Association of deep phenotyping with diagnostic yield of prenatal exome sequencing for fetal brain abnormalities |
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| Affiliation: | 1. Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC;2. Department of Pediatrics, Division of Genetics and Metabolism, University of North Carolina at Chapel Hill, Chapel Hill, NC;3. Department of Genetics, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC;4. Department of Pediatrics, Department of Cell and Developmental Biology, Feinberg School of Medicine, Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University, Chicago, IL;1. Department of Genomic Health, Geisinger;;2. Department of Population Health Sciences, Geisinger;;3. Department of Medicine, Division of Gastroenterology and Hepatology, Geisinger;1. Professor Emeritus, Department of Obstetrics and Gynecology, UCONN Health, Farmington, CT;7. Princess Margaret Cancer Centre, Toronto, ON, Canada;8. University of Toronto, Toronto, ON, Canada;9. Mount Sinai Hospital, Sinai Health, Toronto, ON, Canada;10. Institute of Health Economics, Edmonton, AB, Canada;11. University Health Network, Toronto, ON, Canada;12. Faculty of Law, University of Alberta, Edmonton, AB, Canada;13. School of Public Health, University of Alberta, Edmonton, AB, Canada;14. Health Law Institute, University of Alberta, Edmonton, AB, Canada;15. School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada;16. The Hospital for Sick Children, Toronto, ON, Canada;17. St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada;18. Institute for Clinical Evaluative Sciences, Toronto, ON, Canada;19. Department of Medicine, University of Toronto, Toronto, ON, Canada;20. Sunnybrook Health Sciences Centre, Toronto, ON, Canada;21. Sanofi Genzyme, New York, NY, USA;22. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada;23. Division of Diagnostic Medical Genetics, Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada;24. Memorial Sloan Kettering Cancer Center, New York, NY, USA;25. Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada;26. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health, Toronto, ON Canada;27. Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada;28. Canadian Agency for Drugs and Technologies in Health, Ottawa, ON, Canada;29. BC Cancer, Vancouver, BC, Canada;30. The University of British Columbia, Vancouver, BC, Canada;31. Applied Health Research Centre (AHRC), Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, ON, Canada;32. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada;33. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada;34. Genomics Health Services Research Program, Li Ka Shing Knowledge Institute, St. Michael''s Hospital, Unity Health Toronto, Toronto, ON, Canada;35. Li Ka Shing Knowledge Institute, St. Michael''s Hospital, Unity Health Toronto, Toronto, ON, Canada;36. Department of Surgery, University of Toronto, ON, Canada;37. Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia;38. Ontario Institute for Cancer Research, Toronto, ON, Canada;1. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada;2. Genomics Health Services Research Program, Li Ka Shing Knowledge Institute, St. Michael''s Hospital, Unity Health Toronto, Toronto, ON, Canada;3. Li Ka Shing Knowledge Institute, St. Michael''s Hospital, Unity Health Toronto, Toronto, ON, Canada;4. Department of Surgery, University of Toronto, ON, Canada;5. Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia;6. Ontario Institute for Cancer Research, Toronto, ON, Canada;1. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA;2. Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;3. Pathology, Harvard Medical School, Boston, MA, USA;4. Department of Pathology and Laboratory Medicine, Children''s Mercy Hospital, Kansas City, MO, USA;5. Department of Pediatrics, School of Medicine, University of Missouri, Kansas City, MO, USA;6. Center for Pediatric Genomic Medicine, Children''s Mercy Hospital, Kansas City, MO, USA;7. Invitae, San Francisco, CA, USA;8. Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA;9. ARUP Laboratories, Salt Lake City, UT, USA;10. Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA;11. GeneDx, LLC, Gaithersburg, MD, USA;12. Genetics Division, Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA;13. Ambry Genetics, Aliso Viejo, CA, USA;14. Division of Genomic Diagnostics, Children''s Hospital of Philadelphia, Philadelphia, PA, USA;15. Human Genetics, University of Chicago, Chicago, IL, USA;16. Variantyx, Framingham, MA, USA;17. Quest Diagnostics, Marlborough, MA, USA;18. Women''s Health and Genetics, Labcorp, Research Triangle Park, NC, USA;19. Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA;20. HudsonAlpha Clinical Services Lab, LLC, Huntsville, AL, USA;21. Molecular Diagnostics, New York Genome Center, New York, NY, USA;22. Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA;23. Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada;24. Laboratory for Molecular Medicine, Mass General Brigham, Cambridge, MA, USA;25. Pathology, Brigham and Women''s Hospital, Boston, MA, USA;26. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada;27. Fulgent Genetics, Temple City, CA, USA;28. Women''s Health and Genetics, Labcorp, Westborough, MA, USA;29. Illumina, Inc, San Diego, CA, USA;30. Department of Pediatrics and Pathology, School of Medicine, University of Missouri, Kansas City, MO, USA;31. Department of Pathology, Stanford Medicine, Palo Alto, CA, USA;32. Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada;1. Health Economics Unit, Centre for Health Policy, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia;2. Australian Genomics Health Alliance, Melbourne, VIC, Australia;3. Murdoch Children’s Research Institute, Melbourne, VIC, Australia;4. Department of Nephrology, Monash Medical Centre, Melbourne, Australia;5. Monash University, Melbourne, Australia;6. The KidGen Collaborative, Australian Genomics Health Alliance, Melbourne, Australia;7. Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, Australia;8. Department of Pediatrics, University of Melbourne, Melbourne, Australia;9. Department of Pediatric Nephrology, Royal Children’s Hospital, Melbourne, Australia;10. Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, Australia;11. Centre for Kidney Research, Children’s Hospital at Westmead, Sydney, Australia;12. Sydney Children’s Hospitals Network, Sydney, Australia;13. Faculty of Medicine, The University of Sydney, Sydney, Australia;14. Department of Medical Genetics, Royal Prince Alfred Hospital, Sydney, Australia;15. Garvan Institute of Medical Research, Sydney, Australia;16. Institute for Molecular Bioscience and Faculty of Medicine, The University of Queensland, Brisbane, Australia;17. Department of Renal Medicine, Townsville University Hospital, Townsville, Australia;18. College of Medicine & Dentistry, James Cook University, Townsville, Australia;2. Harvard Medical School, 25 Shattuck St, Boston, MA,02115;3. The Broad Institute of MIT and Cambridge, 415 Main St, Cambridge, MA, 02142;4. Department of Obstetrics and Gynecology, University of South Florida Morsani College of Medicine, 2 Tampa General Circle, Tampa, FL 33606;5. Center for Genomic Medicine, Simches Research Center, Massachusetts General Hospital, 185 Cambridge St, Boston, MA, 02114 |
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| Abstract: | PurposeTo evaluate whether deep prenatal phenotyping of fetal brain abnormalities (FBAs) increases diagnostic yield of trio-exome sequencing (ES) compared with standard phenotyping.MethodsRetrospective exploratory analysis of a multicenter prenatal ES study. Participants were eligible if an FBA was diagnosed and subsequently found to have a normal microarray. Deep phenotyping was defined as phenotype based on targeted ultrasound plus prenatal/postnatal magnetic resonance imaging, autopsy, and/or known phenotypes of other affected family members. Standard phenotyping was based on targeted ultrasound alone. FBAs were categorized by major brain findings on prenatal ultrasound. Cases with positive ES results were compared with those that have negative results by available phenotyping, as well as diagnosed FBAs.ResultsA total of 76 trios with FBAs were identified, of which 25 (33%) cases had positive ES results and 51 (67%) had negative results. Individual modalities of deep phenotyping were not associated with diagnostic ES results. The most common FBAs identified were posterior fossa anomalies and midline defects. Neural tube defects were significantly associated with receipt of a negative ES result (0% vs 22%, P = .01).ConclusionDeep phenotyping was not associated with increased diagnostic yield of ES for FBA in this small cohort. Neural tube defects were associated with negative ES results. |
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| Keywords: | Congenital anomalies Deep phenotyping Exome sequencing Fetal brain anomalies Prenatal diagnosis |
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