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Published at www.nejm.org January 9, 2008 (10.1056/NEJMoa075974)

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ABSTRACT

Background Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role.

Methods As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland.

Results Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor.

Conclusions We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of 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. It will appear in the February 14 issue of the Journal.

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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