Ziqing Ye1,2, Wenhui Hu1, Bingbing Wu3, Yueping Zhang4, Caixia Lei4, Isabelle Williams2, Dror S Shouval5, Hirokazu Kanegane6, Kyung Mo Kim7, Lissy de Ridder8, Neil Shah9, Galina Ling10, Baruch Yerushalmi10, Daniel Kotlarz11, Scott Snapper12, Ruth Horn13, Christoph Klein11, Aleixo M Muise14,15, Ying Huang1, Holm H Uhlig2,16,17,18. 1. Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China. 2. Translational Gastroenterology Unit, University of Oxford, Oxford, UK. 3. Key Lab of Birth Defects, Children's Hospital of Fudan University, Shanghai, China. 4. Shanghai Ji Ai Genetics & IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China. 5. Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramag Gan, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 6. Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. 7. Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital 88, Olympic-Ro 43 Gil, Songpa-Gu, Seoul, Korea. 8. Department of Paediatric Gastroenterology, Erasmus University Medical Center Sophia Children's Hospital, Rotterdam, The Netherlands. 9. Department of Paediatric Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom. 10. Pediatric Gastroenterology Unit, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. 11. Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany. 12. Boston Children's Hospital and Harvard Medical School, Boston, MA. 13. Wellcome Centre for Ethics and Humanities and the Ethox Centre, University of Oxford, UK. 14. SickKids Inflammatory Bowel Disease Centre and Cell Biology Program, Research Institute. 15. Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 16. Department of Pediatrics. 17. Biomedical Research Center, University of Oxford, Oxford, United Kingdom. 18. Translational Gastroenterology Unit.
Abstract
OBJECTIVES: Advances in genetic technologies provide opportunities for patient care and ethical challenges. Clinical care of patients with rare Mendelian disorders is often at the forefront of those developments. Whereas in classical polygenic inflammatory bowel disease (IBD), the predictive value of genetic variants is very low, predictive prenatal genetic diagnosis can inform families at high risk of severe genetic disorders. Patients with IL-10 signalling defects because of pathogenic variants in IL10RA, Il10RB, and IL10 develop severe infantile onset inflammatory bowel disease that is completely penetrant and has a high morbidity and substantial mortality despite treatment. METHODS: We performed a survey among tertiary specialist paediatric centers of 10 countries on the utilization of predictive prenatal genetic diagnosis in IL-10 signalling defects. We retrospectively report prenatal genetics in a series of 8 families. RESULTS: International variation in legislation, guidelines, expert opinion, as well as cultural and religious background of families and clinicians results in variable utilization of preimplantation and prenatal genetic testing for IL-10 signalling defects. Eleven referrals for prenatal diagnosis for IL-10 signalling defects were identified across 4 countries. We report on 8 families who underwent prenatal preimplantation monogenic testing after in vitro fertilization (n = 2) and/or by amniocentesis/chorion villus sampling (n = 6). A genetic diagnosis was established in 1 foetus and excluded in 7 foetuses (all IL10RA variants). CONCLUSIONS: Prenatal genetic testing for IL10R-defects is feasible, yet the legal and ethical considerations are complex and controversial. In some countries, predictive genetics for IL-10-related signalling defects is entering clinical practice.
OBJECTIVES: Advances in genetic technologies provide opportunities for patient care and ethical challenges. Clinical care of patients with rare Mendelian disorders is often at the forefront of those developments. Whereas in classical polygenic inflammatory bowel disease (IBD), the predictive value of genetic variants is very low, predictive prenatal genetic diagnosis can inform families at high risk of severe genetic disorders. Patients with IL-10 signalling defects because of pathogenic variants in IL10RA, Il10RB, and IL10 develop severe infantile onset inflammatory bowel disease that is completely penetrant and has a high morbidity and substantial mortality despite treatment. METHODS: We performed a survey among tertiary specialist paediatric centers of 10 countries on the utilization of predictive prenatal genetic diagnosis in IL-10 signalling defects. We retrospectively report prenatal genetics in a series of 8 families. RESULTS: International variation in legislation, guidelines, expert opinion, as well as cultural and religious background of families and clinicians results in variable utilization of preimplantation and prenatal genetic testing for IL-10 signalling defects. Eleven referrals for prenatal diagnosis for IL-10 signalling defects were identified across 4 countries. We report on 8 families who underwent prenatal preimplantation monogenic testing after in vitro fertilization (n = 2) and/or by amniocentesis/chorion villus sampling (n = 6). A genetic diagnosis was established in 1 foetus and excluded in 7 foetuses (all IL10RA variants). CONCLUSIONS: Prenatal genetic testing for IL10R-defects is feasible, yet the legal and ethical considerations are complex and controversial. In some countries, predictive genetics for IL-10-related signalling defects is entering clinical practice.
Authors: Daniel Kotlarz; Rita Beier; Dhaarini Murugan; Jana Diestelhorst; Ole Jensen; Kaan Boztug; Dietmar Pfeifer; Hans Kreipe; Eva-Doreen Pfister; Ulrich Baumann; Jacek Puchalka; Jens Bohne; Odul Egritas; Buket Dalgic; Kaija-Leena Kolho; Axel Sauerbrey; Stephan Buderus; Tayfun Güngör; Axel Enninger; Yu Kar Ling Koda; Graziella Guariso; Batia Weiss; Selim Corbacioglu; Piotr Socha; Nuray Uslu; Ayse Metin; Ghassan T Wahbeh; Khalid Husain; Dina Ramadan; Waleed Al-Herz; Bodo Grimbacher; Martin Sauer; Karl-Walter Sykora; Sibylle Koletzko; Christoph Klein Journal: Gastroenterology Date: 2012-04-28 Impact factor: 22.682
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