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

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

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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, …

American journal of human genetics, Vol.102(5), pp.985-994

102

05/03/2018

DOI: https://doi.org/10.1016/j.ajhg.2018.03.004

PMID: 29656860

Abstract

Genetics

Genetics(clinical)

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.

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Title: Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies
Creators: Hanyin Cheng (Author) - Baylor Genetics, LLC
Avinash V. Dharmadhikari (Author) - Baylor Genetics, LLC
Sylvia Varland (Author) - University of Bergen
Ning Ma (Author) - Stanford University
Deepti Domingo (Author) - University of Adelaide
Robert Kleyner (Author) - Cold Spring Harbor Laboratory
Alan F. Rope (Author) - Kaiser Permanente
Margaret Yoon (Author) - Cold Spring Harbor Laboratory
Asbjørg Stray-Pedersen (Author) - Baylor College of Medicine;University of Oslo
Jennifer E. Posey (Author) - Baylor College of Medicine
Sarah R. Crews (Author) - Creighton University
Mohammad K. Eldomery (Author) - Baylor College of Medicine
Zeynep Coban Akdemir (Author) - Baylor College of Medicine
Andrea M. Lewis (Author) - Baylor College of Medicine;Texas Children's Hospital Houston
Vernon R. Sutton (Author) - Baylor College of Medicine
Jill A. Rosenfeld (Author) - Baylor College of Medicine
Erin Conboy (Author) - Mayo Clinic Rochester, MN
Katherine Agre (Author) - Mayo Clinic Rochester, MN
Fan Xia (Author) - Baylor Genetics, LLC;Baylor College of Medicine
Magdalena Walkiewicz (Author) - Baylor Genetics, LLC;Baylor College of Medicine;National Institutes of Health
Mauro Longoni (Author) - Harvard University
Frances A. High (Author) - Harvard University
Marjon A. van Slegtenhorst (Author) - Erasmus University Rotterdam
Grazia M.S. Mancini (Author) - Erasmus University Rotterdam
Candice R. Finnila (Author) - HudsonAlpha Institute for Biotechnology
Arie van Haeringen (Author) - Leiden University
Nicolette den Hollander (Author) - Leiden University
Claudia Ruivenkamp (Author) - Leiden University
Sakkubai Naidu (Author) - Kennedy Krieger Institute
Sonal Mahida (Author) - Kennedy Krieger Institute
Elizabeth E. Palmer (Author) - Hunter Health;University of New South Wales
Lucinda Murray (Author) - Hunter Health
Derek Lim (Author) - Birmingham Women's and Children's NHS Foundation Trust
Parul Jayakar (Author) - Nicklaus Children's Hospital
Michael J. Parker (Author) - Sheffield Children's NHS Foundation Trust
Stefania Giusto (Author) - IRCCS Oasi Maria SS. - Troina (EN)
Emanuela Stracuzzi (Author) - IRCCS Oasi Maria SS. - Troina (EN)
Corrado Romano (Author) - IRCCS Oasi Maria SS. - Troina (EN)
Jennifer S. Beighley (Author) - University of Washington
Raphael A. Bernier (Author) - University of Washington
Sébastien Küry (Author) - Centre Hospitalier Universitaire
Mathilde Nizon (Author) - Centre Hospitalier Universitaire
Mark A. Corbett (Author) - University of Adelaide
Marie Shaw (Author) - University of Adelaide
Alison Gardner (Author) - University of Adelaide
Christopher Barnett (Author) - Women's and Children's Hospital Adelaide
Ruth Armstrong (Author) - Cambridge University Hospitals NHS Foundation Trust
Karin S. Kassahn (Author) - Women's and Children's Hospital Adelaide;University of Adelaide
Anke Van Dijck (Author) - University of Antwerp
Geert Vandeweyer (Author) - University of Antwerp
Tjitske Kleefstra (Author) - Radboud University Nijmegen
Jolanda Schieving (Author) - Radboud University Nijmegen
Marjolijn J. Jongmans (Author) - Radboud University Nijmegen
Bert B.A. de Vries (Author) - Radboud University Nijmegen
Rolph Pfundt (Author) - Radboud University Nijmegen
Bronwyn Kerr (Author) - Manchester University NHS Foundation Trust;University of Manchester
Samantha K. Rojas (Author) - Centre hospitalier pour enfants de l'est de l'Ontario
Kym M. Boycott (Author) - Centre hospitalier pour enfants de l'est de l'Ontario
Richard Person (Author) - GeneDX Inc
Rebecca Willaert (Author) - GeneDX Inc
Evan E. Eichler (Author) - University of Washington
R. Frank Kooy (Author) - University of Antwerp
Yaping Yang (Author) - Baylor Genetics, LLC;Baylor College of Medicine
Joseph C. Wu (Author) - Stanford University
James R. Lupski (Author) - Baylor College of Medicine
Thomas Arnesen (Author) - University of Bergen
Gregory M. Cooper (Author) - HudsonAlpha Institute for Biotechnology
Wendy K. Chung (Author) - Columbia University
Jozef Gecz (Author) - University of Adelaide;South Australian Health And Medical Research Institute
Holly A.F. Stessman (Author) - Department of Pharmacology and Neuroscience
Linyan Meng (Author) - Baylor Genetics, LLC;Baylor College of Medicine
Gholson J. Lyon (Author) - Cold Spring Harbor Laboratory
Additional links: Bergevin, Christopher; Puria, Sunil; Piedmont, Ralph L.; Village, Andrew
Publication Details: American journal of human genetics, Vol.102(5), pp.985-994
Series: 102
Number of pages: 10
Grant note: T.A. thanks Nina Glomnes for technical support. We appreciate the study participants and their families, without whom this work would not have been possible. Megan Cho at GeneDx facilitated the collaborations with the clinicians who submitted samples to GeneDx. The Baylor-Hopkins Center for Mendelian Genomics (BHCMG) has been funded by the US National Human Genome Research Institute (NHGRI)/National Heart Lung and Blood Institute (NHLBI) grant number UM1HG006542 . The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003 ), a parallel funding partnership between the Wellcome Trust and the Department of Health , and the Wellcome Trust Sanger Institute (grant WT098051 ). H.A.F.S. is supported by funds from the LB692 Nebraska Tobacco Settlement Biomedical Research Development Program . J.E.P. was supported by NHGRI grant K08 HG008986 . This research was further supported in part by the following to E.E.E.: the Simons Foundation Autism Research Initiative (SFARI 303241 and 337701 ) and National Institutes of Health ( R01MH101221 ). E.E.E. is an investigator of the Howard Hughes Medical Institute. The collection of the proband from HudsonAlpha was supported by Clinical Sequencing Evidence-Generating Research (CSER) study grant number ( NIH/NHGRI 4UM1HG007301-04 ). S.V. and T.A. were funded by the Research Council of Norway ( 249843 ), the Norwegian Cancer Society ( PR-2009-0222 ), and the Norwegian Health Authorities of Western Norway ( 912176 ). G.J.L. is supported by funds from the Stanley Institute for Cognitive Genomics at Cold Spring Harbor Laboratory . Additional acknowledgments can be found in the Supplemental Data . Funding Information: T.A. thanks Nina Glomnes for technical support. We appreciate the study participants and their families, without whom this work would not have been possible. Megan Cho at GeneDx facilitated the collaborations with the clinicians who submitted samples to GeneDx. The Baylor-Hopkins Center for Mendelian Genomics (BHCMG) has been funded by the US National Human Genome Research Institute (NHGRI)/National Heart Lung and Blood Institute (NHLBI) grant number UM1HG006542. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). H.A.F.S. is supported by funds from the LB692 Nebraska Tobacco Settlement Biomedical Research Development Program. J.E.P. was supported by NHGRI grant K08 HG008986. This research was further supported in part by the following to E.E.E.: the Simons Foundation Autism Research Initiative (SFARI 303241 and 337701) and National Institutes of Health (R01MH101221). E.E.E. is an investigator of the Howard Hughes Medical Institute. The collection of the proband from HudsonAlpha was supported by Clinical Sequencing Evidence-Generating Research (CSER) study grant number (NIH/NHGRI 4UM1HG007301-04). S.V. and T.A. were funded by the Research Council of Norway (249843), the Norwegian Cancer Society (PR-2009-0222), and the Norwegian Health Authorities of Western Norway (912176). G.J.L. is supported by funds from the Stanley Institute for Cognitive Genomics at Cold Spring Harbor Laboratory. Additional acknowledgments can be found in the Supplemental Data.
Identifiers: 991005929544002656
Academic Unit: Pharmacology and Neuroscience
Language: English
Resource Type: Journal article