De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay.
Chromatin remodeling through histone acetyltransferase (HAT) and histone deactylase (HDAC) enzymes affects fundamental cellular processes including the cell-cycle, cell differentiation, metabolism, and apoptosis. Nonsense mutations in genes that are involved in histone acetylation and deacetylation result in multiple congenital anomalies with most individuals displaying significant developmental delay, microcephaly and dysmorphism. Here, we report a syndrome caused by de novo heterozygous nonsense mutations in KAT6A (a.k.a., MOZ, MYST3) identified by clinical exome sequencing (CES) in four independent families. The same de novo nonsense mutation (c.3385C>T [p.Arg1129∗]) was observed in three individuals, and the fourth individual had a nearby de novo nonsense mutation (c.3070C>T [p.Arg1024∗]). Neither of these variants was present in 1,815 in-house exomes or in public databases. Common features among all four probands include primary microcephaly, global developmental delay including profound speech delay, and craniofacial dysmorphism, as well as more varied features such as feeding difficulties, cardiac defects, and ocular anomalies. We further demonstrate that KAT6A mutations result in dysregulation of H3K9 and H3K18 acetylation and altered P53 signaling. Through histone and non-histone acetylation, KAT6A affects multiple cellular processes and illustrates the complex role of acetylation in regulating development and disease.
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Valerie A
VA
Arboleda
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Hane
H
Lee
Department of Pediatrics, Division of Medical Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA, USA.
Naghmeh
N
Dorrani
Division of Medical Genetics, CHOC Children's Hospital of Orange County, CA 92868, USA; Genetics Center, Orange, CA 92868, USA.
Neda
N
Zadeh
Department of Pediatrics, Naval Medical Center, San Diego, 92134, USA.
Mary
M
Willis
Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Colleen Forsyth
CF
Macmurdo
Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Melanie A
MA
Manning
Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Andrea
A
Kwan
Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Louanne
L
Hudgins
Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Florian
F
Barthelemy
Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
M Carrie
MC
Miceli
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Fabiola
F
Quintero-Rivera
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Sibel
S
Kantarci
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Samuel P
SP
Strom
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Joshua L
JL
Deignan
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pediatrics, Division of Medical Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Wayne W
WW
Grody
Department of Pediatrics, Division of Medical Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Eric
E
Vilain
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: snelson@ucla.edu.
Stanley F
SF
Nelson
D000015:Abnormalities, Multiple / Q000235:genetics; D000107:Acetylation; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics*; D059472:Exome; D005260:Female; D006579:Heterozygote; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D009154:Mutation; D010375:Pedigree
D018389:Codon, Nonsense; D006657:Histones; D051548:Histone Acetyltransferases; C108712:KAT6A protein, human