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Am J Hum Genet. 2019 Mar 7;104(3):530-541. doi: 10.1016/j.ajhg.2019.01.010. Epub 2019 Feb 28.

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

Cogné B1, Ehresmann S2, Beauregard-Lacroix E2, Rousseau J2, Besnard T1, Garcia T2, Petrovski S3, Avni S4, McWalter K5, Blackburn PR6, Sanders SJ7, Uguen K8, Harris J9, Cohen JS10, Blyth M11, Lehman A12, Berg J13, Li MH14, Kini U15, Joss S16, von der Lippe C17, Gordon CT18, Humberson JB19, Robak L20, Scott DA21, Sutton VR22, Skraban CM23, Johnston JJ24, Poduri A25, Nordenskjöld M26, Shashi V27, Gerkes EH28, Bongers EMHF29, Gilissen C29, Zarate YA30, Kvarnung M26, Lally KP31, Kulch PA32, Daniels B30, Hernandez-Garcia A33, Stong N34, McGaughran J35, Retterer K5, Tveten K36, Sullivan J27, Geisheker MR37, Stray-Pedersen A38, Tarpinian JM39, Klee EW40, Sapp JC24, Zyskind J5, Holla ØL36, Bedoukian E39, Filippini F18, Guimier A41, Picard A42, Busk ØL36, Punetha J33, Pfundt R29, Lindstrand A26, Nordgren A26, Kalb F43, Desai M5, Ebanks AH31, Jhangiani SN44, Dewan T12, Coban Akdemir ZH33, Telegrafi A5, Zackai EH23, Begtrup A5, Song X33, Toutain A45, Wentzensen IM5, Odent S46, Bonneau D47, Latypova X1, Deb W1; CAUSES Study12, Redon S8, Bilan F48, Legendre M48, Troyer C19, Whitlock K49, Caluseriu O49, Murphree MI50, Pichurin PN50, Agre K50, Gavrilova R51, Rinne T29, Park M52, Shain C53, Heinzen EL34, Xiao R54, Amiel J41, Lyonnet S41, Isidor B1, Biesecker LG24, Lowenstein D55, Posey JE33, Denommé-Pichon AS47; Deciphering Developmental Disorders study56, Férec C8, Yang XJ57, Rosenfeld JA33, Gilbert-Dussardier B48, Audebert-Bellanger S58, Redon R59, Stessman HAF60, Nellaker C61, Yang Y54, Lupski JR62, Goldstein DB34, Eichler EE63, Bolduc F64, Bézieau S1, Küry S65, Campeau PM66.

Author information

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.

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

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

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