Association between Microdeletion and Microduplication at 16p11.2 and Autism
Lauren A. Weiss, Ph.D., Yiping Shen, Ph.D., Joshua M. Korn, B.S., Dan E. Arking, Ph.D., David T. Miller, M.D., Ph.D., Ragnheidur Fossdal, B.Sc., Evald Saemundsen, B.A., Hreinn Stefansson, Ph.D., Manuel A.R. Ferreira, Ph.D., Todd Green, B.S., Orah S. Platt, M.D., Douglas M. Ruderfer, M.S., Christopher A. Walsh, M.D., Ph.D., David Altshuler, M.D., Ph.D., Aravinda Chakravarti, Ph.D., Rudolph E. Tanzi, Ph.D., Kari Stefansson, M.D., Ph.D., Susan L. Santangelo, Sc.D., James F. Gusella, Ph.D., Pamela Sklar, M.D., Ph.D., Bai-Lin Wu, M.Med., Ph.D., Mark J. Daly, Ph.D., for the Autism Consortium
Background Autism spectrum disorder is a heritable developmentaldisorder in which chromosomal abnormalities are thought to playa role.
Methods As a first component of a genomewide association studyof families from the Autism Genetic Resource Exchange (AGRE),we used two novel algorithms to search for recurrent copy-numbervariations in genotype data from 751 multiplex families withautism. Specific recurrent de novo events were further evaluatedin clinical-testing data from Children's Hospital Boston andin a large population study in Iceland.
Results Among the AGRE families, we observed five instancesof a de novo deletion of 593 kb on chromosome 16p11.2. Usingcomparative genomic hybridization, we observed the identicaldeletion in 5 of 512 children referred to Children's HospitalBoston for developmental delay, mental retardation, or suspectedautism spectrum disorder, as well as in 3 of 299 persons withautism in an Icelandic population; the deletion was also carriedby 2 of 18,834 unscreened Icelandic control subjects. The reciprocalduplication of this region occurred in 7 affected persons inAGRE families and 4 of the 512 children from Children's HospitalBoston. The duplication also appeared to be a high-penetrancerisk factor.
Conclusions We have identified a novel, recurrent microdeletionand a reciprocal microduplication that carry substantial susceptibilityto autism and appear to account for approximately 1% of cases.We did not identify other regions with similar aggregationsof large de novo mutations.
Source Information
The authors' affiliations and the members of the Autism Consortium and the Autism Genetic Resource Exchange are listed in the Appendix. This article (10.1056/NEJMoa075974) was published at www.nejm.org on January 9, 2008.
Address reprint requests to Dr. Daly at the Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge St., Boston, MA 02114, or at mjdaly{at}chgr.mgh.harvard.edu.
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