Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability - Université de Rennes Accéder directement au contenu
Article Dans Une Revue American Journal of Human Genetics Année : 2019

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

Benjamin Cogné (1, 2) , Sophie Ehresmann (3, 4) , Eliane Beauregard-Lacroix (3, 4) , Justine Rousseau (3, 4) , Thomas Besnard (1, 2) , Thomas Garcia (3, 4) , Slavé Petrovski (5) , Shiri Avni (6) , Kirsty Mcwalter (7) , Patrick Blackburn (7) , Stephan Sanders (8) , Kévin Uguen (9, 10, 11) , Jacqueline Harris (12) , Julie Cohen (13) , Moira Blyth (14) , Anna Lehman (15) , Jonathan Berg (16) , Mindy Li (17) , Usha Kini (18) , Shelagh Joss (19) , Charlotte von Der Lippe (20) , Christopher Gordon (21) , Jennifer Humberson (22) , Laurie A Robak (23) , Daryl Scott (24) , Vernon R. Sutton (23) , Cara Skraban (25) , Jennifer Johnston (26) , Anna Poduri (27) , Magnus Nordenskjöld (28) , Vandana Shashi (29) , Erica Gerkes (30) , Ernie M.H.F. Bongers , Christian Gilissen , Yuri Zarate (31) , Malin Kvarnung (28) , Kevin Lally (32) , Peggy Kulch (33) , Brina Daniels (31) , Andres García (24) , Nicholas Stong (34) , Julie Mcgaughran (35) , Kyle Retterer (6) , Kristian Tveten (36) , Jennifer Sullivan (29) , Madeleine Geisheker (37) , Asbjorg Stray-Pedersen (38) , Jennifer Tarpinian (39) , Eric Klee (7) , Julie Sapp (26) , Jacob Zyskind (6) , Øystein Holla (36) , Emma Bedoukian (39) , Francesca Filippini (21) , Anne Guimier (21, 40) , Arnaud Picard (21, 40) , Øyvind Løvold Busk (36) , Jaya Punetha (24) , Rolph Pfundt (41) , Anna A Lindstrand (28) , Ann A Nordgren (28) , Fayth Kalb (42) , Megha Desai (6) , Ashley Harmon Ebanks (43) , Shalini Jhangiani (24) , Tammie Dewan (15) , Zeynep Coban Akdemir (24) , Aida Telegrafi (6) , Elaine Zackai (25) , Amber Begtrup (6) , Xiaofei Song (24) , Ann Toutain (44, 45) , Ingrid Wentzensen (6) , Sylvie Odent (46, 47, 48) , Dominique Bonneau (49, 50) , Xenia Latypova (1, 2) , Wallid Deb (1, 2) , Sylvia Redon (51, 9, 10) , Frédéric Bilan (52) , Marine Legendre (52) , Caitlin Troyer (22) , Kerri Whitlock (53) , Oana Caluseriu (53) , Marine Murphree (7) , Pavel Pichurin (7) , Katherine Agre (7) , Ralitza Gavrilova (7) , Tuula Rinne (41) , Meredith Park (54) , Catherine Shain (27) , Erin Heinzen (34) , Rui Xiao (24) , Jeanne Amiel (21, 40) , Stanislas Lyonnet (21, 40) , Bertrand Isidor (1, 2) , Leslie Biesecker (26) , Dan Lowenstein (8) , Jennifer Posey (24) , Anne-Sophie Denommé-Pichon (49, 50) , Claude Férec (9, 10, 11) , Xiang-Jiao Yang (55) , Jill A. Rosenfeld (24) , Brigitte Gilbert-Dussardier (52) , Séverine Audebert-Bellanger (56) , Richard Redon (1) , Holly A.F. Stessman (57) , Christoffer Nellaker (5) , Yaping Yang (24) , James R Lupski (24) , David Goldstein (34) , Evan E. Eichler (58) , Francois Bolduc (53) , Stéphane Bézieau (1, 2) , Sébastien Küry (1, 2) , Philippe Campeau (3, 4)
1 ITX - ITX - unité de recherche de l'institut du thorax
2 CHU Nantes - Centre Hospitalier Universitaire de Nantes
3 CHU Sainte Justine [Montréal]
4 UQAM - Université du Québec à Montréal = University of Québec in Montréal
5 University of Oxford
6 GeneDx [Gaithersburg, MD, USA]
7 Mayo Clinic [Rochester]
8 UC San Francisco - University of California [San Francisco]
9 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
10 Etablissement Français du Sang Bretagne
11 CHU - BREST - Hôpital de la Cavale Blanche - CHRU Brest
12 Johns Hopkins University School of Medicine [Baltimore]
13 Kennedy Krieger Institute [Baltimore]
14 Chapel Allerton Hospital
15 UBC - University of British Columbia
16 University of Dundee
17 Rush University Medical Center [Chicago]
18 Oxford University Hospitals NHS Trust
19 Queen Elizabeth University Hospital (Glasgow)
20 Trondheim University
21 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
22 University of Virginia
23 Texas Children's Hospital [Houston, USA]
24 BCM - Baylor College of Medicine
25 University of Pennsylvania
26 NHGRI - National Human Genome Research Institute
27 HMS - Harvard Medical School [Boston]
28 Karolinska University Hospital [Stockholm]
29 Duke University Medical Center
30 University of Groningen [Groningen]
31 UAMS - University of Arkansas for Medical Sciences
32 McGovern Medical School [Houston, Texas]
33 Phoenix Children's Hospital
34 Columbia University [New York]
35 USQ - University of Southern Queensland
36 Telemark Hospital Trust [Skien, Norway]
37 University of Washington [Seattle]
38 Oslo University Hospital [Oslo]
39 CHOP - Children’s Hospital of Philadelphia
40 Hôpital Necker - Enfants Malades [AP-HP]
41 Radboud University Medical Center [Nijmegen]
42 Ann & Robert H. Lurie Children's Hospital of Chicago
43 McGovern Medical School [Houston, Texas]
44 iBraiN - Imaging, Brain & Neuropsychiatry
45 CHU Trousseau [Tours]
46 IGDR - Institut de Génétique et Développement de Rennes
47 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
48 Centre de référence Maladies Rares CLAD-Ouest [Rennes]
49 MITOVASC - MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
50 CHU Angers - Centre Hospitalier Universitaire d'Angers
51 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
52 CHU de Poitiers - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
53 University of Alberta
54 Boston Children's Hospital
55 MUHC - McGill University Health Center [Montreal]
56 CHU - BREST - Hôpital Morvan - CHRU de Brest
57 Creighton University Medical School [Omaha, NE, USA]
58 HHMI - Howard Hughes Medical Institute [Boston]
Slavé Petrovski
Kirsty Mcwalter
Patrick Blackburn
  • Fonction : Auteur
  • PersonId : 830514
Vandana Shashi
  • Fonction : Auteur
  • PersonId : 909391
Ernie M.H.F. Bongers
  • Fonction : Auteur
Christian Gilissen
  • Fonction : Auteur
Rolph Pfundt
  • Fonction : Auteur
  • PersonId : 889767
Elaine Zackai
  • Fonction : Auteur
  • PersonId : 905999
Jennifer Posey
Jill A. Rosenfeld
  • Fonction : Auteur
  • PersonId : 906001

Résumé

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.
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hal-02181523 , version 1 (22-10-2021)

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Paternité - Pas d'utilisation commerciale

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Benjamin Cogné, Sophie Ehresmann, Eliane Beauregard-Lacroix, Justine Rousseau, Thomas Besnard, et al.. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability. American Journal of Human Genetics, 2019, 104 (3), pp.530-541. ⟨10.1016/j.ajhg.2019.01.010⟩. ⟨hal-02181523⟩
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