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

Benjamin Cogné 1 Sophie Ehresmann 2 Eliane Beauregard-Lacroix Justine Rousseau 2 Thomas Besnard 1 Thomas Garcia 2 Slavé Petrovski Shiri Avni Kirsty Mcwalter Patrick Blackburn Stephan Sanders Kévin Uguen 3 Jacqueline Harris Julie Cohen Moira Blyth Anna Lehman Jonathan Berg Mindy Li Usha Kini Shelagh Joss Charlotte Li Christopher Gordon 4 Jennifer Humberson Laurie Robak Daryl Scott Vernon Sutton Cara Skraban Jennifer Johnston Anna Poduri Magnus Nordenskjöld Vandana Shashi 5 Erica Gerkes Ernie M.H.F. Bongers 6 Christian Gilissen 6 Yuri Zarate Malin Kvarnung 7 Kevin Lally Peggy Kulch Brina Daniels Andres García Nicholas Stong 8 Julie Mcgaughran Kyle Retterer 9 Kristian Tveten Jennifer Sullivan Madeleine Geisheker Asbjorg Stray-Pedersen Jennifer Tarpinian Eric Klee Julie Sapp 10 Jacob Zyskind Øystein Holla Emma Bedoukian Francesca Filippini 4 Anne Guimier 4 Arnaud Picard 4 Øyvind Busk Jaya Punetha Rolph Pfundt 11 Anna Li Ann Nordgren Fayth Kalb Megha Desai Ashley Harmon Ebanks Shalini Jhangiani Tammie Dewan Zeynep Coban Akdemir Aida Telegrafi 9 Elaine Zackai Amber Begtrup 9 Xiaofei Song Ann Toutain 12 Ingrid Wentzensen 9 Sylvie Odent 13, 14 Dominique Bonneau 15 Xenia Latypova 1 Wallid Deb 16, 1 Sylvia Redon 17, 3 Frédéric Bilan 18, 19 Marine Legendre 19, 18 Caitlin Troyer Kerri Whitlock Oana Caluseriu Marine Murphree Pavel Pichurin Katherine Agre Ralitza Gavrilova Tuula Rinne Meredith Park Catherine Shain Erin Heinzen 8 Rui Xiao Jeanne Amiel 4 Stanislas Lyonnet 20, 4 Bertrand Isidor 1 Leslie Biesecker Dan Lowenstein 21 Jennifer Posey Anne-Sophie Denommé-Pichon 15 Claude Férec 3 Xiang-Jiao Yang Jill Rosenfeld Brigitte Gilbert-Dussardier 18, 19 Séverine Audebert-Bellanger Richard Redon 1 Holly A.F. Stessman Christoffer Nellaker Yaping Yang James Lupski David Goldstein Evan Eichler 22 Francois Bolduc Stéphane Bézieau 16, 1 Sébastien Küry 16, 1, * Philippe Campeau 2, *
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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Submitted on : Friday, July 12, 2019 - 10:53:19 AM
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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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