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

被引：60

作者：

Cheng, Hanyin ^{[1
]}

Dharmadhikari, Avinash V. ^{[1
]}

Varland, Sylvia ^{[2
,48
]}

Ma, Ning ^{[3
,4
,5
]}

Domingo, Deepti ^{[6
]}

Kleyner, Robert ^{[7
]}

Rope, Alan F. ^{[8
]}

Yoon, Margaret ^{[7
]}

Stray-Pedersen, Asbjorg ^{[9
,10
,11
]}

Posey, Jennifer E. ^{[9
]}

Crews, Sarah R. ^{[1
]}

Eldomery, Mohammad K. ^{[9
]}

Akdemir, Zeynep Coban ^{[9
]}

Lewis, Andrea M. ^{[9
,13
,14
]}

Sutton, Vernon R. ^{[9
]}

Rosenfeld, Jill A. ^{[9
]}

Conboy, Erin ^{[15
]}

Agre, Katherine ^{[15
]}

Xia, Fan ^{[1
,9
]}

Walkiewicz, Magdalena ^{[1
,9
,16
]}

Longoni, Mauro ^{[17
,18
]}

High, Frances A. ^{[17
,19
,20
]}

van Slegtenhorst, Marjon A. ^{[21
]}

Mancini, Grazia M. S. ^{[21
]}

Finnila, Candice R. ^{[22
]}

van Haeringen, Arie ^{[23
]}

den Hollander, Nicolette ^{[23
]}

Ruivenkamp, Claudia ^{[23
]}

Naidu, Sakkubai ^{[24
]}

Mahida, Sonal ^{[24
]}

Palmer, Elizabeth E. ^{[25
,26
]}

Murray, Lucinda ^{[25
]}

Lim, Derek ^{[27
]}

Jayakar, Parul ^{[28
]}

Parker, Michael J. ^{[29
]}

Giusto, Stefania ^{[30
]}

Stracuzzi, Emanuela ^{[30
]}

Romano, Corrado ^{[30
]}

Beighley, Jennifer S. ^{[31
]}

Bernier, Raphael A. ^{[31
]}

Kury, Sebastien ^{[32
]}

Nizon, Mathilde ^{[32
]}

Corbett, Mark A. ^{[33
,34
]}

Shaw, Marie ^{[33
,34
]}

Gardner, Alison ^{[33
,34
]}

Barnett, Christopher ^{[35
]}

Armstrong, Ruth ^{[36
]}

Kassahn, Karin S. ^{[37
,38
]}

Van Dijck, Anke ^{[39
]}

Vandeweyer, Geert ^{[39
]}

机构：

[1] Baylor Genet, Houston, TX 77021 USA

[2] Univ Bergen, Dept Biomed, N-5020 Bergen, Norway

[3] Stanford Univ, Sch Med, Stanford Cardiovasc Inst, Stanford, CA 94305 USA

[4] Stanford Univ, Sch Med, Dept Med, Div Cardiol, Stanford, CA 94305 USA

[5] Stanford Univ, Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA

[6] Univ Adelaide, Fac Genes & Evolut, Sch Biol Sci, Adelaide, SA 5000, Australia

[7] Cold Spring Harbor Lab, Stanley Inst Cognit Gen, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA

[8] Kaiser Permanente Northwest, Dept Med Genet, Portland, OR 97227 USA

[9] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[10] Oslo Univ Hosp, Div Pediat & Adolescent Med, Norwegian Natl Unit Newborn Screening, N-0424 Oslo, Norway

[11] Univ Oslo, Inst Clin Med, N-0318 Oslo, Norway

[12] Creighton Univ, Med Sch, Dept Pharmacol, Omaha, NE 68178 USA

[13] Texas Childrens Hosp, Dept Pediat, Houston, TX 77030 USA

[14] Baylor Coll Med, Houston, TX 77030 USA

[15] Mayo Clin, Dept Clin Genom, Rochester, MN 55905 USA

[16] NIH, NIAID, Bldg 10, Bethesda, MD 20892 USA

[17] Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA

[18] Harvard Med Sch, Dept Surg, Boston, MA 02114 USA

[19] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA

[20] Boston Childrens Hosp, Dept Surg, Boston, MA 02115 USA

[21] Erasmus Univ, Med Ctr, Dept Clin Genet, NL-3015 CN Rotterdam, Netherlands

[22] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA

[23] Leiden Univ, Med Ctr, Dept Clin Genet, NL-2333 Leiden, Netherlands

[24] Kennedy Krieger Inst, 801 North Broadway, Baltimore, MD 21205 USA

[25] Hunter Genet, Genet Learning Disabil Serv, Waratah, NSW 2298, Australia

[26] Univ New South Wales, Sch Womens & Childrens Hlth, Sydney, NSW 2031, Australia

[27] Birmingham Womens & Childrens NHS Fdn Trust, West Midlands Reg Genet Serv, Mindelsohn Way, Birmingham B15 2TG, W Midlands, England

[28] Nicklaus Childrens Hosp, Div Genet & Metab, Miami, FL 33155 USA

[29] Sheffield Childrens Hosp, Sheffield Clin Genet Serv, Sheffield S10 2TH, S Yorkshire, England

[30] Ist Ricovero Cura Carattere Sci, Oasi Res Inst, I-94018 Troina, Italy

[31] Univ Washington, Dept Psychiat, Seattle, WA 98195 USA

[32] CHU Nantes, Dept Med Genet, F-44093 Nantes, France

[33] Univ Adelaide, Adelaide Med Sch, Adelaide, SA 5000, Australia

[34] Univ Adelaide, Robinson Res Inst, Adelaide, SA 5000, Australia

[35] Womens & Childrens Hosp, SA Pathol, South Australian Clin Genet Serv, Paediat & Reprod Genet, Adelaide, SA 5006, Australia

[36] Addenbrookes Hosp, Addenbrookes Treatment Ctr, Clin Genet, East Anglian Med Genet Serv, Cambridge CB2 0QQ, England

[37] Womens & Childrens Hosp, Dept Genet & Mol Pathol, SA Pathol, Adelaide, SA 5006, Australia

[38] Univ Adelaide, Sch Biol Sci, Adelaide, SA 5000, Australia

[39] Univ Antwerp, Dept Med Genet, B-2000 Antwerp, Belgium

[40] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands

[41] St Marys Hosp, Manchester Univ NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester Ctr Genom Med, Manchester M13 9PL, Lancs, England

[42] Univ Manchester, Sch Biol Sci, Div Evolut & Genom Sci, Manchester M13 9PL, Lancs, England

[43] Univ Ottawa, Childrens Hosp, Eastern Ontario Res Inst, Ottawa, ON K1H 8L1, Canada

[44] GeneDx, 207 Perry Pkwy, Gaithersburg, MD 20877 USA

[45] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA

[46] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA

[47] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[48] Haukeland Hosp, Dept Surg, N-5021 Bergen, Norway

[49] Univ Bergen, Dept Mol Biol, N-5020 Bergen, Norway

[50] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2018年 / 102卷 / 05期

基金：

英国惠康基金; 美国国家卫生研究院;

关键词：

N-TERMINAL ACETYLATION; ARF-LIKE GTPASE; ACETYLTRANSFERASE; 10; PROTEIN; DE-NOVO MUTATIONS; SACCHAROMYCES-CEREVISIAE; CELLULAR-PROTEINS; HEART-DISEASE; GENES; IDENTIFICATION; MODEL;

D O I：

10.1016/j.ajhg.2018.03.004

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：985 / 994

页数：10

共 70 条

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