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Science 11 July 2008:
Vol. 321. no. 5886, pp. 218 - 223
DOI: 10.1126/science.1157657
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Research Articles

Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry

Eric M. Morrow,1,2,3,4,5* Seung-Yun Yoo,1,2,4,5* Steven W. Flavell,5,6 Tae-Kyung Kim,5,6 Yingxi Lin,5,6 Robert Sean Hill,1,2,4,5 Nahit M. Mukaddes,7 Soher Balkhy,8 Generoso Gascon,8,9 Asif Hashmi,10 Samira Al-Saad,11 Janice Ware,5,12 Robert M. Joseph,5,13 Rachel Greenblatt,1,2 Danielle Gleason,1,2 Julia A. Ertelt,1,2 Kira A. Apse,1,2,5 Adria Bodell,1,2 Jennifer N. Partlow,1,2 Brenda Barry,1,2 Hui Yao,1 Kyriacos Markianos,1 Russell J. Ferland,14 Michael E. Greenberg,5,6 Christopher A. Walsh1,2,4,5{dagger}

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.

1 Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
2 Department of Neurology and Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
3 Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA.
4 Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
5 Autism Consortium, 10 Shattuck Street, Boston, MA 02115, USA.
6 F. M. Kirby Neurobiology Center, Children's Hospital Boston, and Departments of Neurology and Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
7 Department of Child Psychiatry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
8 Department of Neurosciences and Pediatrics, King Faisal Specialist Hospital and Research Centre, Jeddah, Kingdom of Saudi Arabia.
9 Clinical Neurosciences and Pediatrics, Brown University School of Medicine, Providence, Rhode Island 02912, USA.
10 Department of Neurology, Combined Military Hospital, Lahore, Pakistan.
11 Kuwait Center for Autism, Kuwait City, Kuwait.
12 Developmental Medicine Center, Children's Hospital Boston, Boston, MA 02115, USA.
13 Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA.
14 Department of Biology, Rensselaer Polytechnic Institute, Troy, NY 12180–3590, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: christopher.walsh{at}childrens.harvard.edu

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