Please use this identifier to cite or link to this item: http://docs.prosentient.com.au/prosentientjspui/handle/1/10417
Title: KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.
Authors: Kennedy, Joanna
Goudie, David
Blair, Edward
Chandler, Kate
Joss, Shelagh
McKay, Victoria
Green, Andrew
Armstrong, Ruth
Lees, Melissa
Kamien, Benjamin
Hopper, Bruce
Tan, Tiong Yang
Yap, Patrick
Stark, Zornitza
Okamoto, Nobuhiko
Miyake, Noriko
Matsumoto, Naomichi
Macnamara, Ellen
Murphy, Jennifer L
McCormick, Elizabeth
Hakonarson, Hakon
Falk, Marni J
Li, Dong
Blackburn, Patrick
Klee, Eric
Babovic-Vuksanovic, Dusica
Schelley, Susan
Hudgins, Louanne
Kant, Sarina
Isidor, Bertrand
Cogne, Benjamin
Bradbury, Kimberley
Williams, Mark
Patel, Chirag
Heussler, Helen
Duff-Farrier, Celia
Lakeman, Phillis
Scurr, Ingrid
Kini, Usha
Elting, Mariet
Reijnders, Margot
Schuurs-Hoeijmakers, Janneke
Wafik, Mohamed
Blomhoff, Anne
Ruivenkamp, Claudia A L
Nibbeling, Esther
Dingemans, Alexander J M
Douine, Emilie D
Nelson, Stanley F
Arboleda, Valerie A
Newbury-Ecob, Ruth
Affiliation: Clinical Genetics, University Hospitals Bristol, Southwell St, Bristol, UK.. University of Bristol, Bristol, UK..
Clinical Genetics, Ninewells Hospital & Medical School, Dundee, UK..
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.. Department of Clinical Genetics, Churchill Hospital, Headington, Oxford, UK..
Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester Foundation NHS Trust, Manchester Academic Health Science Centre (MAHSC), Manchester, UK..
West of Scotland Genetics Service, Queen Elizabeth University Hospital, Glasgow, UK..
Cheshire & Merseyside Regional Genetics Service, Liverpool Women's NHS Foundation Trust, Crown Street, Liverpool, UK..
Department of Clinical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.. School of Medicine and Medical Science, University College Dublin, Dublin, Ireland..
East Anglian Medical Genetics Service, Addenbrooke's Hospital, Cambridge, UK..
Clinical Genetics, Great Ormond Street Hospital NHS Trust, London, UK..
Hunter Genetics, Newcastle, Australia..
Hunter Genetics, Newcastle, Australia..
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.. Department of Paediatrics, University of Melbourne, Melbourne, Australia..
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.. Genetic Health Service New Zealand, Auckland, New Zealand..
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia..
Department of Medical Genetics, Osaka Medical Center, Osaka, Japan.. Research Institute for Maternal and Child Health, Osaka Medical Center, Osaka, Japan..
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan..
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan..
National Human Genome Research Institute, NIH, Bethesda, MD, USA..
National Human Genome Research Institute, NIH, Bethesda, MD, USA..
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA..
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA..
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA..
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA..
Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA..
Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.. Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA..
Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.. Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA..
Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA, USA..
Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA, USA..
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands..
Service de Génétique Médicale, CHU Nantes, Nantes, France..
Service de Génétique Médicale, CHU Nantes, Nantes, France..
Clinical Genetics Guys and St Thomas' NHS Foundation Trust, Guys Hospital, London, UK..
Molecular Diagnostics, Mater Group, South Brisbane, Queensland, Australia..
Genetic Health Queensland, Herston, Brisbane, Queensland, Australia..
Child Development Service, Lady Cilento Children's Hospital, Brisbane, Queensland, Australia..
Bristol Genetics Laboratory, Southmead Hospital, Bristol, UK..
Academic Medical Center, Department of Clinical Genetics, Amsterdam, The Netherlands..
Clinical Genetics, University Hospitals Bristol, Southwell St, Bristol, UK..
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.. Department of Clinical Genetics, Churchill Hospital, Headington, Oxford, UK..
Klinisch Geneticus, VU Medisch centrum, Amsterdam, The Netherlands..
Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands..
Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands..
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.. Department of Clinical Genetics, Churchill Hospital, Headington, Oxford, UK..
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway..
Klinische Genetica, Leiden University, Leiden, The Netherlands..
Department of Genetics, University of Groningen, Groningen, The Netherlands..
Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands..
Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA..
Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA..
Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. varboleda@mednet.ucla.edu.. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. varboleda@mednet.ucla.edu..
Clinical Genetics, University Hospitals Bristol, Southwell St, Bristol, UK. Ruth.Newbury-Ecob@UHBristol.nhs.uk.. University of Bristol, Bristol, UK. Ruth.Newbury-Ecob@UHBristol.nhs.uk..
Issue Date: 24-Sep-2018
Citation: Genetics in medicine : official journal of the American College of Medical Genetics 2018-09-24
Abstract: 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. 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. 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. Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.
URI: http://docs.prosentient.com.au/prosentientjspui/handle/1/10417
DOI: 10.1038/s41436-018-0259-2
Type: Journal Article
Subjects: KAT6A syndrome; chromatin modifiers; intellectual disability
genetic diagnosis
phenotypic spectrum
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