|
|||||
|
|
Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries |
|
| Authors: | 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 Lage Kasper Miles Judith Wu Bai-Lin Shen Yiping Neale Benjamin Shaffer Lisa G Daly Mark J Morton Cynthia C Gusella James F |
| Affiliation: | 1 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA 2 Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA 3 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA 4 Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA 5 Department of Neurology, Harvard Medical School, Boston, MA 02115, USA 6 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA 7 Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02143, USA 8 Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, WA 99207, USA 9 Departments of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, MA 02115, USA 10 Division of Clinical Genetics, Children's Hospital Boston, Boston, MA 02115, USA 11 Department of Laboratory Medicine, Children's Hospital Boston, Boston, MA 02115, USA 12 Cancer Research Center, Georgia Health Sciences University, Augusta, GA 30912, USA 13 Department of Obstetrics and Gynecology, Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, GA 30912, USA 14 Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA 15 Department of Neurology, Children's National Medical Center, Washington, DC 20010, USA 16 Department of Neurology, George Washington University of Health Sciences, Washington, DC 20052, USA 17 Autism Consortium of Boston, Boston, MA 02115, USA 18 Pediatric Surgical Research Laboratories, MassGeneral Hospital for Children, Massachusetts General Hospital, Boston, MA 02114, USA 19 Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark 20 Center for Protein Research, University of Copenhagen, 1165 Copenhagen, Denmark 21 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 22 Children's Hospital and Institutes of Biomedical Science, Fudan University, Shanghai 200032, China 23 Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China |
| 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: | |
| 本文献已被 ScienceDirect PubMed 等数据库收录！ | |