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Abstract

To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of “homozygosity mapping” in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.

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We are grateful to the families who participated in this study. We also thank C. Lord for advice on phenotyping; D. Altshuler, M. Daly, and C. Lee for helpful discussions; C. Seidman, J. Seidman, and D. Housman for sharing control DNA; K. Allen, S. Tzakas, and C. Austin for technical assistance; and members of the Program in Medical and Populations Genetics at the Broad Institute, the Autism Consortium, and the Walsh laboratory for helpful discussions. We gratefully acknowledge the National Center for Research Resources Broad Institute Center for Genotyping and Analysis for expert design and execution of the SNP genotyping reported herein and the resources provided by the AGRE Consortium. AGRE is a program of Cure Autism Now (CAN) and is supported, in part, by grant MH64547 from the National Institute of Mental Health to Daniel H. Geschwind (PI). Genotyping services were also provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number N01-HG-65403. We are grateful for support from CAN, the Nancy Lurie Marks Family Foundation, the Simons Foundation, the Harvard Kuwait Project, the Developmental Disabilities Research Center of Children's Hospital Boston (5P30HD018655-26), the Clinical Investigator Training Program of Harvard and Massachusetts Institute of Technology in collaboration with Pfizer Inc. and Merck & Co., the Anne and Paul Marcus Foundation, the Charles H. Hood Foundation, and NIH (1K23MH080954-01 to E.M.M, 1R01 MH083565 to C.A.W., 1K01MH71801 to R.J.F., and 5R01NS048276-05 to M.E.G.). E.M.M. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund and is also grateful for support from the Rappaport Research Scholarship in Neuroscience at Massachusetts General Hospital. S.-Y.Y. is a postdoctoral fellow of the National Alliance for Autism Research. M.E.G. is grateful for support from the F. M. Kirby Foundation. C.A.W. is an Investigator of the Howard Hughes Medical Institute.

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Science
Volume 321 | Issue 5886
11 July 2008

Submission history

Received: 11 March 2008
Accepted: 12 May 2008
Published in print: 11 July 2008

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Notes

Supporting Online Material
Methods Figs. S1 to S3
Tables S1 to S7
References

Authors

Affiliations

Eric M. Morrow*
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology and Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA.
Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Autism Consortium, 10 Shattuck Street, Boston, MA 02115, USA.
Seung-Yun Yoo*
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology and Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Autism Consortium, 10 Shattuck Street, Boston, MA 02115, USA.
Steven W. Flavell
Autism Consortium, 10 Shattuck Street, Boston, MA 02115, USA.
F. M. Kirby Neurobiology Center, Children's Hospital Boston, and Departments of Neurology and Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Tae-Kyung Kim
Autism Consortium, 10 Shattuck Street, Boston, MA 02115, USA.
F. M. Kirby Neurobiology Center, Children's Hospital Boston, and Departments of Neurology and Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Yingxi Lin
Autism Consortium, 10 Shattuck Street, Boston, MA 02115, USA.
F. M. Kirby Neurobiology Center, Children's Hospital Boston, and Departments of Neurology and Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Robert Sean Hill
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology and Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Autism Consortium, 10 Shattuck Street, Boston, MA 02115, USA.
Nahit M. Mukaddes
Department of Child Psychiatry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Soher Balkhy
Department of Neurosciences and Pediatrics, King Faisal Specialist Hospital and Research Centre, Jeddah, Kingdom of Saudi Arabia.
Generoso Gascon
Department of Neurosciences and Pediatrics, King Faisal Specialist Hospital and Research Centre, Jeddah, Kingdom of Saudi Arabia.
Clinical Neurosciences and Pediatrics, Brown University School of Medicine, Providence, Rhode Island 02912, USA.
Asif Hashmi
Department of Neurology, Combined Military Hospital, Lahore, Pakistan.
Samira Al-Saad
Kuwait Center for Autism, Kuwait City, Kuwait.
Janice Ware
Autism Consortium, 10 Shattuck Street, Boston, MA 02115, USA.
Developmental Medicine Center, Children's Hospital Boston, Boston, MA 02115, USA.
Robert M. Joseph
Autism Consortium, 10 Shattuck Street, Boston, MA 02115, USA.
Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA.
Rachel Greenblatt
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology and Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Danielle Gleason
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology and Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Julia A. Ertelt
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology and Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Kira A. Apse
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology and Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Autism Consortium, 10 Shattuck Street, Boston, MA 02115, USA.
Adria Bodell
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology and Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Jennifer N. Partlow
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology and Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Brenda Barry
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology and Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Hui Yao
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Kyriacos Markianos
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Russell J. Ferland
Department of Biology, Rensselaer Polytechnic Institute, Troy, NY 12180–3590, USA.
Michael E. Greenberg
Autism Consortium, 10 Shattuck Street, Boston, MA 02115, USA.
F. M. Kirby Neurobiology Center, Children's Hospital Boston, and Departments of Neurology and Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Christopher A. Walsh†
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology and Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Autism Consortium, 10 Shattuck Street, Boston, MA 02115, USA.

Notes

†
To whom correspondence should be addressed. E-mail: [email protected]

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