Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries

Michael E Talkowski; Jill A Rosenfeld; Ian Blumenthal; Vamsee Pillalamarri; Colby Chiang; Adrian Heilbut; Carl Ernst; Carrie Hanscom; Elizabeth Rossin; Amelia M Lindgren; Shahrin Pereira; Douglas Ruderfer; Andrew Kirby; Stephan Ripke; David J Harris; Ji-Hyun Lee; Kyungsoo Ha; Hyung-Goo Kim; Benjamin D Solomon; Andrea L Gropman; Diane Lucente; Katherine Sims; Toshiro K Ohsumi; Mark L Borowsky; Stephanie Loranger; Bradley Quade; Kasper Lage Hansen; Judith Miles; Bai-Lin Wu; Yiping Shen; Benjamin Neale; Lisa G Shaffer; Mark J Daly; Cynthia C Morton; James F Gusella

doi:10.1016/j.cell.2012.03.028

Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries

Michael E Talkowski, Jill A Rosenfeld, Ian Blumenthal, Vamsee Pillalamarri, Colby Chiang, Adrian Heilbut, Carl Ernst, Carrie Hanscom, Elizabeth Rossin, Amelia M Lindgren, Shahrin Pereira, Douglas Ruderfer, Andrew Kirby, Stephan Ripke, David J Harris, Ji-Hyun Lee, Kyungsoo Ha, Hyung-Goo Kim, Benjamin D Solomon, Andrea L GropmanDiane Lucente, Katherine Sims, Toshiro K Ohsumi, Mark L Borowsky, Stephanie Loranger, Bradley Quade, Kasper Lage Hansen, Judith Miles, Bai-Lin Wu, Yiping Shen, Benjamin Neale, Lisa G Shaffer, Mark J Daly, Cynthia C Morton, James F Gusella

374 Citations (Scopus)

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.

Original language	English
Journal	Cell
Volume	149
Issue number	3
Pages (from-to)	525-37
Number of pages	13
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2012.03.028
Publication status	Published - 27 Apr 2012

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Talkowski, M. E., Rosenfeld, J. A., Blumenthal, I., Pillalamarri, V., Chiang, C., Heilbut, A., Ernst, C., Hanscom, C., Rossin, E., Lindgren, A. M., Pereira, S., Ruderfer, D., Kirby, A., Ripke, S., Harris, D. J., Lee, J-H., Ha, K., Kim, H-G., Solomon, B. D., ... Gusella, J. F. (2012). Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell, 149(3), 525-37. https://doi.org/10.1016/j.cell.2012.03.028

Talkowski, ME, Rosenfeld, JA, Blumenthal, I, Pillalamarri, V, Chiang, C, Heilbut, A, Ernst, C, Hanscom, C, Rossin, E, Lindgren, AM, Pereira, S, Ruderfer, D, Kirby, A, Ripke, S, Harris, DJ, Lee, J-H, Ha, K, Kim, H-G, Solomon, BD, Gropman, AL, Lucente, D, Sims, K, Ohsumi, TK, Borowsky, ML, Loranger, S, Quade, B, Hansen, KL, Miles, J, Wu, B-L, Shen, Y, Neale, B, Shaffer, LG, Daly, MJ, Morton, CC & Gusella, JF 2012, 'Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries', Cell, vol. 149, no. 3, pp. 525-37. https://doi.org/10.1016/j.cell.2012.03.028

@article{7569eb1973ca450ba3806d89c3c52b64,

title = "Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries",

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.",

keywords = "Autistic Disorder, Child, Child Development Disorders, Pervasive, Chromosome Aberrations, Chromosome Breakage, Chromosome Deletion, DNA Copy Number Variations, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Nervous System, Schizophrenia, Sequence Analysis, DNA, Signal Transduction",

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

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doi = "10.1016/j.cell.2012.03.028",

language = "English",

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T1 - Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries

AU - Talkowski, Michael E

AU - Rosenfeld, Jill A

AU - Blumenthal, Ian

AU - Pillalamarri, Vamsee

AU - Chiang, Colby

AU - Heilbut, Adrian

AU - Ernst, Carl

AU - Hanscom, Carrie

AU - Rossin, Elizabeth

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 - Gropman, Andrea L

AU - Lucente, Diane

AU - Sims, Katherine

AU - Ohsumi, Toshiro K

AU - Borowsky, Mark L

AU - Loranger, Stephanie

AU - Quade, Bradley

AU - Hansen, Kasper Lage

AU - Miles, Judith

AU - Wu, Bai-Lin

AU - Shen, Yiping

AU - Neale, Benjamin

AU - Shaffer, Lisa G

AU - Daly, Mark J

AU - Morton, Cynthia C

AU - Gusella, James F

PY - 2012/4/27

Y1 - 2012/4/27

N2 - 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.

AB - 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.

KW - Autistic Disorder

KW - Child

KW - Child Development Disorders, Pervasive

KW - Chromosome Aberrations

KW - Chromosome Breakage

KW - Chromosome Deletion

KW - DNA Copy Number Variations

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Nervous System

KW - Schizophrenia

KW - Sequence Analysis, DNA

KW - Signal Transduction

U2 - 10.1016/j.cell.2012.03.028

DO - 10.1016/j.cell.2012.03.028

M3 - Journal article

C2 - 22521361

SN - 0092-8674

VL - 149

SP - 525

EP - 537

JO - Cell

JF - Cell

IS - 3

ER -

Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries

Abstract

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