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A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia
Published on: June 15, 2011
Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders
Brian J O'Roak1, Laura Vives, Wenqing Fu
1Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Science (New York, N.Y.)
|November 20, 2012
Summary
Researchers identified key genes linked to autism spectrum disorder (ASD) using a cost-effective sequencing method. This study highlights specific gene mutations contributing to ASD and associated subphenotypes.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- Exome sequencing studies for autism spectrum disorders (ASDs) have revealed numerous de novo mutations but few recurrently disrupted genes.
- Identifying recurrently disrupted genes is crucial for understanding ASD etiology and developing targeted interventions.
Purpose of the Study:
- To develop and apply an ultra-low-cost candidate gene resequencing method for large cohorts.
- To identify novel genes and genetic variants associated with autism spectrum disorders.
Main Methods:
- A modified molecular inversion probe method was developed for cost-effective resequencing.
- 44 candidate genes were captured and sequenced in a cohort of 2446 ASD probands.
Main Results:
- 27 de novo events were discovered across 16 genes, with 59% predicted to impact protein function or splicing.
- Recurrent disruptive mutations in six genes (CHD8, DYRK1A, GRIN2B, TBR1, PTEN, TBL1XR1) may account for 1% of sporadic ASDs.
- Associations between specific genes and subphenotypes (e.g., CHD8-macrocephaly, DYRK1A-microcephaly) were supported.
Conclusions:
- The developed method enables efficient, large-scale genetic studies for complex disorders like ASD.
- Specific genes, including CHD8 and DYRK1A, are strongly implicated in ASD etiology and associated with distinct subphenotypes.
- The findings reinforce the role of a β-catenin-chromatin-remodeling network in ASD development.
