Association between microdeletion and microduplication at 16p11.2 and autism

Area of Science:

• Genetics
• Developmental Neuroscience
• Human Genomics

Background:

• Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic component.
• Chromosomal abnormalities are increasingly recognized as contributing factors to ASD etiology.
• Understanding the genetic underpinnings of ASD is crucial for diagnosis and potential interventions.

Purpose of the Study:

• To identify recurrent copy-number variations (CNVs) associated with autism spectrum disorder (ASD).
• To investigate the role of specific microdeletions and microduplications in ASD susceptibility.
• To assess the prevalence and penetrance of identified genetic variants in diverse populations.

Main Methods:

• Utilized novel algorithms for copy-number variation analysis in genotype data from 751 multiplex families with autism (Autism Genetic Resource Exchange - AGRE).
• Evaluated specific recurrent de novo events using clinical testing data and a large population study in Iceland.
• Employed comparative genomic hybridization to confirm deletions and duplications in independent cohorts.

Main Results:

• Identified a recurrent de novo deletion of 593 kb on chromosome 16p11.2 in five AGRE families.
• Confirmed the 16p11.2 deletion in children with developmental disorders and in an Icelandic autism cohort, with a low frequency in controls.
• Observed the reciprocal duplication of the 16p11.2 region in affected individuals across cohorts, indicating a high-penetrance risk factor.

Conclusions:

• Discovered a novel, recurrent microdeletion and reciprocal microduplication at 16p11.2 associated with substantial autism susceptibility.
• These genetic alterations account for approximately 1% of autism spectrum disorder cases.
• No other genomic regions showed similar aggregations of large de novo mutations in this study.