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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Autistic Disorder / etiology*
  • Autistic Disorder / metabolism
  • Autistic Disorder / pathology
  • Child
  • Child, Preschool
  • Female
  • Genetic Association Studies
  • Humans
  • Infant
  • Intellectual Disability / etiology*
  • Intellectual Disability / metabolism
  • Intellectual Disability / pathology
  • Male
  • Mutation, Missense*
  • Nuclear Proteins / genetics*
  • Prognosis
  • Sequence Homology
  • Syndrome
  • Young Adult

Substances

  • Adaptor Proteins, Signal Transducing
  • Nuclear Proteins
  • transformation-transcription domain-associated protein