Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains

Madeleine R. Geisheker; Gabriel Heymann; Tianyun Wang; Bradley P. Coe; Tychele N. Turner; Holly A.F. Stessman; Kendra Hoekzema; Malin Kvarnung; Marie Shaw; Kathryn Friend; Jan Liebelt; Christopher Barnett; Elizabeth M. Thompson; Eric Haan; Hui Guo; Britt Marie Anderlid; Ann Nordgren; Anna Lindstrand; Geert Vandeweyer; Antonino Alberti; Emanuela Avola; Mirella Vinci; Stefania Giusto; Tiziano Pramparo; Karen Pierce; Srinivasa Nalabolu; Jacob J. Michaelson; Zdenek Sedlacek; Gijs W.E. Santen; Hilde Peeters; Hakon Hakonarson; Eric Courchesne; Corrado Romano; R. Frank Kooy; Raphael A. Bernier; Magnus Nordenskjöld; Jozef Gecz; Kun Xia; Larry S. Zweifel; Evan E. Eichler

doi:10.1038/nn.4589

Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains

Madeleine R. Geisheker, Gabriel Heymann, Tianyun Wang, Bradley P. Coe, Tychele N. Turner, Holly A.F. Stessman, Kendra Hoekzema, Malin Kvarnung, Marie Shaw, Kathryn Friend, Jan Liebelt, Christopher Barnett, Elizabeth M. Thompson, Eric Haan, Hui Guo, Britt Marie Anderlid, Ann Nordgren, Anna Lindstrand, Geert Vandeweyer, Antonino AlbertiEmanuela Avola, Mirella Vinci, Stefania Giusto, Tiziano Pramparo, Karen Pierce, Srinivasa Nalabolu, Jacob J. Michaelson, Zdenek Sedlacek, Gijs W.E. Santen, Hilde Peeters, Hakon Hakonarson, Eric Courchesne, Corrado Romano, R. Frank Kooy, Raphael A. Bernier, Magnus Nordenskjöld, Jozef Gecz, Kun Xia, Larry S. Zweifel, Evan E. Eichler

Research output: Contribution to journal › Article › peer-review

129 Citations (Scopus)

Abstract

Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.

Original language	English
Pages (from-to)	1043-1051
Number of pages	9
Journal	Nature Neuroscience
Volume	20
Issue number	8
DOIs	https://doi.org/10.1038/nn.4589
Publication status	Published or Issued - 1 Aug 2017

ASJC Scopus subject areas

General Neuroscience

Access to Document

10.1038/nn.4589

Cite this

Geisheker, M. R., Heymann, G., Wang, T., Coe, B. P., Turner, T. N., Stessman, H. A. F., Hoekzema, K., Kvarnung, M., Shaw, M., Friend, K., Liebelt, J., Barnett, C., Thompson, E. M., Haan, E., Guo, H., Anderlid, B. M., Nordgren, A., Lindstrand, A., Vandeweyer, G., ... Eichler, E. E. (2017). Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Nature Neuroscience, 20(8), 1043-1051. https://doi.org/10.1038/nn.4589

@article{ac39ca0388d44b219ca2f34d80010fc0,

title = "Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains",

abstract = "Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.",

author = "Geisheker, {Madeleine R.} and Gabriel Heymann and Tianyun Wang and Coe, {Bradley P.} and Turner, {Tychele N.} and Stessman, {Holly A.F.} and Kendra Hoekzema and Malin Kvarnung and Marie Shaw and Kathryn Friend and Jan Liebelt and Christopher Barnett and Thompson, {Elizabeth M.} and Eric Haan and Hui Guo and Anderlid, {Britt Marie} and Ann Nordgren and Anna Lindstrand and Geert Vandeweyer and Antonino Alberti and Emanuela Avola and Mirella Vinci and Stefania Giusto and Tiziano Pramparo and Karen Pierce and Srinivasa Nalabolu and Michaelson, {Jacob J.} and Zdenek Sedlacek and Santen, {Gijs W.E.} and Hilde Peeters and Hakon Hakonarson and Eric Courchesne and Corrado Romano and Kooy, {R. Frank} and Bernier, {Raphael A.} and Magnus Nordenskj{\"o}ld and Jozef Gecz and Kun Xia and Zweifel, {Larry S.} and Eichler, {Evan E.}",

year = "2017",

month = aug,

day = "1",

doi = "10.1038/nn.4589",

language = "English",

volume = "20",

pages = "1043--1051",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Nature Research",

number = "8",

}

Geisheker, MR, Heymann, G, Wang, T, Coe, BP, Turner, TN, Stessman, HAF, Hoekzema, K, Kvarnung, M, Shaw, M, Friend, K, Liebelt, J, Barnett, C, Thompson, EM, Haan, E, Guo, H, Anderlid, BM, Nordgren, A, Lindstrand, A, Vandeweyer, G, Alberti, A, Avola, E, Vinci, M, Giusto, S, Pramparo, T, Pierce, K, Nalabolu, S, Michaelson, JJ, Sedlacek, Z, Santen, GWE, Peeters, H, Hakonarson, H, Courchesne, E, Romano, C, Kooy, RF, Bernier, RA, Nordenskjöld, M, Gecz, J, Xia, K, Zweifel, LS & Eichler, EE 2017, 'Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains', Nature Neuroscience, vol. 20, no. 8, pp. 1043-1051. https://doi.org/10.1038/nn.4589

TY - JOUR

T1 - Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains

AU - Geisheker, Madeleine R.

AU - Heymann, Gabriel

AU - Wang, Tianyun

AU - Coe, Bradley P.

AU - Turner, Tychele N.

AU - Stessman, Holly A.F.

AU - Hoekzema, Kendra

AU - Kvarnung, Malin

AU - Shaw, Marie

AU - Friend, Kathryn

AU - Liebelt, Jan

AU - Barnett, Christopher

AU - Thompson, Elizabeth M.

AU - Haan, Eric

AU - Guo, Hui

AU - Anderlid, Britt Marie

AU - Nordgren, Ann

AU - Lindstrand, Anna

AU - Vandeweyer, Geert

AU - Alberti, Antonino

AU - Avola, Emanuela

AU - Vinci, Mirella

AU - Giusto, Stefania

AU - Pramparo, Tiziano

AU - Pierce, Karen

AU - Nalabolu, Srinivasa

AU - Michaelson, Jacob J.

AU - Sedlacek, Zdenek

AU - Santen, Gijs W.E.

AU - Peeters, Hilde

AU - Hakonarson, Hakon

AU - Courchesne, Eric

AU - Romano, Corrado

AU - Kooy, R. Frank

AU - Bernier, Raphael A.

AU - Nordenskjöld, Magnus

AU - Gecz, Jozef

AU - Xia, Kun

AU - Zweifel, Larry S.

AU - Eichler, Evan E.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.

AB - Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.

UR - http://www.scopus.com/inward/record.url?scp=85026416277&partnerID=8YFLogxK

U2 - 10.1038/nn.4589

DO - 10.1038/nn.4589

M3 - Article

C2 - 28628100

AN - SCOPUS:85026416277

SN - 1097-6256

VL - 20

SP - 1043

EP - 1051

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 8

ER -

Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Cite this