Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries
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Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. / Talkowski, Michael E; Rosenfeld, Jill A; Blumenthal, Ian; Pillalamarri, Vamsee; Chiang, Colby; Heilbut, Adrian; Ernst, Carl; Hanscom, Carrie; Rossin, Elizabeth; Lindgren, Amelia M; Pereira, Shahrin; Ruderfer, Douglas; Kirby, Andrew; Ripke, Stephan; Harris, David J; Lee, Ji-Hyun; Ha, Kyungsoo; Kim, Hyung-Goo; Solomon, Benjamin D; Gropman, Andrea L; Lucente, Diane; Sims, Katherine; Ohsumi, Toshiro K; Borowsky, Mark L; Loranger, Stephanie; Quade, Bradley; Hansen, Kasper Lage; Miles, Judith; Wu, Bai-Lin; Shen, Yiping; Neale, Benjamin; Shaffer, Lisa G; Daly, Mark J; Morton, Cynthia C; Gusella, James F.
In: Cell, Vol. 149, No. 3, 27.04.2012, p. 525-37.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
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
N1 - Copyright © 2012 Elsevier Inc. All rights reserved.
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
VL - 149
SP - 525
EP - 537
JO - Cell
JF - Cell
SN - 0092-8674
IS - 3
ER -
ID: 144042440