Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15
Hum Mol Genet.
Cheng H1, Gottlieb L2,3, Marchi E4, Kleyner R5, Bhardwaj P5, Rope AF6,7, Rosenheck S5, Moutton S8,9, Philippe C9,10, Eyaid W11, Alkuraya FS12,13, Toribio J14, Mena R15,16, Prada CE17,18, Stessman H19, Bernier R20, Wermuth M21, Kauffmann B21, Blaumeiser B22, Kooy RF23, Baralle D24,25, Mancini GMS26, Conway SJ27, Xia F1,28, Chen Z1,28, Meng L1,28, Mihajlovic L29, Marmorstein R2,3,30, Lyon GJ4,5.
1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2 Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
3 Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
4 Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
5 Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA.
6 Kaiser Permanente Center for Health Research, Portland, OR 97227, USA.
7 Genome Medical, South San Francisco, CA 94080, USA.
8 Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, Dijon, France.
9 Génétique des Anomalies du développement, INSERM U1231, Lipides Nutrition et Cancer, UMR1231, Université de Bourgogne, F-21000, Dijon 21070, France.
10 Laboratoire de Génétique, Innovation Diagnostic Génomique des Maladies Rares UF6254, Plate-forme de Biologie Hospitalo-Universitaire, Centre Hospitalier Universitaire, Dijon 21070, France.
11 King Abdulaziz Medical City, King Saud Bin AbdulAziz University-Health Science, King Abdullah International Medical Research Center, Riyadh 11426, Saudi Arabia.
12 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
13 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
14 Division of Cardiology, CEDIMAT, Santo Domingo 51000, Dominican Republic.
15 Neonatal Intensive Care Unit, Centro de Obstetricia y Ginecologia, Santo Domingo, Dominican Republic.
16 Division Of Neonatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.
17 Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.
18 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
19 Department of Pharmacology, Creighton University Medical School, Omaha, NE 68178, USA.
20 Department of Psychiatry, University of Washington, Seattle, WA 98195, USA.
21 Klinik für Kinder-und Jugendmedizin, Neuropädiatrie, Klinikum Links der Weser, Senator-Weβling-Str.1. in 28211 Bremen, Germany.
22 University and University Hospital of Antwerp, Antwerp, Belgium.
23 Department of Medical Genetics, University of Antwerp, Antwerp 2000, Belgium.
24 Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO16 5YA, UK.
25 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
26 Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam 3015 GD, The Netherlands.
27 HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
28 Baylor Genetics, Houston, TX 77021, USA.
29 GeneInfo, Human Genetics, 18000 Niš, Serbia.
30 Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Year of Publication:
N-alpha-acetylation is one of the most common co-translational protein modifications in humans and is essential for normal cell function. NAA10 encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. The auxiliary and regulatory subunits of the NatA complex are NAA15 and Huntington-interacting protein (HYPK), respectively. Through a genotype-first approach with exome sequencing, we identified and phenotypically characterized 30 individuals from 30 unrelated families with 17 different de novo or inherited, dominantly acting missense variants in NAA10 or NAA15. Clinical features of affected individuals include variable levels of intellectual disability, delayed speech and motor milestones and autism spectrum disorder. Additionally, some subjects present with mild craniofacial dysmorphology, congenital cardiac anomalies and seizures. One of the individuals is an 11-year-old boy with a frameshift variant in exon 7 of NAA10, who presents most notably with microphthalmia, which confirms a prior finding with a single family with Lenz microphthalmia syndrome. Biochemical analyses of variants as part of the human NatA complex, as well as enzymatic analyses with and without the HYPK regulatory subunit, help to explain some of the phenotypic differences seen among the different variants.