Journal
CELL
Volume 149, Issue 3, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.cell.2012.03.028
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Funding
- National Institutes of Health [GM061354, HD065286]
- Simons Foundation Autism Research Initiative
- Autism Speaks
- Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health and Human Services
- National Institute of Mental Health National Research Service [MH087123]
- Massachusetts General Hospital Executive Committee
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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.
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