Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants |
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| Institution: | 1. Sainte-Justine Hospital Research Center University of Montreal, Montreal, QC, Canada;2. Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada;3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;4. Department of Genetics and INSERM UMR 1141, APHP-Nord Université de Paris, Robert DEBRE Hospital, Paris and ERN-ITHACA, Paris, France;5. Department of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;6. Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;7. Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;8. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA;9. Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;10. Roberts Individualized Medical Genetics Center, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;11. Cook Children’s Health Care System, Fort Worth, TX, USA;12. Department of Medical Genetics and Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada;13. Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada;14. Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada;15. Department of Pediatrics, Government Medical College, Kozhikode, Kerala, India;16. Texas Children’s Hospital, Houston, TX, USA;17. University of Tennessee Health Science Center, Le Bonheur Children’s Hospital, Memphis, TN, USA;18. Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA;19. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy;20. Department of Public Health and Pediatric Sciences, University of Torino, Turin, Italy;21. Genetic department, AP-HP, Sorbonne Université Paris, France;22. Service de Génétique Clinique, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU de Montpellier, Montpellier, France;23. Department of Pathology, Centre for Genomic and Personalized Medicine, UNIROUEN Normandie University, Inserm U1245, Normandy, Rouen, France;24. Département anatomie et cytologie pathologiques, CHU Toulouse, Toulouse, France;25. Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India;26. Centre for Clinical Genetics, Sydney Children’s Hospital Randwick, Sydney, Australia;27. BC Children’s Hospital Research Institute and Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada;28. Genetic Research Institute, University of Zulia, Maracaibo, Venezuela;29. Medical Genetics, University of Los Andes, Mérida, Venezuela;30. Department of Medical Genetics, Istanbul Health Science University, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey;31. Department of Pediatric Neurology, Hospital Quirónsalud School of Medicine, Universidad Europea, Madrid, Spain;32. Inova Health system, Falls Church, VA, USA;33. Department of Pediatrics, Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA;34. Medical Genetics, CHU Grenoble Alpes, Université Grenoble Alpes, Inserm, U1216, GIN, Grenoble, France;35. Division of Medical Genetics, Department of Pediatrics, University of Utah Health, Salt Lake City, UT, USA;36. Department of Pediatrics, University of Washington, Seattle, WA, USA;37. Brotman-Baty Institute for Precision Medicine, Seattle, WA, USA;38. Department of Genome Sciences, University of Washington, Seattle, WA, USA;39. Goodman Cancer Center, Department of Medicine, McGill University, Montreal, QC, Canada;1. Sainte-Justine Hospital Research Center University of Montreal, Montreal, QC, Canada;2. Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada;3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;4. Department of Genetics and INSERM UMR 1141, APHP-Nord Université de Paris, Robert DEBRE Hospital, Paris and ERN-ITHACA, Paris, France;5. Department of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA;6. Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;7. Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;8. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA;9. Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;10. Roberts Individualized Medical Genetics Center, Children’s Hospital of Philadelphia, Philadelphia, PA, USA;11. Cook Children’s Health Care System, Fort Worth, TX, USA;12. Department of Medical Genetics and Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada;13. Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada;14. Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada;15. Department of Pediatrics, Government Medical College, Kozhikode, Kerala, India;16. Texas Children’s Hospital, Houston, TX, USA;17. University of Tennessee Health Science Center, Le Bonheur Children’s Hospital, Memphis, TN, USA;18. Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA;19. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy;20. Department of Public Health and Pediatric Sciences, University of Torino, Turin, Italy;21. Genetic department, AP-HP, Sorbonne Université Paris, France;22. Service de Génétique Clinique, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU de Montpellier, Montpellier, France;23. Department of Pathology, Centre for Genomic and Personalized Medicine, UNIROUEN Normandie University, Inserm U1245, Normandy, Rouen, France;24. Département anatomie et cytologie pathologiques, CHU Toulouse, Toulouse, France;25. Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India;26. Centre for Clinical Genetics, Sydney Children’s Hospital Randwick, Sydney, Australia;27. BC Children’s Hospital Research Institute and Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada;28. Genetic Research Institute, University of Zulia, Maracaibo, Venezuela;29. Medical Genetics, University of Los Andes, Mérida, Venezuela;30. Department of Medical Genetics, Istanbul Health Science University, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey;31. Department of Pediatric Neurology, Hospital Quirónsalud School of Medicine, Universidad Europea, Madrid, Spain;32. Inova Health system, Falls Church, VA, USA;33. Department of Pediatrics, Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA;34. Medical Genetics, CHU Grenoble Alpes, Université Grenoble Alpes, Inserm, U1216, GIN, Grenoble, France;35. Division of Medical Genetics, Department of Pediatrics, University of Utah Health, Salt Lake City, UT, USA;36. Department of Pediatrics, University of Washington, Seattle, WA, USA;37. Brotman-Baty Institute for Precision Medicine, Seattle, WA, USA;38. Department of Genome Sciences, University of Washington, Seattle, WA, USA;39. Goodman Cancer Center, Department of Medicine, McGill University, Montreal, QC, Canada |
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| Abstract: | PurposeGenitopatellar syndrome and Say–Barber–Biesecker–Young–Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized.MethodsWe herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum.ResultsWe demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent.ConclusionOur work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals. |
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