Clinical validity assessment of genes frequently tested on intellectual disability/autism sequencing panels |
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| Affiliation: | 1. Autism & Developmental Medicine Institute, Geisinger, Danville, PA;2. Drexel University College of Medicine, Philadelphia, PA;3. Invitae, San Francisco, CA;4. Illumina, Inc, San Diego, CA;5. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;6. Natera, San Carlos, CA;7. Department of Pathology and Laboratory Medicine, Children’s Hospital of Los Angeles, Los Angeles, CA;8. Keck School of Medicine, University of Southern California, Los Angeles, CA;9. Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY;10. Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, Mexico;11. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA;12. New York Medical College, Valhalla, NY;13. University of Illinois Chicago, Chicago, IL;14. National Human Genome Research Institute, Bethesda, MD;15. Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa;16. Laboratoire de Génétique Humaine, University of Liège, Liège, Belgium;17. Trillium Health Partners, Mississauga, Ontario, Canada;18. University of Washington, Seattle, WA;19. University of North Carolina, Chapel Hill, NC;20. St. Michael''s Hospital, Unity Health Toronto, Toronto, Ontario, Canada;21. Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada;22. Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, NC;23. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia;24. The Warren Alpert Medical School of Brown University, Providence, RI;25. Department of Neurology, University of California Los Angeles, Los Angeles, CA;26. The Jackson Laboratory for Genomic Medicine, Farmington, CT;27. University Medical Center Ljubljana, Ljubljana, Slovenia;28. Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, Institut de Biologie Paris Seine, Paris, France;29. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA;30. Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany;1. Shriners Hospital for Children - Canada, McGill University, Montreal, QC, Canada;2. Children''s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada;1. Morgan & Mendel Genomics, Inc, Bronx, NY;2. Albert Einstein College of Medicine, Bronx, NY;3. Fred Hutchinson Cancer Center, Seattle, WA;4. Mayo Clinic, Scottsdale, AZ;5. The University of Melbourne, Melbourne, Victoria, Australia;6. Ontario Institute of Cancer Research, Toronto, Ontario, Canada;7. Montefiore Medical Center, Bronx, NY;1. Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany;2. Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany;1. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada;2. Genomics Health Services and Policy Research Program, Li Ka Shing Knowledge Institute, St. Michael''s Hospital, Unity Health Toronto, Toronto, Ontario, Canada;3. Lunenfeld Tanenbaum Research Institute, Sinai Health, Toronto, Ontario, Canada;4. Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health, Toronto, Ontario, Canada;5. Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada;6. Li Ka Shing Knowledge Institute, St. Michael''s Hospital, Unity Health Toronto, Toronto, Ontario, Canada;7. Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada;8. Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia;9. Ontario Institute for Cancer Research, Toronto, Ontario, Canada;1. Department of Genetics, Cell Biology, and Development, College of Biological Sciences, University of Minnesota, Minneapolis, MN;2. Department of Biology, Macalester College, Saint Paul, MN;3. Libraries, University of Minnesota, Minneapolis, MN;1. Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia;2. Melbourne Law School, The University of Melbourne, Carlton, Victoria, Australia;3. Center for Biomedical Ethics and Law, Department of Public Health and Primary Care, Faculty of Medicine, KU Leuven, Leuven, Belgium;4. Leuven Institute for Human Genetics and Society (LIGAS), KU Leuven, Leuven, Belgium;5. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands;6. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands |
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| Abstract: | ![]()
PurposeNeurodevelopmental disorders (NDDs), such as intellectual disability (ID) and autism spectrum disorder (ASD), exhibit genetic and phenotypic heterogeneity, making them difficult to differentiate without a molecular diagnosis. The Clinical Genome Resource Intellectual Disability/Autism Gene Curation Expert Panel (GCEP) uses systematic curation to distinguish ID/ASD genes that are appropriate for clinical testing (ie, with substantial evidence supporting their relationship to disease) from those that are not.MethodsUsing the Clinical Genome Resource gene–disease validity curation framework, the ID/Autism GCEP classified genes frequently included on clinical ID/ASD testing panels as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship.ResultsAs of September 2021, 156 gene–disease pairs have been evaluated. Although most (75%) were determined to have definitive roles in NDDs, 22 (14%) genes evaluated had either Limited or Disputed evidence. Such genes are currently not recommended for use in clinical testing owing to the limited ability to assess the effect of identified variants.ConclusionOur understanding of gene–disease relationships evolves over time; new relationships are discovered and previously-held conclusions may be questioned. Without periodic re-examination, inaccurate gene–disease claims may be perpetuated. The ID/Autism GCEP will continue to evaluate these claims to improve diagnosis and clinical care for NDDs. |
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| Keywords: | Autism ClinGen Gene–disease validity Intellectual disability Neurodevelopmental disorders |
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