Cell

, volume 149 , issue 3 , pages 525-537

Sequencing Chromosomal Abnormalities Reveals Neurodevelopmental Loci that Confer Risk across Diagnostic Boundaries

Michael E. Talkowski ¹

Marwan Shinawi ²

Ian Blumenthal ¹

Vamsee Pillalamarri ¹

Colby Chiang ¹

Adrian Heilbut ¹

Carl Ernst ¹

Carrie Hanscom ¹

Elizabeth J. Rossin ^{1, 3}

Amelia M. Lindgren ⁴

Shahrin Pereira ⁴

Douglas Ruderfer ^{1, 3}

Andrew Kirby ^{1, 3}

Stephan Ripke ^{1, 3}

David J Harris ⁵

Ji Hyun Lee ¹

Kyungsoo Ha ⁶

Hyung-Goo Kim ⁷

Benjamin D. Solomon ⁸

S. Ashwal ^{9, 10}

Diane Lucente ¹

K. Sims ¹

Toshiro K. Ohsumi ¹¹

Mark L Borowsky ¹¹

Stephanie Loranger ¹²

Bradley J. Quade ¹³

Kasper Lage ¹⁴

Judith H. Miles ¹⁵

Bai-Lin Wu ^{16, 17, 18}

Yiping Shen ¹

B. Neale ^{1, 3}

Lisa G. Shaffer ²

Mark J. Daly ¹

C.R. Morton ^{3, 4, 18}

J. F. Gusella ¹

Hide authors affiliations Show authors affiliations: 18 affiliations

Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA |

Signature Genomic Laboratories, PerkinElmer Inc, Spokane, WA 99207, USA. |

Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02143, USA |

⁴

Departments of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, MA 02115, USA |

⁵

Division of Clinical Genetics, Children's Hospital Boston, Boston, MA 02115, USA |

⁶

Cancer Research Center, Georgia Health Sciences University, Augusta, GA 30912, USA |

⁷

Department of Obstetrics and Gynecology, Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, GA 30912, USA |

⁸

Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA |

⁹

Department of Neurology, Children's National Medical Center, Washington, DC 20010, USA |

¹⁰

Department of Neurology, George Washington University of Health Sciences, Washington, DC 20052, USA |

¹¹

Department of Molecular Biology Massachusetts General Hospital, Boston, MA 02114, USA. |

¹²

Autism Consortium of Boston, Boston, MA 02115, USA |

¹³

Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. |

¹⁴

Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA |

¹⁵

Departments of Pediatrics, Medical Genetics and Pathology, The Thompson Center for Autism and Neurodevelopmental Disorders, University of Missouri Hospitals and Clinics, Columbia, MO 65201, USA |

¹⁶

Children's Hospital and Institutes of Biomedical Science, Fudan University, Shanghai 200032, China |

¹⁷

Department of Laboratory Medicine, Children's Hospital Boston, Boston, MA 02115, USA |

¹⁸

Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA |

Publication type: Journal Article

Publication date: 2012-04-19

Elsevier

Cell

scimago Q1

wos Q1

SJR: 22.612

CiteScore: 74.8

Impact factor: 42.5

ISSN: 00928674, 10974172

DOI: 10.1016/j.cell.2012.03.028

Copy DOI

PubMed ID: 22521361

General Biochemistry, Genetics and Molecular Biology

Abstract

Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.

Found

1 citation

Rodriguez Marliette

3 publications, 260 citations

h-index: 3

1 citation

Berry Alessandra

78 publications, 2 816 citations, 15 reviews

h-index: 29

Istituto Superiore di Sanità

Regina Elena National Cancer Institute

Top-30

Journals

	2 4 6 8 10 12 14 16 18
PLoS ONE	PLoS ONE, 17, 3.37% PLoS ONE 17 publications, 3.37%
American Journal of Medical Genetics, Part A	American Journal of Medical Genetics, Part A, 17, 3.37% American Journal of Medical Genetics, Part A 17 publications, 3.37%
Molecular Psychiatry	Molecular Psychiatry, 15, 2.97% Molecular Psychiatry 15 publications, 2.97%
Translational Psychiatry	Translational Psychiatry, 15, 2.97% Translational Psychiatry 15 publications, 2.97%
American Journal of Human Genetics	American Journal of Human Genetics, 15, 2.97% American Journal of Human Genetics 15 publications, 2.97%
Human Molecular Genetics	Human Molecular Genetics, 13, 2.57% Human Molecular Genetics 13 publications, 2.57%
Molecular Autism	Molecular Autism, 10, 1.98% Molecular Autism 10 publications, 1.98%
Frontiers in Cellular Neuroscience	Frontiers in Cellular Neuroscience, 8, 1.58% Frontiers in Cellular Neuroscience 8 publications, 1.58%
Scientific Reports	Scientific Reports, 8, 1.58% Scientific Reports 8 publications, 1.58%
Cell Reports	Cell Reports, 8, 1.58% Cell Reports 8 publications, 1.58%
European Journal of Human Genetics	European Journal of Human Genetics, 7, 1.39% European Journal of Human Genetics 7 publications, 1.39%
Nature Reviews Genetics	Nature Reviews Genetics, 7, 1.39% Nature Reviews Genetics 7 publications, 1.39%
Journal of Medical Genetics	Journal of Medical Genetics, 7, 1.39% Journal of Medical Genetics 7 publications, 1.39%
International Journal of Molecular Sciences	International Journal of Molecular Sciences, 6, 1.19% International Journal of Molecular Sciences 6 publications, 1.19%
Nature Genetics	Nature Genetics, 6, 1.19% Nature Genetics 6 publications, 1.19%
Human Genetics	Human Genetics, 6, 1.19% Human Genetics 6 publications, 1.19%
Neuron	Neuron, 6, 1.19% Neuron 6 publications, 1.19%
Nature Communications	Nature Communications, 5, 0.99% Nature Communications 5 publications, 0.99%
Journal of Neuroscience	Journal of Neuroscience, 5, 0.99% Journal of Neuroscience 5 publications, 0.99%
Nature Neuroscience	Nature Neuroscience, 4, 0.79% Nature Neuroscience 4 publications, 0.79%
European Journal of Medical Genetics	European Journal of Medical Genetics, 4, 0.79% European Journal of Medical Genetics 4 publications, 0.79%
Cell	Cell, 4, 0.79% Cell 4 publications, 0.79%
PLoS Genetics	PLoS Genetics, 4, 0.79% PLoS Genetics 4 publications, 0.79%
Trends in Genetics	Trends in Genetics, 4, 0.79% Trends in Genetics 4 publications, 0.79%
Neuroscience and Biobehavioral Reviews	Neuroscience and Biobehavioral Reviews, 4, 0.79% Neuroscience and Biobehavioral Reviews 4 publications, 0.79%
Clinical Genetics	Clinical Genetics, 4, 0.79% Clinical Genetics 4 publications, 0.79%
Complex Psychiatry	Complex Psychiatry, 3, 0.59% Complex Psychiatry 3 publications, 0.59%
Genes	Genes, 3, 0.59% Genes 3 publications, 0.59%
Frontiers in Synaptic Neuroscience	Frontiers in Synaptic Neuroscience, 3, 0.59% Frontiers in Synaptic Neuroscience 3 publications, 0.59%
	2 4 6 8 10 12 14 16 18

Publishers

	20 40 60 80 100 120 140
Springer Nature	Springer Nature, 132, 26.14% Springer Nature 132 publications, 26.14%
Elsevier	Elsevier, 112, 22.18% Elsevier 112 publications, 22.18%
Wiley	Wiley, 56, 11.09% Wiley 56 publications, 11.09%
Cold Spring Harbor Laboratory	Cold Spring Harbor Laboratory, 47, 9.31% Cold Spring Harbor Laboratory 47 publications, 9.31%
Frontiers Media S.A.	Frontiers Media S.A., 22, 4.36% Frontiers Media S.A. 22 publications, 4.36%
Public Library of Science (PLoS)	Public Library of Science (PLoS), 21, 4.16% Public Library of Science (PLoS) 21 publications, 4.16%
Oxford University Press	Oxford University Press, 21, 4.16% Oxford University Press 21 publications, 4.16%
MDPI	MDPI, 19, 3.76% MDPI 19 publications, 3.76%
BMJ	BMJ, 7, 1.39% BMJ 7 publications, 1.39%
Taylor & Francis	Taylor & Francis, 6, 1.19% Taylor & Francis 6 publications, 1.19%
Society for Neuroscience	Society for Neuroscience, 6, 1.19% Society for Neuroscience 6 publications, 1.19%
S. Karger AG	S. Karger AG, 5, 0.99% S. Karger AG 5 publications, 0.99%
The Company of Biologists	The Company of Biologists, 3, 0.59% The Company of Biologists 3 publications, 0.59%
The Endocrine Society	The Endocrine Society, 3, 0.59% The Endocrine Society 3 publications, 0.59%
SAGE	SAGE, 3, 0.59% SAGE 3 publications, 0.59%
American Association for the Advancement of Science (AAAS)	American Association for the Advancement of Science (AAAS), 3, 0.59% American Association for the Advancement of Science (AAAS) 3 publications, 0.59%
American Society for Clinical Investigation	American Society for Clinical Investigation, 2, 0.4% American Society for Clinical Investigation 2 publications, 0.4%
Ovid Technologies (Wolters Kluwer Health)	Ovid Technologies (Wolters Kluwer Health), 2, 0.4% Ovid Technologies (Wolters Kluwer Health) 2 publications, 0.4%
Georg Thieme Verlag KG	Georg Thieme Verlag KG, 2, 0.4% Georg Thieme Verlag KG 2 publications, 0.4%
Cambridge University Press	Cambridge University Press, 2, 0.4% Cambridge University Press 2 publications, 0.4%
Hindawi Limited	Hindawi Limited, 2, 0.4% Hindawi Limited 2 publications, 0.4%
Proceedings of the National Academy of Sciences (PNAS)	Proceedings of the National Academy of Sciences (PNAS), 2, 0.4% Proceedings of the National Academy of Sciences (PNAS) 2 publications, 0.4%
Annual Reviews	Annual Reviews, 2, 0.4% Annual Reviews 2 publications, 0.4%
American Psychiatric Association Publishing	American Psychiatric Association Publishing, 1, 0.2% American Psychiatric Association Publishing 1 publication, 0.2%
EDP Sciences	EDP Sciences, 1, 0.2% EDP Sciences 1 publication, 0.2%
American Academy of Pediatrics	American Academy of Pediatrics, 1, 0.2% American Academy of Pediatrics 1 publication, 0.2%
F1000 Research	F1000 Research, 1, 0.2% F1000 Research 1 publication, 0.2%
Impact Journals	Impact Journals, 1, 0.2% Impact Journals 1 publication, 0.2%
Massachusetts Medical Society	Massachusetts Medical Society, 1, 0.2% Massachusetts Medical Society 1 publication, 0.2%
	20 40 60 80 100 120 140

We do not take into account publications without a DOI.
Statistics recalculated weekly.

Are you a researcher?

Create a profile to get free access to personal recommendations for colleagues and new articles.

Metrics

505

Cite this

GOST |

Cite this

GOST Copy

Talkowski M. E. et al. Sequencing Chromosomal Abnormalities Reveals Neurodevelopmental Loci that Confer Risk across Diagnostic Boundaries // Cell. 2012. Vol. 149. No. 3. pp. 525-537.

GOST all authors (up to 50) Copy

Talkowski M. E., Shinawi M., Blumenthal I., Pillalamarri V., Chiang C., Heilbut A., Ernst C., Hanscom C., Rossin E. J., Lindgren A. M., Pereira S., Ruderfer D., Kirby A., Ripke S., Harris D. J., Lee J. H., Ha K., Kim H., Solomon B. D., Ashwal S., Lucente D., Sims K., Ohsumi T. K., Borowsky M. L., Loranger S., Quade B. J., Lage K., Miles J. H., Wu B., Shen Y., Neale B., Shaffer L. G., Daly M. J., Morton C., Gusella J. F. Sequencing Chromosomal Abnormalities Reveals Neurodevelopmental Loci that Confer Risk across Diagnostic Boundaries // Cell. 2012. Vol. 149. No. 3. pp. 525-537.

RIS |

Cite this

RIS Copy

TY - JOUR

DO - 10.1016/j.cell.2012.03.028

UR - https://doi.org/10.1016/j.cell.2012.03.028

TI - Sequencing Chromosomal Abnormalities Reveals Neurodevelopmental Loci that Confer Risk across Diagnostic Boundaries

T2 - Cell

AU - Talkowski, Michael E.

AU - Shinawi, Marwan

AU - Blumenthal, Ian

AU - Pillalamarri, Vamsee

AU - Chiang, Colby

AU - Heilbut, Adrian

AU - Ernst, Carl

AU - Hanscom, Carrie

AU - Rossin, Elizabeth J.

AU - Lindgren, Amelia M.

AU - Pereira, Shahrin

AU - Ruderfer, Douglas

AU - Kirby, Andrew

AU - Ripke, Stephan

AU - Harris, David J

AU - Lee, Ji Hyun

AU - Ha, Kyungsoo

AU - Kim, Hyung-Goo

AU - Solomon, Benjamin D.

AU - Ashwal, S.

AU - Lucente, Diane

AU - Sims, K.

AU - Ohsumi, Toshiro K.

AU - Borowsky, Mark L

AU - Loranger, Stephanie

AU - Quade, Bradley J.

AU - Lage, Kasper

AU - Miles, Judith H.

AU - Wu, Bai-Lin

AU - Shen, Yiping

AU - Neale, B.

AU - Shaffer, Lisa G.

AU - Daly, Mark J.

AU - Morton, C.R.

AU - Gusella, J. F.

PY - 2012

DA - 2012/04/19

PB - Elsevier

SP - 525-537

IS - 3

VL - 149

PMID - 22521361

SN - 0092-8674

SN - 1097-4172

ER -

BibTex |

Cite this

BibTex (up to 50 authors) Copy

@article{2012_Talkowski,

author = {Michael E. Talkowski and Marwan Shinawi and Ian Blumenthal and Vamsee Pillalamarri and Colby Chiang and Adrian Heilbut and Carl Ernst and Carrie Hanscom and Elizabeth J. Rossin and Amelia M. Lindgren and Shahrin Pereira and Douglas Ruderfer and Andrew Kirby and Stephan Ripke and David J Harris and Ji Hyun Lee and Kyungsoo Ha and Hyung-Goo Kim and Benjamin D. Solomon and S. Ashwal and Diane Lucente and K. Sims and Toshiro K. Ohsumi and Mark L Borowsky and Stephanie Loranger and Bradley J. Quade and Kasper Lage and Judith H. Miles and Bai-Lin Wu and Yiping Shen and B. Neale and Lisa G. Shaffer and Mark J. Daly and C.R. Morton and J. F. Gusella},

title = {Sequencing Chromosomal Abnormalities Reveals Neurodevelopmental Loci that Confer Risk across Diagnostic Boundaries},

journal = {Cell},

year = {2012},

volume = {149},

publisher = {Elsevier},

month = {apr},

url = {https://doi.org/10.1016/j.cell.2012.03.028},

number = {3},

pages = {525--537},

doi = {10.1016/j.cell.2012.03.028}

}

MLA

Cite this

MLA Copy

Talkowski, Michael E., et al. “Sequencing Chromosomal Abnormalities Reveals Neurodevelopmental Loci that Confer Risk across Diagnostic Boundaries.” Cell, vol. 149, no. 3, Apr. 2012, pp. 525-537. https://doi.org/10.1016/j.cell.2012.03.028.

Publisher

Elsevier

Journal

Cell

scimago Q1

wos Q1

SJR

22.612

CiteScore

74.8

Impact factor

42.5

ISSN

00928674 (Print)

10974172 (Electronic)