Abstract

Twin and family studies have shown that autism is approximately 90% heritable, and in about 10% of patients, the disorder can be explained by genetic syndromes and known chromosomal anomalies. The present study is an initial component of a genome-wide associational analysis of families from the Autism Genetic Resource Exchange (AGRE). Two novel algorithms were used to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Particular recurrent de novo events were further examined in clinical test data from Children's Hospital Boston and in a large population study carried out in Iceland. Among the AGRE families studied were 5 instances of a de novo deletion of 593 kb on chromosome 16p11.2. Comparative genomic hybridization studies demonstrated the identical deletion in 5 of 512 children referred to Children's Hospital Boston because of developmental delay, mental retardation, or suspected autism spectrum disorder. It was also observed in 3 of 299 individuals with autism in the Icelandic population. Two of 18,834 unscreened Icelandic control subjects also carried the deletion. The reciprocal duplication of this region was observed in 7 affected individuals in AGRE families and in 4 of the children from Children's Hospital. The duplication appeared to be a high-penetrance risk factor. The novel recurrent microdeletion and reciprocal microduplication identified in this study carry with them substantial susceptibility to autism, accounting for approximately 1% of cases. The lack of other notable recurrent events suggests that only a fraction of cases of familial idiopathic autism may be explained by large de novo copy-number mutations.