Li Xin Zhang1, Gabrielle Lemire2, Claudia Gonzaga-Jauregui3, Sirinart Molidperee1, Carolina Galaz-Montoya3, David S Liu3, Alain Verloes4, Amelle G Shillington5, Kosuke Izumi6, Alyssa L Ritter7, Beth Keena6, Elaine Zackai7,8, Dong Li9, Elizabeth Bhoj7, Jennifer M Tarpinian10, Emma Bedoukian10, Mary K Kukolich11, A Micheil Innes12, Grace U Ediae13, Sarah L Sawyer14, Karippoth Mohandas Nair15, Para Chottil Soumya15, Kinattinkara R Subbaraman15, Frank J Probst3,16, Jennifer A Bassetti3,16, Reid V Sutton3,16, Richard A Gibbs3, Chester Brown17, Philip M Boone18, Ingrid A Holm18, Marco Tartaglia19, Giovanni Battista Ferrero20, Marcello Niceta19, Maria Lisa Dentici19, Francesca Clementina Radio19, Boris Keren21, Constance F Wells22, Christine Coubes22, Annie Laquerrière23, Jacqueline Aziza24, Charlotte Dubucs24, Sheela Nampoothiri25, David Mowat26, Millan S Patel27, Ana Bracho28, Francisco Cammarata-Scalisi29, Alper Gezdirici30, Alberto Fernandez-Jaen31, Natalie Hauser32, Yuri A Zarate33, Katherine A Bosanko33, Klaus Dieterich34, John C Carey35, Jessica X Chong36,37, Deborah A Nickerson37,38, Michael J Bamshad36,37, Brendan H Lee3, Xiang-Jiao Yang39, James R Lupski3,16, Philippe M Campeau40. 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 UMR1141, 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. 40. Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada. p.campeau@umontreal.ca.
Abstract
PURPOSE: Genitopatellar 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. METHODS: We 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. RESULTS: We 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. CONCLUSION: Our 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.
PURPOSE: Genitopatellar 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. METHODS: We 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. RESULTS: We 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. CONCLUSION: Our 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.
Authors: Jill Clayton-Smith; James O'Sullivan; Sarah Daly; Sanjeev Bhaskar; Ruth Day; Beverley Anderson; Anne K Voss; Tim Thomas; Leslie G Biesecker; Philip Smith; Alan Fryer; Kate E Chandler; Bronwyn Kerr; May Tassabehji; Sally-Ann Lynch; Malgorzata Krajewska-Walasek; Shane McKee; Janine Smith; Elizabeth Sweeney; Sahar Mansour; Shehla Mohammed; Dian Donnai; Graeme Black Journal: Am J Hum Genet Date: 2011-11-11 Impact factor: 11.025
Authors: Philippe M Campeau; Jaeseung C Kim; James T Lu; Jeremy A Schwartzentruber; Omar A Abdul-Rahman; Silke Schlaubitz; David M Murdock; Ming-Ming Jiang; Edward J Lammer; Gregory M Enns; William J Rhead; Jon Rowland; Stephen P Robertson; Valérie Cormier-Daire; Matthew N Bainbridge; Xiang-Jiao Yang; Marie-Claude Gingras; Richard A Gibbs; David S Rosenblatt; Jacek Majewski; Brendan H Lee Journal: Am J Hum Genet Date: 2012-01-19 Impact factor: 11.025
Authors: Michael A Simpson; Charu Deshpande; Dimitra Dafou; Lisenka E L M Vissers; Wesley J Woollard; Susan E Holder; Gabriele Gillessen-Kaesbach; Ronny Derks; Susan M White; Ruthy Cohen-Snuijf; Sarina G Kant; Lies H Hoefsloot; Willie Reardon; Han G Brunner; Ernie M H F Bongers; Richard C Trembath Journal: Am J Hum Genet Date: 2012-01-19 Impact factor: 11.025
Authors: Michael Kraft; Ion Cristian Cirstea; Anne Kathrin Voss; Tim Thomas; Ina Goehring; Bilal N Sheikh; Lavinia Gordon; Hamish Scott; Gordon K Smyth; Mohammad Reza Ahmadian; Udo Trautmann; Martin Zenker; Marco Tartaglia; Arif Ekici; André Reis; Helmuth-Guenther Dörr; Anita Rauch; Christian Thomas Thiel Journal: J Clin Invest Date: 2011-08-01 Impact factor: 14.808
Authors: Yannick Doyon; Christelle Cayrou; Mukta Ullah; Anne-Julie Landry; Valérie Côté; William Selleck; William S Lane; Song Tan; Xiang-Jiao Yang; Jacques Côté Journal: Mol Cell Date: 2006-01-06 Impact factor: 17.970
Authors: Megan Yabumoto; Jessica Kianmahd; Meghna Singh; Maria F Palafox; Angela Wei; Kathryn Elliott; Dana H Goodloe; S Joy Dean; Catherine Gooch; Brianna K Murray; Erin Swartz; Samantha A Schrier Vergano; Meghan C Towne; Kimberly Nugent; Elizabeth R Roeder; Christina Kresge; Beth A Pletcher; Katheryn Grand; John M Graham; Ryan Gates; Natalia Gomez-Ospina; Subhadra Ramanathan; Robin Dawn Clark; Kimberly Glaser; Paul J Benke; Julie S Cohen; Ali Fatemi; Weiyi Mu; Kristin W Baranano; Jill A Madden; Cynthia S Gubbels; Timothy W Yu; Pankaj B Agrawal; Mary-Kathryn Chambers; Chanika Phornphutkul; John A Pugh; Kate A Tauber; Svetlana Azova; Jessica R Smith; Anne O'Donnell-Luria; Hannah Medsker; Siddharth Srivastava; Deborah Krakow; Daniela N Schweitzer; Valerie A Arboleda Journal: Mol Genet Genomic Med Date: 2021-09-14 Impact factor: 2.183