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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 Robak 23 Daryl Scott 24 Vernon 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 Busk 36 Jaya Punetha 24 Rolph Pfundt 41 Anna Lindstrand 28 Ann 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 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 Lupski 24 David Goldstein 34 Evan Eichler 58 Francois Bolduc 53 Stéphane Bézieau 1, 2 Sébastien Küry 1, 2, * Philippe Campeau 3, 4, *
* Corresponding author
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.
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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, Elsevier (Cell Press), 2019, 104 (3), pp.530-541. ⟨10.1016/j.ajhg.2019.01.010⟩. ⟨hal-02181523⟩

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