2. Academic Validation
  3. De Novo KAT5 Variants Cause a Syndrome with Recognizable Facial Dysmorphisms, Cerebellar Atrophy, Sleep Disturbance, and Epilepsy

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.
Jonathan Humbert 1,  Smrithi Salian 2,  Periklis Makrythanasis 3,  Gabrielle Lemire 2,  Justine Rousseau 2,  Sophie Ehresmann 2,  Thomas Garcia 2,  Rami Alasiri 4,  Armand Bottani 5,  Sylviane Hanquinet 6,  Erin Beaver 7,  Jennifer Heeley 7,  Ann C M Smith 8,  Seth I Berger 9,  Stylianos E Antonarakis 10,  Xiang-Jiao Yang 4,  Jacques Côté 1,  Philippe M Campeau 11
Affiliations

Affiliations

  • 1 St-Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Axe Oncologie du Centre de Recherche du Centre Hospitalier Universitaire de Quebec-Université Laval, Quebec City, QC G1R 3S3, Canada.
  • 2 Sainte-Justine Hospital Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada.
  • 3 Biomedical Research Foundation of the Academy of Athens, Athens 115 27, Greece; Department of Genetic Medicine and Development, University of Geneva Medical School and Geneva University Hospitals, 1211 Geneva, Switzerland.
  • 4 Rosalind and Morris Goodman Cancer Research Centre, Department of Medicine, McGill University, Montreal, QC H3A 1A3, Canada.
  • 5 Service of Genetic Medicine, Geneva University Hospitals, 1211 Geneva, Switzerland.
  • 6 Unit of Pediatric Radiology, Geneva University Hospitals, 1211 Geneva, Switzerland.
  • 7 Mercy Kids Genetics, St. Louis, MO 63141, USA.
  • 8 Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20894, USA.
  • 9 Children's National Health System, Washington, DC 20010, USA.
  • 10 Department of Genetic Medicine and Development, University of Geneva Medical School and Geneva University Hospitals, 1211 Geneva, Switzerland.
  • 11 Sainte-Justine Hospital Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address: [email protected].
PMID: 32822602 DOI: 10.1016/j.ajhg.2020.08.002
Abstract

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.

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