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

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.Post-translational modifications including acetylation, methylation, phosphorylation, and ubiquitination, of core histones directly alter DNA-histone and histone-histone interactions and thus influence nucleosome dynamics. 1 Tight regulation of these marks is required by cells for proper gene transcription, 2 DNA repair, 3 and DNA replication. One major activator of transcription is the acetylation of histone tails, which act by neutralizing the positive charges of lysine residues or by recruiting chromatin remodelers and transcription factors. 4 This tightly regulated process is performed by histone acetyltransferases (HATs) and reversed by histone deacetylases

Structure of the human SAGA coactivator complex: The divergent architecture of human SAGA allows modular coordination of transcription activation and co-transcriptional splicing

“…The best characterized function of SAGA's TRRAP module, is serving as an interaction hub for transcriptional activators and thus playing a critical role in many cancers and diseases (10,30,(41)(42)(43)(44)(45). The SUPT20H CTD resembles a lid that covers a solvent filled tunnel below the FAT domain (Fig.…”

Molecules, Mechanisms, and Disorders of Self-Domestication: Keys for Understanding Emotional and Social Communication from an Evolutionary Perspective

“…In addition to the fact that only sometimes the so-called common sequence variants (meaning that the minor allele frequency [MAF] is greater than 5% in the population) or their combinations are implied in the development of ASD, more important for the pathogenesis of ASD are rare (MAF < 1%) or very rare (MAF < 0.1%) single nucleotide variants (SNVs), as well as rare variations in the number of copies (copy number variation, CNV), especially deletions, but also duplications [ 148 , 149 , 150 , 151 , 152 ]. As of April 20, 2020, the Simons Foundation Autism Research Initiative (SFARI), the largest international database for ASD researchers, had a total of 835 genes whose changes or variants are associated with ASD ( ).…”

System-wide analyses of the fission yeast poly(A)+ RNA interactome reveal insights into organisation and function of RNA-protein complexes

“…Interestingly, SPAC25G10.01, a homologue of TRRAP, which is a component of the histone acetylation complex in humans, is also highly enriched. Mutations in TRRAP have been found to be a cause of autism and syndromic intellectual disability in humans (Cogné et al, 2019). It is tempting to speculate that RNA binding might play a regulatory role in modulating the activity of the histone acetyltransferase complex, an exciting possibility that could be tested in the future.…”