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Am J Hum Genet. 2018 May 3;102(5):985-994. doi: 10.1016/j.ajhg.2018.03.004. Epub 2018 Apr 12.

Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.

Author information

1
Baylor Genetics, Houston, TX, 77021, USA.
2
Department of Biomedicine, University of Bergen, N-5020 Bergen, Norway; Department of Surgery, Haukeland University Hospital, N-5021 Bergen, Norway.
3
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
School of Biological Sciences, Faculty of Genes and Evolution, the University of Adelaide, Adelaide, SA 5000, Australia.
5
Stanley Institute for Cognitive Genomics, 1Bungtown Road, Cold Spring Harbor Laboratory, NY 11724, USA.
6
Department of Medical Genetics, Kaiser Permanente Northwest, Portland, OR 97227, USA.
7
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, N-0424 Oslo, and Institute of Clinical Medicine, University of Oslo, N-0318 Oslo, Norway.
8
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
9
Department of Pharmacology, Creighton University Medical School, Omaha, NE, 68178, USA.
10
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX 77030, USA.
11
Department of Clinical Genomics, Mayo Clinic, MN 55905, USA.
12
Baylor Genetics, Houston, TX, 77021, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
13
Baylor Genetics, Houston, TX, 77021, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; The National Institute of Allergy and Infectious Disease, The National Institutes of Health, Bethesda, MD 20892, USA.
14
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA.
15
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pediatrics, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Boston Children's Hospital, Boston, MA 02115, USA.
16
Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
17
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
18
Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2333, The Netherlands.
19
Kennedy Krieger Institute, 801 North Broadway Baltimore, MD 21205, USA.
20
Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2031, Australia.
21
Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
22
West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Mindelsohn Way, Birmingham B15 2TG, UK.
23
Division of Genetics and Metabolism, Nicklaus Children's Hospital, Miami, FL 33155, USA.
24
Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH, UK.
25
Oasi Research Institute - Istituto di Ricovero e Cura a Carattere Scientifico, Troina 94018, Italy.
26
Department of Psychiatry, University of Washington, Seattle WA, 98195, USA.
27
Department of Medical Genetics, Centre Hospitalier Universitaire, Nantes 44093, France.
28
Adelaide Medical School and Robinson Research Institute, the University of Adelaide, Adelaide, SA 5000, Australia.
29
Paediatric and Reproductive Genetics, South Australian Clinical Genetics Service, SA Pathology (at Women's and Children's Hospital), Adelaide, SA 5006, Australia.
30
East Anglian Medical Genetics Service, Clinical Genetics, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
31
Department of Genetics and Molecular Pathology, SA Pathology, Women's and Children's Hospital, North Adelaide, SA 5006, Australia; School of Biological Sciences, University of Adelaide, Adelaide, SA 5000, Australia.
32
Department of Medical Genetics, University of Antwerp, Antwerp 2000, Belgium.
33
Department of Human Genetics, Radboud University Medical Center, Nijmegen 6500HB, The Netherlands.
34
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9PL, UK; Division of Evolution and Genomic Sciences School of Biological Sciences, University of Manchester, Manchester M13 9PL, UK.
35
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
36
GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
37
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
38
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center of Baylor College of Medicine, Houston, TX 77030, USA.
39
Department of Biomedicine, University of Bergen, N-5020 Bergen, Norway; Department of Surgery, Haukeland University Hospital, N-5021 Bergen, Norway; Department of Molecular Biology, University of Bergen, N-5020 Bergen, Norway.
40
Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY 10032, USA.
41
School of Biological Sciences, Faculty of Genes and Evolution, the University of Adelaide, Adelaide, SA 5000, Australia; Adelaide Medical School and Robinson Research Institute, the University of Adelaide, Adelaide, SA 5000, Australia; Healthy Mothers, Babies and Children, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia.
42
Baylor Genetics, Houston, TX, 77021, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: lmeng@bcm.edu.
43
Stanley Institute for Cognitive Genomics, 1Bungtown Road, Cold Spring Harbor Laboratory, NY 11724, USA. Electronic address: gholsonjlyon@gmail.com.

Abstract

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

KEYWORDS:

N-terminal acetylation (NTA); N-terminal acetyltransferases (NATs); NAA10; NAA15; NatA complex; Ogden syndrome; autism; congenital heart defects; intellectual disability; neurodevelopmental disorder

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