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

, Deciphering Developmental Disorders (DDD) Study, Benjamin Cogné, Sophie Ehresmann, Eliane Beauregard-Lacroix, Justine Rousseau, Thomas Besnard, Thomas Garcia, Slavé Petrovski, Shiri Avni, Kirsty McWalter, Patrick R. Blackburn, Stephan J. Sanders, Kévin Uguen, Jacqueline Harris, Julie S. Cohen, Moira Blyth, Anna Lehman, Jonathan Berg, Mindy H. LiUsha Kini, Shelagh Joss, Charlotte von der Lippe, Christopher T. Gordon, Jennifer B. Humberson, Laurie Robak, Daryl A. Scott, Vernon R. Sutton, Cara M. Skraban, Jennifer J. Johnston, Annapurna Poduri, Magnus Nordenskjöld, Vandana Shashi, Erica H. Gerkes, Ernie M. H. F. Bongers, Christian Gilissen, Yuri A. Zarate, Malin Kvarnung, Kevin P. Lally, Peggy A. Kulch, Brina Daniels, Andres Hernandez-Garcia, Nicholas Stong, Julie McGaughran, Kyle Retterer, Kristian Tveten, Jennifer Sullivan, Madeleine R. Geisheker, Asbjorg Stray-Pedersen, Jennifer M. Tarpinian, Eric W. Klee, Julie C. Sapp, Sébastien Küry, Philippe M. Campeau (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)530-541
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number3
Early online date28 Feb 2019
Publication statusPublished - 7 Mar 2019


  • autism spectrum disorder
  • congenital malformations
  • de novo variants
  • histone acetylation
  • intellectual disability
  • neurodevelopmental disorders

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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