Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

Benjamin Cogné¹, Sophie Ehresmann², Eliane Beauregard-Lacroix², Justine Rousseau², Thomas Besnard¹, Thomas Garcia², Slavé Petrovski³, Shiri Avni⁴, Kirsty McWalter⁵, Patrick R Blackburn⁶, Stephan J Sanders⁷, Kévin Uguen⁸, Jacqueline Harris⁹, Julie S Cohen¹⁰, Moira Blyth¹¹, Anna Lehman¹², Jonathan Berg¹³, Mindy H Li¹⁴, Usha Kini¹⁵, Shelagh Joss¹⁶, Charlotte von der Lippe¹⁷, Christopher T Gordon¹⁸, Jennifer B Humberson¹⁹, Laurie Robak²⁰, Daryl A Scott²¹, Vernon R Sutton²², Cara M Skraban²³, Jennifer J Johnston²⁴, Annapurna Poduri²⁵, Magnus Nordenskjöld²⁶, Vandana Shashi²⁷, Erica H Gerkes²⁸, Ernie M H F Bongers²⁹, Christian Gilissen²⁹, Yuri A Zarate³⁰, Malin Kvarnung²⁶, Kevin P Lally³¹, Peggy A Kulch³², Brina Daniels³⁰, Andres Hernandez-Garcia³³, Nicholas Stong³⁴, Julie McGaughran³⁵, Kyle Retterer⁵, Kristian Tveten³⁶, Jennifer Sullivan²⁷, Madeleine R Geisheker³⁷, Asbjorg Stray-Pedersen³⁸, Jennifer M Tarpinian³⁹, Eric W Klee⁴⁰, Julie C Sapp²⁴, Jacob Zyskind⁵, Øystein L Holla³⁶, Emma Bedoukian³⁹, Francesca Filippini¹⁸, Anne Guimier⁴¹, Arnaud Picard⁴², Øyvind L Busk³⁶, Jaya Punetha³³, Rolph Pfundt²⁹, Anna Lindstrand²⁶, Ann Nordgren²⁶, Fayth Kalb⁴³, Megha Desai⁵, Ashley Harmon Ebanks³¹, Shalini N Jhangiani⁴⁴, Tammie Dewan¹², Zeynep H Coban Akdemir³³, Aida Telegrafi⁵, Elaine H Zackai²³, Amber Begtrup⁵, Xiaofei Song³³, Annick Toutain⁴⁵, Ingrid M Wentzensen⁵, Sylvie Odent⁴⁶, Dominique Bonneau⁴⁷, Xénia Latypova¹, Wallid Deb¹; CAUSES Study¹²; Sylvia Redon⁸, Frédéric Bilan⁴⁸, Marine Legendre⁴⁸, Caitlin Troyer¹⁹, Kerri Whitlock⁴⁹, Oana Caluseriu⁴⁹, Marine I Murphree⁵⁰, Pavel N Pichurin⁵⁰, Katherine Agre⁵⁰, Ralitza Gavrilova⁵¹, Tuula Rinne²⁹, Meredith Park⁵², Catherine Shain⁵³, Erin L Heinzen³⁴, Rui Xiao⁵⁴, Jeanne Amiel⁴¹, Stanislas Lyonnet⁴¹, Bertrand Isidor¹, Leslie G Biesecker²⁴, Dan Lowenstein⁵⁵, Jennifer E Posey³³, Anne-Sophie Denommé-Pichon⁴⁷; Deciphering Developmental Disorders study⁵⁶; Claude Férec⁸, Xiang-Jiao Yang⁵⁷, Jill A Rosenfeld³³, Brigitte Gilbert-Dussardier⁴⁸, Séverine Audebert-Bellanger⁵⁸, Richard Redon⁵⁹, Holly A F Stessman⁶⁰, Christoffer Nellaker⁶¹, Yaping Yang⁵⁴, James R Lupski⁶², David B Goldstein³⁴, Evan E Eichler⁶³, Francois Bolduc⁶⁴, Stéphane Bézieau¹, Sébastien Küry⁶⁵, Philippe M Campeau⁶⁶

Affiliations

¹ 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.
² Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada.
³ Department of Medicine, University of Melbourne, Austin Health and Royal Melbourne Hospital, Melbourne, VIC 3010, Australia; AstraZeneca Centre for Genomics Research, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Cambridge CB2 0AA, UK.
⁴ Visual Geometry Group, Department of Engineering Science, University of Oxford, Oxford OX1 3PJ, UK.
⁵ GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
⁶ 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.
⁷ Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
⁸ 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.
⁹ 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.
¹⁰ Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD 21205, USA; Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
¹¹ Department of Clinical Genetics, Chapel Allerton Hospital, Yorkshire Regional Genetics Service, Leeds Teaching Hospitals National Health Service Trust, Chapeltown Road, Leeds LS7 4SA, UK.
¹² Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
¹³ Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
¹⁴ Rush University Medical Center, Department of Pediatrics, Division of Genetics, Chicago, IL 60612, USA.
¹⁵ Oxford Centre for Genomic Medicine, Oxford University Hospitals National Health Service Trust, Oxford OX3 7LE, UK.
¹⁶ West of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
¹⁷ Department of Medical Genetics, St. Olav's Hospital, Trondheim University Hospital, 7006 Trondheim, Norway.
¹⁸ 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.
¹⁹ Division of Genetics, Department of Pediatrics, University of Virginia Children's Hospital, Charlottesville, VA 22903, USA.
²⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
²¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
²² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
²³ 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.
²⁴ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4472, USA.
²⁵ Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
²⁶ 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.
²⁷ Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
²⁸ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, 9700 RB, the Netherlands.
²⁹ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
³⁰ Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.
³¹ 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.
³² Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
³³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
³⁴ Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
³⁵ Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia; School of Medicine, The University of Queensland, Brisbane, Queensland 4029, Australia.
³⁶ Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway.
³⁷ Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
³⁸ Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolecent Medicine, Oslo University Hospital, Rikshospitalet, Pb 4950 Nydalen, N-0424 Oslo, Norway.
³⁹ Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴⁰ 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; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA; Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
⁴¹ 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; Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), 75015 Paris, France.
⁴² Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 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.
⁴³ Division of Genetics, Birth Defects, and Metabolism, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
⁴⁴ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁴⁵ Service de Génétique, Centre Hospitalier Universitaire de Tours, 2 Boulevard Tonnellé, 37044 Tours, France; Inserm U1253, Ibrain, Université de Tours, 37032 Tours, France.
⁴⁶ 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.
⁴⁷ 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.
⁴⁸ Centre Hospitalier Universitaire de Poitiers, Service de Génétique, BP577, 86021 Poitiers, France; Equipe d'accueil 3808, Université Poitiers, Poitiers 86034, France.
⁴⁹ Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada.
⁵⁰ Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
⁵¹ Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
⁵² Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
⁵³ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁵⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
⁵⁵ Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵⁶ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
⁵⁷ 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.
⁵⁸ Service de Génétique médicale et de biologie de la reproduction, Centre Hospitalier Regional Universitaire Brest, 29200 Brest, France.
⁵⁹ INSERM, CNRS, UNIV Nantes, l'institut du thorax, 44007 Nantes, France.
⁶⁰ Department of Pharmacology, Creighton University Medical School, Omaha, NE 68178, USA.
⁶¹ 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; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK.
⁶² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, 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.
⁶³ Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
⁶⁴ 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.
⁶⁵ 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. Electronic address: sebastien.kury@chu-nantes.fr.
⁶⁶ Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H3T1J4, Canada. Electronic address: p.campeau@umontreal.ca.

PMID: 30827496
PMCID: PMC6407527
DOI: 10.1016/j.ajhg.2019.01.010

Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

Benjamin Cogné et al. Am J Hum Genet. 2019.

. 2019 Mar 7;104(3):530-541.

doi: 10.1016/j.ajhg.2019.01.010. Epub 2019 Feb 28.

Authors

Affiliations

¹ 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.
² Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada.
³ Department of Medicine, University of Melbourne, Austin Health and Royal Melbourne Hospital, Melbourne, VIC 3010, Australia; AstraZeneca Centre for Genomics Research, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Cambridge CB2 0AA, UK.
⁴ Visual Geometry Group, Department of Engineering Science, University of Oxford, Oxford OX1 3PJ, UK.
⁵ GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
⁶ 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.
⁷ Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
⁸ 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.
⁹ 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.
¹⁰ Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD 21205, USA; Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
¹¹ Department of Clinical Genetics, Chapel Allerton Hospital, Yorkshire Regional Genetics Service, Leeds Teaching Hospitals National Health Service Trust, Chapeltown Road, Leeds LS7 4SA, UK.
¹² Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
¹³ Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
¹⁴ Rush University Medical Center, Department of Pediatrics, Division of Genetics, Chicago, IL 60612, USA.
¹⁵ Oxford Centre for Genomic Medicine, Oxford University Hospitals National Health Service Trust, Oxford OX3 7LE, UK.
¹⁶ West of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
¹⁷ Department of Medical Genetics, St. Olav's Hospital, Trondheim University Hospital, 7006 Trondheim, Norway.
¹⁸ 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.
¹⁹ Division of Genetics, Department of Pediatrics, University of Virginia Children's Hospital, Charlottesville, VA 22903, USA.
²⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
²¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
²² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
²³ 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.
²⁴ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4472, USA.
²⁵ Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
²⁶ 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.
²⁷ Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
²⁸ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, 9700 RB, the Netherlands.
²⁹ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525 GA, the Netherlands.
³⁰ Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.
³¹ 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.
³² Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
³³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
³⁴ Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
³⁵ Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia; School of Medicine, The University of Queensland, Brisbane, Queensland 4029, Australia.
³⁶ Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway.
³⁷ Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
³⁸ Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolecent Medicine, Oslo University Hospital, Rikshospitalet, Pb 4950 Nydalen, N-0424 Oslo, Norway.
³⁹ Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴⁰ 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; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA; Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
⁴¹ 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; Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), 75015 Paris, France.
⁴² Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 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.
⁴³ Division of Genetics, Birth Defects, and Metabolism, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
⁴⁴ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁴⁵ Service de Génétique, Centre Hospitalier Universitaire de Tours, 2 Boulevard Tonnellé, 37044 Tours, France; Inserm U1253, Ibrain, Université de Tours, 37032 Tours, France.
⁴⁶ 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.
⁴⁷ 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.
⁴⁸ Centre Hospitalier Universitaire de Poitiers, Service de Génétique, BP577, 86021 Poitiers, France; Equipe d'accueil 3808, Université Poitiers, Poitiers 86034, France.
⁴⁹ Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2H7, Canada.
⁵⁰ Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
⁵¹ Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
⁵² Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
⁵³ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁵⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
⁵⁵ Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵⁶ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
⁵⁷ 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.
⁵⁸ Service de Génétique médicale et de biologie de la reproduction, Centre Hospitalier Regional Universitaire Brest, 29200 Brest, France.
⁵⁹ INSERM, CNRS, UNIV Nantes, l'institut du thorax, 44007 Nantes, France.
⁶⁰ Department of Pharmacology, Creighton University Medical School, Omaha, NE 68178, USA.
⁶¹ 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; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK.
⁶² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, 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.
⁶³ Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
⁶⁴ 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.
⁶⁵ 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. Electronic address: sebastien.kury@chu-nantes.fr.
⁶⁶ Centre Hospitalier Universitaire Sainte-Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H3T1J4, Canada. Electronic address: p.campeau@umontreal.ca.

PMID: 30827496
PMCID: PMC6407527
DOI: 10.1016/j.ajhg.2019.01.010

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.

Keywords: TRRAP; autism spectrum disorder; congenital malformations; de novo variants; histone acetylation; intellectual disability; neurodevelopmental disorders.

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Figures

**Figure 1**
Genotype-Phenotype Correlation Associated with *TRRAP* Variants (A) Predicted *de novo* and apparently *de novo* variants in affected individuals are represented on the TRRAP protein. The variants in red represent individuals with apparent ID and malformations, the variants in purple represent individuals with isolated ID with or without ASD, and the variants in blue represent individuals with only ASD and an IQ above 70. If more than one individual was heterozygous for the variant, the number of affected individuals is indicated in the circle. Adapted from ProteinPaint. (B) Amino acid conservation of each mutated residue. The overall amino acid similarity with the human sequence is shown on the left. (C) Homology model of human TRRAP (GenBank: NP_001231509.1) predicted by PHYRE2 Protein Fold Recognition Server represented by UCSF Chimera. Mutated residues in the 1031–1159 cluster are shown. Abbreviations are as follows: FAT—FRAP, ATM, and TRRAP; PIKK-like—phosphatidylinositol 3-kinase-related protein kinase-like; and FATC—FRAP, ATM, and TRRAP C-terminal.

**Figure 2**
*TRRAP* Sequence Is Intolerant to Missense Variants (A) CADD scores of the 17 variants identified in affected individuals are compared to scores for gnomAD singleton missense variants. In order to avoid CADD training circularity, we compared the individuals’ variants to variants seen once in gnomAD. (B) *TRRAP* missense tolerance ratio (MTR) plot. The MTR is a statistic that quantifies the extent of purifying selection that has been acting specifically against missense variants in the human population. For *TRRAP*, we adopted the 21-codon sliding window and used exome-sequencing standing-variation data in the gnomAD database, version 2.0. MTR data were downloaded from Missense Tolerance Ratio (MTR) Gene Viewer (see Web Resources). An MTR = 1 (blue dashed line) represents neutrality (i.e., observing the same proportion of missense variants in the window as expected on the basis of the underlying sequence context). Red segments of the MTR plot have achieved exome-wide FDR<0.10 for a significance test of a window’s deviation from MTR = 1. The black dashed line signifies gene-specific median MTR, the brown dashed line signifies gene-specific 25^th centile MTR, and the orange dashed line signifies gene-specific fifth centile MTR. The locations of our 23 case-ascertained *de novo* variants are denoted by red stars along *TRRAP*’s MTR plot. The 17 different variants are numbered within circles as follows: (1) p.Leu805Phe; (2) p.Phe860Leu; (3) p.Arg893Leu; (4) p.Ile1031Met; (5) p.Arg1035Gln; (6) p.Ser1037Arg; (7) p.Ala1043Thr; (8) p.Glu1104Gly; (9) p.Glu1106Lys; (10) p.Gly1111Trp; (11) p.Gly1159Arg; (12) p.Arg1859Cys; (13) p.Trp1866Arg; (14) p.Trp1866Cys; (15) p.Gly1883Arg; (16) p.Pro1932Leu; and (17) p.Arg3757Gln. We found that *de novo* variants were significantly enriched in the intolerant 50% of *TRRAP*’s protein-coding sequence; 18 (78%) of the 23 *de novo* events affected the most intolerant 50% of the *TRRAP* sequence (binomial exact test p = 0.01). Strikingly, only the most recurring *de novo* missense variant (GenBank: NM_001244580.1 p. Ala1043Thr) resided outside of the intolerant *TRRAP* sequence. (C) Localization of the mutated TRRAP residues on 3D protein models including 14 out of 17 likely pathogenic variants and two out of six additional variants of unknown significance are shown. The representation of the structure of human TRRAP (GenBank: NP_001231509.1) was predicted by PHYRE2 Protein Fold Recognition Server by comparison to its *Saccharomyces cerevisiae* ortholog, according to the cryo-EM structure of the SAGA (Spt-Ada-Gcn5-acetyltransferase) and NuA4 coactivator subunit Tra1 present in the protein data bank (PDB: 5OJS). Variants in regions non-homologous to Tra1 are not represented. Structure representation was made with UCSF Chimera.

**Figure 3**
Photographs of Individuals with *TRRAP* Variants (A) Individual 1 at the age of 8 years. Note the telecanthus, broad nasal bridge, widely spaced eyes, relatively thin upper vermilion, flared eyebrows, and ectropion. (B) Individual 5 at the age of 8.5 years. Note the wide mouth, thin upper lip, and widely spaced eyes with a wide and depressed nasal bridge. (C) Individual 6 at the age of 29 years. Note the sparse eyebrows, upslanting palpebral fissures, smooth philtrum, thin upper lip, and low columella. (D) Individual 9 at the age of 11 years. Note the deeply set eyes, sparse eyebrows, and wide nasal bridge. (E) Individual 8. Note the telecanthus, low-set ears with upturned earlobes, and, on the fourth picture from the left, the single transverse palmar crease. (F) Individual 12 at the age of 5 years. Note the prominent forehead, arched eyebrows, short palpebral fissures, epicanthal folds, depressed nasal bridge, and thick upper vermilion. (G) Individual 13 at the age of 14 years. Note the upslanted palpebral fissures and prominent forehead. (H) Individual 10 at the ages of 1 month, 16 months, and 3 years. Note the cleft lip and palate, wide mouth, epicanthic fold, prognathism, and supernumerary nipples. (I) Individual 15 at the age of 12 years. Note the wide nasal bridge and upslanting palpebral fissures. (J) Individual 19 at the ages of 2.5 years and 8 years. Note folded-down upper eyelid and sparse medial eyebrows. (K) Individual 16 at the age of 2 years. Note the prominent forehead, epicanthic fold, telecanthus, flat nasal bridge, and low-set ears. (L) Individual 20 at the age of 10 years. Note the widely spaced eyes, telecanthus, wide nasal bridge and ridge, and thin upper vermilion. (M) Individual 18. Note the narrow nose, flared eyebrows, almond-shaped eyes with hypoplastic infraorbital ridges, telecanthus, smooth philtrum, and small, low-set, and posteriorly rotated ears. (N) Individual 21. Note the short palpebral fissures, epicanthal folds, and thin upper vermilion. (O) Individual 22 at the age of 24 years. Note the broad nasal bridge, deeply set eyes, upslanted palpebral fissures, widely spaced eyes, and posteriorly rotated ears. (P) Individual 23 at the age of 19 years. Note the deeply set eyes, upslanted palpebral fissures, widely spaced eyes, epicanthal folds, and posteriorly rotated ears. (Q) Individual 24. Note the smooth philtrum and wide nasal ridge. (R) Average facial gestalt visualization of nine healthy age- and gender-matched controls on the left; on the right, nine individuals with variants in the 1031–1159 cluster. Facial images are flipped and aligned to preserve bilateral asymmetry.

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Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

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Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

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