De Novo KAT5 Variants Cause a Syndrome with Recognizable Facial Dysmorphisms, Cerebellar Atrophy, Sleep Disturbance, and Epilepsy

Am J Hum Genet. 2020 Sep 3;107(3):564-574. doi: 10.1016/j.ajhg.2020.08.002. Epub 2020 Aug 20.


KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause 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 variant 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 affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. 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, and suggesting a recognizable syndrome.

Keywords: KAT5; TIP60; brain malformations; epigenetic; epilepsy; histone; histone acetyltransferase; intellectual disability; sleep disturbance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / diagnostic imaging
  • Abnormalities, Multiple / genetics
  • Abnormalities, Multiple / physiopathology
  • Adolescent
  • Adult
  • Atrophy / diagnostic imaging
  • Atrophy / genetics*
  • Atrophy / physiopathology
  • Cerebellar Diseases / diagnostic imaging
  • Cerebellar Diseases / genetics*
  • Cerebellar Diseases / physiopathology
  • Child, Preschool
  • Chromatin / genetics
  • Chromatin Assembly and Disassembly / genetics
  • DNA Repair / genetics
  • Epilepsy / diagnostic imaging
  • Epilepsy / genetics
  • Epilepsy / physiopathology
  • Female
  • Heterozygote
  • Histones / genetics
  • Humans
  • Intellectual Disability / diagnostic imaging
  • Intellectual Disability / genetics*
  • Intellectual Disability / physiopathology
  • Lysine Acetyltransferase 5 / genetics*
  • Male
  • Mutation, Missense / genetics
  • Protein Processing, Post-Translational / genetics


  • Chromatin
  • Histones
  • KAT5 protein, human
  • Lysine Acetyltransferase 5