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

Hanyin Cheng; Avinash V Dharmadhikari; Sylvia Varland; Ning Ma; Deepti Domingo; Robert Kleyner; Alan F Rope; Margaret Yoon; Asbjørg Stray-Pedersen; Jennifer E Posey; Sarah R Crews; Mohammad K Eldomery; Zeynep Coban Akdemir; Andrea M Lewis; Vernon R Sutton; Jill A Rosenfeld; Erin Conboy; Katherine Agre; Fan Xia; Magdalena Walkiewicz; Mauro Longoni; Frances A High; Marjon A van Slegtenhorst; Grazia M S Mancini; Candice R Finnila; Arie van Haeringen; Nicolette den Hollander; Claudia Ruivenkamp; Sakkubai Naidu; Sonal Mahida; Elizabeth E Palmer; Lucinda Murray; Derek Lim; Parul Jayakar; Michael J Parker; Stefania Giusto; Emanuela Stracuzzi; Corrado Romano; Jennifer S Beighley; Raphael A Bernier; Sébastien Küry; Mathilde Nizon; Mark A Corbett; Marie Shaw; Alison Gardner; Christopher Barnett; Ruth Armstrong; Karin S Kassahn; Anke Van Dijck; Geert Vandeweyer; Tjitske Kleefstra; Jolanda Schieving; Marjolijn J Jongmans; Bert B A de Vries; Rolph Pfundt; Bronwyn Kerr; Samantha K Rojas; Kym M Boycott; Richard Person; Rebecca Willaert; Evan E Eichler; R Frank Kooy; Yaping Yang; Joseph C Wu; James R Lupski; Thomas Arnesen; Gregory M Cooper; Wendy K Chung; Jozef Gecz; Holly A F Stessman; Linyan Meng; Gholson J Lyon

doi:10.1016/j.ajhg.2018.03.004

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

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

Authors

Hanyin Cheng¹, Avinash V Dharmadhikari¹, Sylvia Varland², Ning Ma³, Deepti Domingo⁴, Robert Kleyner⁵, Alan F Rope⁶, Margaret Yoon⁵, Asbjørg Stray-Pedersen⁷, Jennifer E Posey⁸, Sarah R Crews⁹, Mohammad K Eldomery⁸, Zeynep Coban Akdemir⁸, Andrea M Lewis¹⁰, Vernon R Sutton⁸, Jill A Rosenfeld⁸, Erin Conboy¹¹, Katherine Agre¹¹, Fan Xia¹², Magdalena Walkiewicz¹³, Mauro Longoni¹⁴, Frances A High¹⁵, Marjon A van Slegtenhorst¹⁶, Grazia M S Mancini¹⁶, Candice R Finnila¹⁷, Arie van Haeringen¹⁸, Nicolette den Hollander¹⁸, Claudia Ruivenkamp¹⁸, Sakkubai Naidu¹⁹, Sonal Mahida¹⁹, Elizabeth E Palmer²⁰, Lucinda Murray²¹, Derek Lim²², Parul Jayakar²³, Michael J Parker²⁴, Stefania Giusto²⁵, Emanuela Stracuzzi²⁵, Corrado Romano²⁵, Jennifer S Beighley²⁶, Raphael A Bernier²⁶, Sébastien Küry²⁷, Mathilde Nizon²⁷, Mark A Corbett²⁸, Marie Shaw²⁸, Alison Gardner²⁸, Christopher Barnett²⁹, Ruth Armstrong³⁰, Karin S Kassahn³¹, Anke Van Dijck³², Geert Vandeweyer³², Tjitske Kleefstra³³, Jolanda Schieving³³, Marjolijn J Jongmans³³, Bert B A de Vries³³, Rolph Pfundt³³, Bronwyn Kerr³⁴, Samantha K Rojas³⁵, Kym M Boycott³⁵, Richard Person³⁶, Rebecca Willaert³⁶, Evan E Eichler³⁷, R Frank Kooy³², Yaping Yang¹², Joseph C Wu³, James R Lupski³⁸, Thomas Arnesen³⁹, Gregory M Cooper¹⁷, Wendy K Chung⁴⁰, Jozef Gecz⁴¹, Holly A F Stessman⁹, Linyan Meng⁴², Gholson J Lyon⁴³

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple / genetics*
Adolescent
Adult
Autism Spectrum Disorder / genetics*
Cell Line
Child
Exons / genetics
Female
Gene Expression Regulation
Genetic Predisposition to Disease*
Genetic Variation*
Humans
Intellectual Disability / genetics*
Male
Middle Aged
Mutation / genetics
N-Terminal Acetyltransferase A / genetics*
N-Terminal Acetyltransferase A / metabolism
N-Terminal Acetyltransferase E / genetics*
N-Terminal Acetyltransferase E / metabolism
Pedigree
Phenotype
RNA, Messenger / genetics
RNA, Messenger / metabolism
Saccharomyces cerevisiae / metabolism

Substances

NAA15 protein, human
RNA, Messenger
N-Terminal Acetyltransferase A
N-Terminal Acetyltransferase E

Abstract

Publication types

MeSH terms

Substances

Grants and funding