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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,5,6Tae-Kyung Kim,5,6Yingxi Lin,5,6Robert Sean Hill,1,2,4,5Nahit M. Mukaddes,7Soher Balkhy,8Generoso Gascon,8,9Asif Hashmi,10Samira Al-Saad,11Janice Ware,5,12Robert M. Joseph,5,13Rachel Greenblatt,1,2Danielle Gleason,1,2Julia A. Ertelt,1,2Kira A. Apse,1,2,5Adria Bodell,1,2Jennifer N. Partlow,1,2Brenda Barry,1,2Hui Yao,1Kyriacos Markianos,1Russell J. Ferland,14Michael E. Greenberg,5,6Christopher A. Walsh1,2,4,5
To find inherited causes of autism-spectrum disorders, we studiedfamilies in which parents share ancestors, enhancing the roleof inherited factors. We mapped several loci, some containinglarge, inherited, homozygous deletions that are likely mutations.The largest deletions implicated genes, including PCDH10 (protocadherin10) and DIA1 (deleted in autism1, or c3orf58), whose level ofexpression changes in response to neuronal activity, a markerof genes involved in synaptic changes that underlie learning.A subset of genes, including NHE9 (Na+/H+ exchanger 9), showedadditional potential mutations in patients with unrelated parents.Our findings highlight the utility of "homozygosity mapping"in heterogeneous disorders like autism but also suggest thatdefective regulation of gene expression after neural activitymay 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.
To whom correspondence should be addressed. E-mail: christopher.walsh{at}childrens.harvard.edu
To whom correspondence should be addressed. E-mail: 
