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

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• 作者：Michael  ; E. Talkowski¹ ; ⁵ ; ⁷ ; Jill  ; A. Rosenfeld⁸ ; Ian Blumenthal¹ ; Vamsee Pillalamarri¹ ; Colby Chiang¹ ; Adrian Heilbut¹ ; Carl Ernst¹ ; Carrie Hanscom¹ ; Elizabeth Rossin¹ ; ² ; ⁷ ; Amelia M. Lindgren⁹ ; Shahrin Pereira⁹ ; Douglas Ruderfer¹ ; ⁷ ; Andrew Kirby¹ ; ² ; ⁷ ; Stephan Ripke¹ ; ² ; ⁷ ; David J. Harris¹⁰ ; Ji-Hyun Lee¹ ; Kyungsoo Ha¹² ; Hyung-Goo Kim¹³ ; Benjamin  ; D. Solomon¹⁴ ; Andrea  ; L. Gropman¹⁵ ; ¹⁶ ; Diane Lucente¹ ; Katherine Sims¹ ; Toshiro  ; K. Ohsumi³ ; Mark  ; L. Borowsky³ ; Stephanie Loranger¹⁷ ; Bradley Quade⁴ ; Kasper Lage² ; ⁷ ; ¹⁸ ; ¹⁹ ; ²⁰ ; Judith Miles²¹ ; Bai-Lin Wu⁴ ; ¹¹ ; ²² ; Yiping Shen¹ ; ⁴ ; ¹¹ ; ²³ ; Benjamin Neale¹ ; ² ; ⁷ ; Lisa  ; G. Shaffer⁸ ; Mark  ; J. Daly¹ ; ² ; ⁷ ; ¹⁷ ; Cynthia  ; C. Morton⁷ ; ⁴ ; ⁹ ; James  ; F. Gusella¹ ; ⁶ ; ⁷ ; ¹⁷ ; ^{gusella@helix.mgh.harvard.edu}
• 刊名：Cell
• 出版年：2012
• 期刊代码：50_00928674
• 类别：med
• 出版时间：27 April, 2012
• 卷：149
• 期：3
• 页码：525-537
• 文件大小：1912 K

摘要

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Summary

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聽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.