Association between Microdeletion and Microduplication at 16p11.2 and Autism

TLDR

Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role. Using two novel algorithms, the authors performed a genome‑wide association study on 751 multiplex autism families from the Autism Genetic Resource Exchange, then evaluated recurrent de novo copy‑number variations in clinical data from Children’s Hospital Boston and a large Icelandic population study. Recurrent microdeletion and reciprocal microduplication at 16p11.2 were identified, each occurring in multiple AGRE families, Boston children, and Icelandic cohorts, with the duplication showing high penetrance and together accounting for about 1 % of autism cases, while no other loci displayed similar mutation aggregation.

Abstract

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