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 & 52 others 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 Stessman, Linyan Meng, Gholson J. Lyon

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)985-994
Number of pages10
JournalAmerican Journal of Human Genetics
Volume102
Issue number5
DOIs
StatePublished - May 3 2018

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N-Terminal Acetyltransferase A
Intellectual Disability
Genes
Acetylation
Translational Protein Modification
Exome
Haploinsufficiency
Human Development
Catalytic Domain
Seizures
Yeasts
Genotype
Autism Spectrum Disorder
Genome
RNA
Cell Line
Growth

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies. / Cheng, Hanyin; Dharmadhikari, Avinash V.; Varland, Sylvia; Ma, Ning; Domingo, Deepti; Kleyner, Robert; Rope, Alan F.; Yoon, Margaret; Stray-Pedersen, Asbjørg; Posey, Jennifer E.; Crews, Sarah R.; Eldomery, Mohammad K.; Akdemir, Zeynep Coban; Lewis, Andrea M.; Sutton, Vernon R.; Rosenfeld, Jill A.; Conboy, Erin; Agre, Katherine; Xia, Fan; Walkiewicz, Magdalena; Longoni, Mauro; High, Frances A.; van Slegtenhorst, Marjon A.; Mancini, Grazia M.S.; Finnila, Candice R.; van Haeringen, Arie; den Hollander, Nicolette; Ruivenkamp, Claudia; Naidu, Sakkubai; Mahida, Sonal; Palmer, Elizabeth E.; Murray, Lucinda; Lim, Derek; Jayakar, Parul; Parker, Michael J.; Giusto, Stefania; Stracuzzi, Emanuela; Romano, Corrado; Beighley, Jennifer S.; Bernier, Raphael A.; Küry, Sébastien; Nizon, Mathilde; Corbett, Mark A.; Shaw, Marie; Gardner, Alison; Barnett, Christopher; Armstrong, Ruth; Kassahn, Karin S.; Van Dijck, Anke; Vandeweyer, Geert; Kleefstra, Tjitske; Schieving, Jolanda; Jongmans, Marjolijn J.; de Vries, Bert B.A.; Pfundt, Rolph; Kerr, Bronwyn; Rojas, Samantha K.; Boycott, Kym M.; Person, Richard; Willaert, Rebecca; Eichler, Evan E.; Kooy, R. Frank; Yang, Yaping; Wu, Joseph C.; Lupski, James R.; Arnesen, Thomas; Cooper, Gregory M.; Chung, Wendy K.; Gecz, Jozef; Stessman, Holly; Meng, Linyan; Lyon, Gholson J.

In: American Journal of Human Genetics, Vol. 102, No. 5, 03.05.2018, p. 985-994.

Research output: Contribution to journalArticle

Cheng, H, Dharmadhikari, AV, Varland, S, Ma, N, Domingo, D, Kleyner, R, Rope, AF, Yoon, M, Stray-Pedersen, A, Posey, JE, Crews, SR, Eldomery, MK, Akdemir, ZC, Lewis, AM, Sutton, VR, Rosenfeld, JA, Conboy, E, Agre, K, Xia, F, Walkiewicz, M, Longoni, M, High, FA, van Slegtenhorst, MA, Mancini, GMS, Finnila, CR, van Haeringen, A, den Hollander, N, Ruivenkamp, C, Naidu, S, Mahida, S, Palmer, EE, Murray, L, Lim, D, Jayakar, P, Parker, MJ, Giusto, S, Stracuzzi, E, Romano, C, Beighley, JS, Bernier, RA, Küry, S, Nizon, M, Corbett, MA, Shaw, M, Gardner, A, Barnett, C, Armstrong, R, Kassahn, KS, Van Dijck, A, Vandeweyer, G, Kleefstra, T, Schieving, J, Jongmans, MJ, de Vries, BBA, Pfundt, R, Kerr, B, Rojas, SK, Boycott, KM, Person, R, Willaert, R, Eichler, EE, Kooy, RF, Yang, Y, Wu, JC, Lupski, JR, Arnesen, T, Cooper, GM, Chung, WK, Gecz, J, Stessman, H, Meng, L & Lyon, GJ 2018, 'Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies', American Journal of Human Genetics, vol. 102, no. 5, pp. 985-994. https://doi.org/10.1016/j.ajhg.2018.03.004
Cheng, Hanyin ; Dharmadhikari, Avinash V. ; Varland, Sylvia ; Ma, Ning ; Domingo, Deepti ; Kleyner, Robert ; Rope, Alan F. ; Yoon, Margaret ; Stray-Pedersen, Asbjørg ; Posey, Jennifer E. ; Crews, Sarah R. ; Eldomery, Mohammad K. ; Akdemir, Zeynep Coban ; Lewis, Andrea M. ; Sutton, Vernon R. ; Rosenfeld, Jill A. ; Conboy, Erin ; Agre, Katherine ; Xia, Fan ; Walkiewicz, Magdalena ; Longoni, Mauro ; High, Frances A. ; van Slegtenhorst, Marjon A. ; Mancini, Grazia M.S. ; Finnila, Candice R. ; van Haeringen, Arie ; den Hollander, Nicolette ; Ruivenkamp, Claudia ; Naidu, Sakkubai ; Mahida, Sonal ; Palmer, Elizabeth E. ; Murray, Lucinda ; Lim, Derek ; Jayakar, Parul ; Parker, Michael J. ; Giusto, Stefania ; Stracuzzi, Emanuela ; Romano, Corrado ; Beighley, Jennifer S. ; Bernier, Raphael A. ; Küry, Sébastien ; Nizon, Mathilde ; Corbett, Mark A. ; Shaw, Marie ; Gardner, Alison ; Barnett, Christopher ; Armstrong, Ruth ; Kassahn, Karin S. ; Van Dijck, Anke ; Vandeweyer, Geert ; Kleefstra, Tjitske ; Schieving, Jolanda ; Jongmans, Marjolijn J. ; de Vries, Bert B.A. ; Pfundt, Rolph ; Kerr, Bronwyn ; Rojas, Samantha K. ; Boycott, Kym M. ; Person, Richard ; Willaert, Rebecca ; Eichler, Evan E. ; Kooy, R. Frank ; Yang, Yaping ; Wu, Joseph C. ; Lupski, James R. ; Arnesen, Thomas ; Cooper, Gregory M. ; Chung, Wendy K. ; Gecz, Jozef ; Stessman, Holly ; Meng, Linyan ; Lyon, Gholson J. / Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies. In: American Journal of Human Genetics. 2018 ; Vol. 102, No. 5. pp. 985-994.
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title = "Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies",
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.",
author = "Hanyin Cheng and Dharmadhikari, {Avinash V.} and Sylvia Varland and Ning Ma and Deepti Domingo and Robert Kleyner and Rope, {Alan F.} and Margaret Yoon and Asbj{\o}rg Stray-Pedersen and Posey, {Jennifer E.} and Crews, {Sarah R.} and Eldomery, {Mohammad K.} and Akdemir, {Zeynep Coban} and Lewis, {Andrea M.} and Sutton, {Vernon R.} and Rosenfeld, {Jill A.} and Erin Conboy and Katherine Agre and Fan Xia and Magdalena Walkiewicz and Mauro Longoni and High, {Frances A.} and {van Slegtenhorst}, {Marjon A.} and Mancini, {Grazia M.S.} and Finnila, {Candice R.} and {van Haeringen}, Arie and {den Hollander}, Nicolette and Claudia Ruivenkamp and Sakkubai Naidu and Sonal Mahida and Palmer, {Elizabeth E.} and Lucinda Murray and Derek Lim and Parul Jayakar and Parker, {Michael J.} and Stefania Giusto and Emanuela Stracuzzi and Corrado Romano and Beighley, {Jennifer S.} and Bernier, {Raphael A.} and S{\'e}bastien K{\"u}ry and Mathilde Nizon and Corbett, {Mark A.} and Marie Shaw and Alison Gardner and Christopher Barnett and Ruth Armstrong and Kassahn, {Karin S.} and {Van Dijck}, Anke and Geert Vandeweyer and Tjitske Kleefstra and Jolanda Schieving and Jongmans, {Marjolijn J.} and {de Vries}, {Bert B.A.} and Rolph Pfundt and Bronwyn Kerr and Rojas, {Samantha K.} and Boycott, {Kym M.} and Richard Person and Rebecca Willaert and Eichler, {Evan E.} and Kooy, {R. Frank} and Yaping Yang and Wu, {Joseph C.} and Lupski, {James R.} and Thomas Arnesen and Cooper, {Gregory M.} and Chung, {Wendy K.} and Jozef Gecz and Holly Stessman and Linyan Meng and Lyon, {Gholson J.}",
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T1 - Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

AU - Cheng, Hanyin

AU - Dharmadhikari, Avinash V.

AU - Varland, Sylvia

AU - Ma, Ning

AU - Domingo, Deepti

AU - Kleyner, Robert

AU - Rope, Alan F.

AU - Yoon, Margaret

AU - Stray-Pedersen, Asbjørg

AU - Posey, Jennifer E.

AU - Crews, Sarah R.

AU - Eldomery, Mohammad K.

AU - Akdemir, Zeynep Coban

AU - Lewis, Andrea M.

AU - Sutton, Vernon R.

AU - Rosenfeld, Jill A.

AU - Conboy, Erin

AU - Agre, Katherine

AU - Xia, Fan

AU - Walkiewicz, Magdalena

AU - Longoni, Mauro

AU - High, Frances A.

AU - van Slegtenhorst, Marjon A.

AU - Mancini, Grazia M.S.

AU - Finnila, Candice R.

AU - van Haeringen, Arie

AU - den Hollander, Nicolette

AU - Ruivenkamp, Claudia

AU - Naidu, Sakkubai

AU - Mahida, Sonal

AU - Palmer, Elizabeth E.

AU - Murray, Lucinda

AU - Lim, Derek

AU - Jayakar, Parul

AU - Parker, Michael J.

AU - Giusto, Stefania

AU - Stracuzzi, Emanuela

AU - Romano, Corrado

AU - Beighley, Jennifer S.

AU - Bernier, Raphael A.

AU - Küry, Sébastien

AU - Nizon, Mathilde

AU - Corbett, Mark A.

AU - Shaw, Marie

AU - Gardner, Alison

AU - Barnett, Christopher

AU - Armstrong, Ruth

AU - Kassahn, Karin S.

AU - Van Dijck, Anke

AU - Vandeweyer, Geert

AU - Kleefstra, Tjitske

AU - Schieving, Jolanda

AU - Jongmans, Marjolijn J.

AU - de Vries, Bert B.A.

AU - Pfundt, Rolph

AU - Kerr, Bronwyn

AU - Rojas, Samantha K.

AU - Boycott, Kym M.

AU - Person, Richard

AU - Willaert, Rebecca

AU - Eichler, Evan E.

AU - Kooy, R. Frank

AU - Yang, Yaping

AU - Wu, Joseph C.

AU - Lupski, James R.

AU - Arnesen, Thomas

AU - Cooper, Gregory M.

AU - Chung, Wendy K.

AU - Gecz, Jozef

AU - Stessman, Holly

AU - Meng, Linyan

AU - Lyon, Gholson J.

PY - 2018/5/3

Y1 - 2018/5/3

N2 - 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.

AB - 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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