Reference database helps narrow list of mutations suspected in ASD

Autism spectrum disorder (ASD) is a group of complex conditions that can be heritable, or can stem from de novo mutations (single-letter alterations in the genetic code that are not inherited). While genetic sequencing studies have, in recent years, turned up many de novo mutations suspected of being associated with ASD, it has been unclear which of those mutations actually contribute to risk for the disorder.

This week in Nature Genetics, researchers from the Stanley Center for Psychiatric Research at Broad Institute, Harvard Medical School, and Massachusetts General Hospital report that they have winnowed the list of de novo candidates by cross-referencing the suspect mutations with those found in the Exome Aggregation Consortium (ExAC) database. The database, which was initially used to identify mutations responsible for rare genetic diseases, houses reference exomes (genetic sequencing readouts of the protein-coding regions of the genome)from over 60,000 healthy individuals.

The team, which was led by senior author Mark Daly and first author Jack Kosmicki, found that roughly one third of the de novo mutations previously associated with ASD, intellectual disability, or developmental delay are, in fact, found in the general population and thus do not contribute to neurodevelopmental risk. Eliminating these suspect mutations from subsequent analyses is helping to paint a clearer picture of genetic contributions to ASD. The work also shows the value of using large reference databases like ExAC to evaluate the potential pathogenicity of candidate mutations, even in complex diseases.