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Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia |
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| Authors: | Moreno-De-Luca Daniel;SGENE Consortium Mulle Jennifer G;Simons Simplex Collection Genetics Consortium Kaminsky Erin B Sanders Stephan J;GeneSTAR Myers Scott M Adam Margaret P Pakula Amy T Eisenhauer Nancy J Uhas Kim Weik LuAnn Guy Lisa Care Melanie E Morel Chantal F Boni Charlotte Salbert Bonnie Anne Chandrareddy Ashadeep Demmer Laurie A Chow Eva W C Surti Urvashi Aradhya Swaroop Pickering Diane L Golden Denae M Sanger Warren G Aston Emily Brothman Arthur R Gliem Troy J Thorland Erik C Ackley Todd Iyer Ram Huang Shuwen Barber John C Crolla John A Warren Stephen T Martin Christa L |
| Institution: | 1 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA 2 Child Study Center, Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA 3 Geisinger Medical Center, Danville, PA 17821, USA 4 Marcus Autism Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30329, USA 5 Children's Hospital of Wisconsin, Milwaukee, WI 53233, USA 6 Fred A. Litwin Family Centre in Genetic Medicine, University Health Network & Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada 7 Division of Genetics, Tufts Medical Center, Boston, MA 02111, USA 8 Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario M6J 1H4, Canada 9 University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA 10 GeneDx, Gaithersburg, MD 20877, USA 11 Human Genetics Laboratory, University of Nebraska Medical Center, Omaha, NE 68102, USA 12 ARUP Laboratories, University of Utah, Salt Lake City, UT 84108, USA 13 Mayo Clinic, Rochester, MN 55905, USA 14 Michigan Medical Genetics Laboratories, Ann Arbor, MI 48109, USA 15 Salisbury NHS Foundation Trust, Wessex Regional Genetics Laboratory, Salisbury SP2 8BJ, UK 16 Departments of Pediatrics and Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA |
| Abstract: | Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10?5). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only. |
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