Joanna Kennedy1,2, David Goudie3, Edward Blair4,5, Kate Chandler6, Shelagh Joss7, Victoria McKay8, Andrew Green9,10, Ruth Armstrong11, Melissa Lees12, Benjamin Kamien13, Bruce Hopper13, Tiong Yang Tan14,15, Patrick Yap14,16, Zornitza Stark14, Nobuhiko Okamoto17,18, Noriko Miyake19, Naomichi Matsumoto19, Ellen Macnamara20, Jennifer L Murphy20, Elizabeth McCormick21, Hakon Hakonarson22, Marni J Falk21, Dong Li22, Patrick Blackburn23, Eric Klee23,24, Dusica Babovic-Vuksanovic23,24, Susan Schelley25, Louanne Hudgins25, Sarina Kant26, Bertrand Isidor27, Benjamin Cogne27, Kimberley Bradbury28, Mark Williams29, Chirag Patel30, Helen Heussler31, Celia Duff-Farrier32, Phillis Lakeman33, Ingrid Scurr1, Usha Kini4,5, Mariet Elting34, Margot Reijnders35, Janneke Schuurs-Hoeijmakers35, Mohamed Wafik4,5, Anne Blomhoff36, Claudia A L Ruivenkamp37, Esther Nibbeling38, Alexander J M Dingemans35, Emilie D Douine39, Stanley F Nelson39,40, Maja Hempel41, Tatjana Bierhals41, Davor Lessel41, Jessika Johannsen42, Valerie A Arboleda43,44, Ruth Newbury-Ecob45,46. 1. Clinical Genetics, University Hospitals Bristol, Southwell St, Bristol, UK. 2. University of Bristol, Bristol, UK. 3. Clinical Genetics, Ninewells Hospital & Medical School, Dundee, UK. 4. Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. 5. Department of Clinical Genetics, Churchill Hospital, Headington, Oxford, UK. 6. Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester Foundation NHS Trust, Manchester Academic Health Science Centre (MAHSC), Manchester, UK. 7. West of Scotland Genetics Service, Queen Elizabeth University Hospital, Glasgow, UK. 8. Cheshire & Merseyside Regional Genetics Service, Liverpool Women's NHS Foundation Trust, Crown Street, Liverpool, UK. 9. Department of Clinical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland. 10. School of Medicine and Medical Science, University College Dublin, Dublin, Ireland. 11. East Anglian Medical Genetics Service, Addenbrooke's Hospital, Cambridge, UK. 12. Clinical Genetics, Great Ormond Street Hospital NHS Trust, London, UK. 13. Hunter Genetics, Newcastle, Australia. 14. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia. 15. Department of Paediatrics, University of Melbourne, Melbourne, Australia. 16. Genetic Health Service New Zealand, Auckland, New Zealand. 17. Department of Medical Genetics, Osaka Medical Center, Osaka, Japan. 18. Research Institute for Maternal and Child Health, Osaka Medical Center, Osaka, Japan. 19. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. 20. National Human Genome Research Institute, NIH, Bethesda, MD, USA. 21. Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 22. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 23. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA. 24. Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA. 25. Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA, USA. 26. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. 27. Service de Génétique Médicale, CHU Nantes, Nantes, France. 28. Clinical Genetics Guys and St Thomas' NHS Foundation Trust, Guys Hospital, London, UK. 29. Molecular Diagnostics, Mater Group, South Brisbane, Queensland, Australia. 30. Genetic Health Queensland, Herston, Brisbane, Queensland, Australia. 31. Child Development Service, Lady Cilento Children's Hospital, Brisbane, Queensland, Australia. 32. Bristol Genetics Laboratory, Southmead Hospital, Bristol, UK. 33. Academic Medical Center, Department of Clinical Genetics, Amsterdam, The Netherlands. 34. Klinisch Geneticus, VU Medisch centrum, Amsterdam, The Netherlands. 35. Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands. 36. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. 37. Klinische Genetica, Leiden University, Leiden, The Netherlands. 38. Department of Genetics, University of Groningen, Groningen, The Netherlands. 39. Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. 40. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. 41. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. 42. Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. 43. Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. varboleda@mednet.ucla.edu. 44. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. varboleda@mednet.ucla.edu. 45. Clinical Genetics, University Hospitals Bristol, Southwell St, Bristol, UK. Ruth.Newbury-Ecob@UHBristol.nhs.uk. 46. University of Bristol, Bristol, UK. Ruth.Newbury-Ecob@UHBristol.nhs.uk.
Abstract
PURPOSE: Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported. METHODS: We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review. RESULTS: We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction. CONCLUSION: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.
PURPOSE: Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported. METHODS: We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review. RESULTS: We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction. CONCLUSION: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.
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Authors: Melina Claussnitzer; Judy H Cho; Rory Collins; Nancy J Cox; Emmanouil T Dermitzakis; Matthew E Hurles; Sekar Kathiresan; Eimear E Kenny; Cecilia M Lindgren; Daniel G MacArthur; Kathryn N North; Sharon E Plon; Heidi L Rehm; Neil Risch; Charles N Rotimi; Jay Shendure; Nicole Soranzo; Mark I McCarthy Journal: Nature Date: 2020-01-08 Impact factor: 49.962
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Authors: Roser Urreizti; Estrella Lopez-Martin; Antonio Martinez-Monseny; Montse Pujadas; Laura Castilla-Vallmanya; Luis Alberto Pérez-Jurado; Mercedes Serrano; Daniel Natera-de Benito; Beatriz Martínez-Delgado; Manuel Posada-de-la-Paz; Javier Alonso; Purificación Marin-Reina; Mar O'Callaghan; Daniel Grinberg; Eva Bermejo-Sánchez; Susanna Balcells Journal: Orphanet J Rare Dis Date: 2020-02-10 Impact factor: 4.123