RNA sequencing of fibroblasts from patients with pathogenic KAT5 variants

KAT5 encodes an essential lysine acetyltransferase previously called TIP60 involved in gene expression, DNA repair, chromatin remodeling, apoptosis and cell proliferation; but it remains unclear whether variants in this gene causes a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified mutant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in patient-derived fibroblasts showed deregulation of multiple genes controlling development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control), in agreement with sleep anomalies in all the patients. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy and facial dysmorphisms suggesting a recognizable syndrome.