Medical Science and Biochemistry, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada. Electronic address: aleixo.muise@utoronto.ca.
Abstract
BACKGROUND & AIMS: A proportion of infants and young children with inflammatory bowel diseases (IBDs) 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, aged 0-18 years (median age at diagnosis, 11.96 years) 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 years and 2.3% of children aged 6-18 years. Of the 17 patients with monogenic Crohn's disease, 35% had abdominal pain, 24% had nonbloody 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 years (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.
BACKGROUND & AIMS: A proportion of infants and young children with inflammatory bowel diseases (IBDs) 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, aged 0-18 years (median age at diagnosis, 11.96 years) 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 years and 2.3% of children aged 6-18 years. Of the 17 patients with monogenic Crohn's disease, 35% had abdominal pain, 24% had nonbloody 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 years (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.
Authors: C L Bennett; J Christie; F Ramsdell; M E Brunkow; P J Ferguson; L Whitesell; T E Kelly; F T Saulsbury; P F Chance; H D Ochs Journal: Nat Genet Date: 2001-01 Impact factor: 38.330
Authors: Kimberly Splinter; David R Adams; Carlos A Bacino; Hugo J Bellen; Jonathan A Bernstein; Alys M Cheatle-Jarvela; Christine M Eng; Cecilia Esteves; William A Gahl; Rizwan Hamid; Howard J Jacob; Bijal Kikani; David M Koeller; Isaac S Kohane; Brendan H Lee; Joseph Loscalzo; Xi Luo; Alexa T McCray; Thomas O Metz; John J Mulvihill; Stanley F Nelson; Christina G S Palmer; John A Phillips; Leslie Pick; John H Postlethwait; Chloe Reuter; Vandana Shashi; David A Sweetser; Cynthia J Tifft; Nicole M Walley; Michael F Wangler; Monte Westerfield; Matthew T Wheeler; Anastasia L Wise; Elizabeth A Worthey; Shinya Yamamoto; Euan A Ashley Journal: N Engl J Med Date: 2018-10-10 Impact factor: 91.245
Authors: Abdul Elkadri; Cornelia Thoeni; Sophie J Deharvengt; Ryan Murchie; Conghui Guo; James D Stavropoulos; Christian R Marshall; Paul Wales; Robert Bandsma; Ernest Cutz; Chaim M Roifman; David Chitayat; Yaron Avitzur; Radu V Stan; Aleixo M Muise Journal: Cell Mol Gastroenterol Hepatol Date: 2015-07
Authors: Hailiang Huang; Ming Fang; Luke Jostins; Maša Umićević Mirkov; Gabrielle Boucher; Carl A Anderson; Vibeke Andersen; Isabelle Cleynen; Adrian Cortes; François Crins; Mauro D'Amato; Valérie Deffontaine; Julia Dmitrieva; Elisa Docampo; Mahmoud Elansary; Kyle Kai-How Farh; Andre Franke; Ann-Stephan Gori; Philippe Goyette; Jonas Halfvarson; Talin Haritunians; Jo Knight; Ian C Lawrance; Charlie W Lees; Edouard Louis; Rob Mariman; Theo Meuwissen; Myriam Mni; Yukihide Momozawa; Miles Parkes; Sarah L Spain; Emilie Théâtre; Gosia Trynka; Jack Satsangi; Suzanne van Sommeren; Severine Vermeire; Ramnik J Xavier; Rinse K Weersma; Richard H Duerr; Christopher G Mathew; John D Rioux; Dermot P B McGovern; Judy H Cho; Michel Georges; Mark J Daly; Jeffrey C Barrett Journal: Nature Date: 2017-06-28 Impact factor: 49.962
Authors: Eric I Benchimol; Charles N Bernstein; Alain Bitton; Matthew W Carroll; Harminder Singh; Anthony R Otley; Maria Vutcovici; Wael El-Matary; Geoffrey C Nguyen; Anne M Griffiths; David R Mack; Kevan Jacobson; Nassim Mojaverian; Divine Tanyingoh; Yunsong Cui; Zoann J Nugent; Janie Coulombe; Laura E Targownik; Jennifer L Jones; Desmond Leddin; Sanjay K Murthy; Gilaad G Kaplan Journal: Am J Gastroenterol Date: 2017-04-18 Impact factor: 10.864
Authors: Walter H A Kahr; Fred G Pluthero; Abdul Elkadri; Neil Warner; Marko Drobac; Chang Hua Chen; Richard W Lo; Ling Li; Ren Li; Qi Li; Cornelia Thoeni; Jie Pan; Gabriella Leung; Irene Lara-Corrales; Ryan Murchie; Ernest Cutz; Ronald M Laxer; Julia Upton; Chaim M Roifman; Rae S M Yeung; John H Brumell; Aleixo M Muise Journal: Nat Commun Date: 2017-04-03 Impact factor: 14.919
Authors: Lauren V Collen; David Y Kim; Michael Field; Ibeawuchi Okoroafor; Gwen Saccocia; Sydney Driscoll Whitcomb; Julia Green; Michelle Dao Dong; Jared Barends; Bridget Carey; Madison E Weatherly; Shira Rockowitz; Piotr Sliz; Enju Liu; Alal Eran; Leslie Grushkin-Lerner; Athos Bousvaros; Aleixo M Muise; Christoph Klein; Vanessa Mitsialis; Jodie Ouahed; Scott B Snapper Journal: J Crohns Colitis Date: 2022-09-08 Impact factor: 10.020
Authors: Ryusuke Nambu; Neil Warner; Daniel J Mulder; Daniel Kotlarz; Dermot P B McGovern; Judy Cho; Christoph Klein; Scott B Snapper; Anne M Griffiths; Itaru Iwama; Aleixo M Muise Journal: Clin Gastroenterol Hepatol Date: 2021-03-18 Impact factor: 11.382
Authors: M Jamee; S Hosseinzadeh; N Sharifinejad; M Zaki-Dizaji; M Matloubi; M Hasani; S Baris; M Alsabbagh; B Lo; G Azizi Journal: Clin Exp Immunol Date: 2021-05-03 Impact factor: 5.732
Authors: Holm H Uhlig; Fabienne Charbit-Henrion; Daniel Kotlarz; Dror S Shouval; Tobias Schwerd; Caterina Strisciuglio; Lissy de Ridder; Johan van Limbergen; Marina Macchi; Scott B Snapper; Frank M Ruemmele; David C Wilson; Simon P L Travis; Anne M Griffiths; Dan Turner; Christoph Klein; Aleixo M Muise; Richard K Russell Journal: J Pediatr Gastroenterol Nutr Date: 2021-03-01 Impact factor: 3.288
Authors: Daniel J Mulder; Sam Khalouei; Neil Warner; Claudia Gonzaga-Jauregui; Peter C Church; Thomas D Walters; Arun K Ramani; Anne M Griffiths; Iris Cohn; Aleixo M Muise Journal: Clin Transl Gastroenterol Date: 2020-12 Impact factor: 4.396
Authors: Paul M Tyler; Molly L Bucklin; Mengting Zhao; Timothy J Maher; Andrew J Rice; Weizhen Ji; Neil Warner; Jie Pan; Raffaella Morotti; Paul McCarthy; Anne Griffiths; Annemarie M C van Rossum; Iris H I M Hollink; Virgil A S H Dalm; Jason Catanzaro; Saquib A Lakhani; Aleixo M Muise; Carrie L Lucas Journal: Nat Immunol Date: 2021-07-29 Impact factor: 25.606
Authors: Mara Cananzi; Aleixo M Muise; Luca Bosa; Vritika Batura; Davide Colavito; Karoline Fiedler; Paola Gaio; Conghui Guo; Qi Li; Antonio Marzollo; Claudia Mescoli; Ryusuke Nambu; Jie Pan; Giorgio Perilongo; Neil Warner; Shiqi Zhang; Daniel Kotlarz; Christoph Klein; Scott B Snapper; Thomas D Walters; Alberta Leon; Anne M Griffiths Journal: Sci Rep Date: 2021-03-15 Impact factor: 4.379