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    • To identify genes with significant expression differences

    2022-01-15

    To identify genes with significant xylometazoline differences, we performed differential gene expression analysis between the two individuals with TRRAP variants (combined as biological replicates) and two unaffected controls. Gene ontology (GO) enrichment analysis of these genes with the GOrilla web application indicates an enrichment for the adrenergic receptor signaling pathway, genes important for neurological function, and potassium and ATP-sensitive ion transporters (Figure S2B, Supplemental Data, Table S5). The two individuals who were tested carried variants outside the cluster associated with the more syndromic ID; if there are distinct effects on gene regulation, it will be worth comparing gene expression between the two groups. Finally, because it has been shown that TRRAP has direct interactions with different partners not related to the HAT complex, we cannot exclude the possibility that the transcriptome alteration might be caused by a mechanism other than impaired HAT activity. Thus, we highlighted candidate pathways that might be useful for uncovering the pathomechanism of TRRAP variants in future studies. TRRAP acts as a scaffold in HAT complexes. Although it does not have a direct role in acetylation, we hypothesize that pathogenic effects of variants might be due to dysregulation of acetylation, a major process that has been associated with several neurodevelopmental disorders. Pathogenic variants of KAT6B (MIM: 605880) cause both Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS [MIM: 603736])35, 36, 37 and genitopatellar syndrome (GPS [MIM: 606170]),38, 39 and pathogenic variants in KAT6A and BRPF1 mutations have also been associated with a neurodevelopmental disorder.40, 41, 42 Rubinstein-Taybi syndrome (MIM: 180849 and 613684) is associated with variants in HAT-complex-encoding genes, namely CREBBP and EP300.43, 44, 45, 46 In addition to cognitive impairment, abnormal histone acetylation can also result in behavioral disorders, as evidenced by the associations found between non-syndromic ASD and/or schizophrenia and alterations in several lysine acetyltransferase and lysine deacetylase genes, including BRD1, HDAC4, HDAC6, and HDAC9.34, 47, 48, 49, 50 Variants in TRRAP were associated with neuropsychiatric disorders, including childhood disintegrative disorder, schizophrenia,18, 19 and ASD. The ASD report included individuals 18 and 19, who had p.Trp1866Arg and p.Trp1866Cys, respectively. We thus confirmed the association with ASD and provide evidence that it can be found either isolated or associated with ID. On the basis of the ExAC dataset alone without studies on neuropsychiatric disorders, TRRAP is in the top five human genes that are most intolerant of missense variants: it has a missense z-score of 10.1. Although this study includes only the first 24 identified individuals, a strength of the study is that it was primarily ascertained by sequencing, reducing phenotypic ascertainment bias. Given the highly constrained region of the observed variants coupled with the population constraint and evolutionary conservation, we hypothesize that variants outside of these regions are likely to be associated with prenatal lethality, although we cannot exclude the possibility that milder phenotypes might be underrepresented in current exome datasets. It is worth noting that we exclusively identified missense variants in the affected individuals. Given the loss-of-function (LoF) intolerance of TRRAP in ExAC (pLI = 1.00), we would expect to identify at least some LoF variants if haploinsufficiency of TRRAP was the causal mechanism. In DECIPHER (accessed May 14, 2018), no small or intragenic deletions involving TRRAP have been identified. Thus, when the significant clustering is taken into account, our results suggest that missense variants might act either as gain-of-function or dominant-negative variants and that haploinsufficiency of TRRAP is likely to be prenatally lethal, although we cannot exclude the possibility that an LoF effect of non-clustering variants is associated with a milder phenotype.