Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/20445
Title: Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.
Authors: Cogné, Benjamin;Ehresmann, Sophie;Beauregard-Lacroix, Eliane;Rousseau, Justine;Besnard, Thomas;Garcia, Thomas;Petrovski, Slavé;Avni, Shiri;McWalter, Kirsty;Blackburn, Patrick R;Sanders, Stephan J;Picard, Arnaud;Busk, Øyvind L;Punetha, Jaya;Pfundt, Rolph;Lindstrand, Anna;Nordgren, Ann;Kalb, Fayth;Desai, Megha;Ebanks, Ashley Harmon;Jhangiani, Shalini N;Song, Xiaofei;Dewan, Tammie;Coban Akdemir, Zeynep H;Telegrafi, Aida;Zackai, Elaine H;Begtrup, Amber;Toutain, Annick;Wentzensen, Ingrid M;Odent, Sylvie;Bonneau, Dominique;Latypova, Xénia;Deb, Wallid;Redon, Sylvia;Bilan, Frédéric;Legendre, Marine;Agre, Katherine;Troyer, Caitlin;Whitlock, Kerri;Caluseriu, Oana;Murphree, Marine I;Pichurin, Pavel N;Gavrilova, Ralitza;Rinne, Tuula;Park, Meredith;Shain, Catherine;Heinzen, Erin L;Xiao, Rui;Amiel, Jeanne;Lyonnet, Stanislas;Isidor, Bertrand;Yang, Xiang-Jiao;Biesecker, Leslie G;Lowenstein, Dan;Posey, Jennifer E;Denommé-Pichon, Anne-Sophie;Férec, Claude;Rosenfeld, Jill A;Gilbert-Dussardier, Brigitte;Audebert-Bellanger, Séverine;Redon, Richard;Stessman, Holly A F;Nellaker, Christoffer;Yang, Yaping;Lupski, James R;Goldstein, David B;Uguen, Kévin;Eichler, Evan E;Bolduc, Francois;Bézieau, Stéphane;Küry, Sébastien;Campeau, Philippe M;Harris, Jacqueline;Cohen, Julie S;Blyth, Moira;Lehman, Anna;Berg, Jonathan;Li, Mindy H;Kini, Usha;Joss, Shelagh;von der Lippe, Charlotte;Gordon, Christopher T;Humberson, Jennifer B;Robak, Laurie;Scott, Daryl A;Sutton, Vernon R;Skraban, Cara M;Johnston, Jennifer J;Poduri, Annapurna;Nordenskjöld, Magnus;Shashi, Vandana;Gerkes, Erica H;Bongers, Ernie M H F;Gilissen, Christian;Zarate, Yuri A;Kvarnung, Malin;Lally, Kevin P;Kulch, Peggy A;Daniels, Brina;Hernandez-Garcia, Andres;Stong, Nicholas;McGaughran, Julie;Retterer, Kyle;Tveten, Kristian;Sullivan, Jennifer;Geisheker, Madeleine R;Stray-Pedersen, Asbjorg;Tarpinian, Jennifer M;Klee, Eric W;Sapp, Julie C;Zyskind, Jacob;Holla, Øystein L;Bedoukian, Emma;Filippini, Francesca;Guimier, Anne
Affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA..
Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden
Rosalind & Morris Goodman Cancer Research Center and Department of Medicine, McGill University, Montreal, QC H3A 1A3, Canada
Department of Biochemistry, McGill University and McGill University Health Center, Montreal, QC H3A 1A3, Canada
Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada
Division of Pediatric Neurology, University of Alberta, Edmonton, AB, Canada; Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden
School of Medicine, The University of Queensland, Brisbane, Queensland 4029, Australia
Centre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes, France
INSERM, CNRS, UNIV Nantes, l'institut du thorax, 44007 Nantes, France
Centre Hospitalier Universitaire de Poitiers, Service de Génétique, BP577, 86021 Poitiers, France
Department of Medical Genetics, St. Olav's Hospital, Trondheim University Hospital, 7006 Trondheim, Norway
Division of Genetics, Department of Pediatrics, University of Virginia Children's Hospital, Charlottesville, VA 22903, USA
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4472, USA
Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, 9700 RB, the Netherlands
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands
Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
Department of Pediatric Surgery, The McGovern Medical School at the University of Texas Health Science Center and Children's Memorial Hermann Hospital, Houston, TX 77030, USA
Equipe d'accueil 3808, Université Poitiers, Poitiers 86034, France
Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA
Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA
GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA
Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Baylor Genetics, Houston, TX 77021, USA
Texas Children's Hospital, Houston, TX 77030, USA
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA
Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolecent Medicine, Oslo University Hospital, Rikshospitalet, Pb 4950 Nydalen, N-0424 Oslo, Norway
Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4472, USA
GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA
Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway
Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands
Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
Division of Genetics, Birth Defects, and Metabolism, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA
GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA
Department of Pediatric Surgery, The McGovern Medical School at the University of Texas Health Science Center and Children's Memorial Hermann Hospital, Houston, TX 77030, USA
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
Division of Genetics, Department of Pediatrics, University of Virginia Children's Hospital, Charlottesville, VA 22903, USA
Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada
Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands
Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4472, USA
Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Howard Hughes Medical Institute, Seattle, WA 98195, USA..
Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK
Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, UK
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
Center for Individualized Medicine, Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
UMR 1078, Génétique, Génomique Fonctionnelle et Biotechnologies, Inserm, L'Etablissement Français du Sang, Institut Brestois Santé Agro Matière, Université de Brest Occidentale, 29200 Brest, France
Service de Génétique médicale et de biologie de la reproduction, Centre Hospitalier Regional Universitaire Brest, 29200 Brest, France
Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD 21205, USA
Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD 21205, USA
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA..
Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD 21205, USA
Laboratory of Embryology and Genetics of Human Malformations, Institut National de la Santé et de la Recherche Médicale (Inserm), UMR 1163, Institut Imagine, 75015 Paris, France
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France
Texas Children's Hospital, Houston, TX 77030, USA
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Center for Individualized Medicine, Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA..
Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France
Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), 75015 Paris, France
Service de Chirurgie Maxillofaciale et Plastique, Centre de référence des Malformations de la Face et de la Cavité Buccale, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), 75015 Paris, France
Service de Génétique, Centre Hospitalier Universitaire de Tours, 2 Boulevard Tonnellé, 37044 Tours, France
Inserm U1253, Ibrain, Université de Tours, 37032 Tours, France
Service de Génétique Clinique, Centre Référence Déficiences Intellectuelles de Causes Rares, Centre de Référence Anomalies du Développement, Centre Labellisé pour les Anomalies du Développement (CLAD) Ouest, Centre Hospitalier Universitaire de Rennes, 35203 Rennes, France
Institut de Génétique et Développement de Rennes, UMR 6290, Université de Rennes, 2 Avenue du Professeur Léon Bernard, 35043 Rennes, France
Centre Hospitalier Universitaire de Angers, Département de Biochimie et Génétique, 49933 Angers Cedex 9, France
Mitochondrial and Cardiovascular Pathophysiology (MITOVASC), Unité mixte de Recherche, Centre National de la Recherche Scientifique 6015, Inserm 1083, Université d'Angers, 49933 Angers, France
West of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK
Oxford Centre for Genomic Medicine, Oxford University Hospitals National Health Service Trust, Oxford OX3 7LE, UK
Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
Department of Clinical Genetics, Chapel Allerton Hospital, Yorkshire Regional Genetics Service, Leeds Teaching Hospitals National Health Service Trust, Chapeltown Road, Leeds LS7 4SA, UK
Visual Geometry Group, Department of Engineering Science, University of Oxford, Oxford OX1 3PJ, UK
AstraZeneca Centre for Genomics Research, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Cambridge CB2 0AA, UK
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
Department of Medicine, University of Melbourne, Austin Health and Royal Melbourne Hospital, Melbourne, VIC 3010, Australia
Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Service de Génétique médicale et de biologie de la reproduction, Centre Hospitalier Regional Universitaire Brest, 29200 Brest, France
INSERM, CNRS, UNIV Nantes, l'institut du thorax, 44007 Nantes, France
Department of Pharmacology, Creighton University Medical School, Omaha, NE 68178, USA
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA
Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Pediatrics, University of Montreal, Montreal, QC H3T1J4, Canada
INSERM, CNRS, UNIV Nantes, l'institut du thorax, 44007 Nantes, France
Centre Hospitalier Universitaire de Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes, France
Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK
GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA..
Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA..
Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
Rush University Medical Center, Department of Pediatrics, Division of Genetics, Chicago, IL 60612, USA
Issue Date: 7-Mar-2019
EDate: 2019
Citation: American journal of human genetics 2019; 104(3): 530-541
Abstract: Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
URI: http://ahro.austin.org.au/austinjspui/handle/1/20445
DOI: 10.1016/j.ajhg.2019.01.010
ORCID: 0000-0002-1527-961X
PubMed URL: 30827496
Type: Journal Article
Subjects: TRRAP
autism spectrum disorder
congenital malformations
de novo variants
histone acetylation
intellectual disability
neurodevelopmental disorders
Appears in Collections:Journal articles

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