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

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Though addictions to substances including alcohol are highly heritable, there have been no studies regarding the possible applicability of genetic counseling to this set of conditions. Adults (≥18 years old) with a personal and/or family history of alcohol addiction were recruited to participate in an online survey-based study comprising 43 questions about beliefs/concern about recurrence risk and etiology of alcohol addiction and its impact on childbearing decisions, and perceptions of potential utility of genetic counseling for alcohol addiction. We applied primarily descriptive statistics, but also tested the hypotheses that perceiving genetic counseling to be useful would be associated with: 1) increasing importance attributed to genetics in the etiology of alcohol addiction, and 2) greater concern about recurrence of alcohol addiction (in self and/or children). Overall, the 113 participants recognized the multifactorial nature of alcohol addiction but reported a wide range of estimated recurrence risks for first-degree relatives. Overall, 62% perceived genetic counseling for alcohol addiction to be potentially beneficial. Participants were more likely to perceive a benefit from genetic counseling if they were concerned about recurrence for themselves (p = .021) or perceived genetics to be etiologically important in alcohol addiction (p = .024). Future studies are warranted to evaluate the outcomes of genetic counseling for addictions with respect to patient understanding, lifestyle modifications and psychological adaptation.