Exome Sequencing in Sporadic Autism Spectrum Disorders Identifies Severe De Novo Mutations

Published June 1, 2011 in Nature Genetics

Another study of spontaneous mutations identified four genes that are likely to play a causal role in the development of autism. Instead of searching more broadly for copy number variants throughout the genome, researchers focused exclusively on the protein-coding region of the genome called the exome. This approach has a greater potential to identify single candidate genes for ASD. The study sequenced the exomes of 20 people with autism and their parents and identified 21 spontaneous or de novomutations. Of the 21 mutations, four were determined to be potentially causative (FOXP1, GRIN2B, SCN1A, and LAMC3). Of note, the four participants carrying these mutations were profoundly affected by autism. Three of the four genes identified in the study had previously been associated with autism, intellectual disability without autism, and epilepsy. The fourth mutation, LAMC3, had never before been linked to autism and represents a potential new avenue of research. Within the study, two of the four children had been hit with a "genetic double-whammy" – both inheriting a harmful gene mutation from his parent and having a de novo mutation. For example, the child with a FOXP1 mutation also inherited a defective copy of CNTNAP2, believed to be involved in language development. This child had severe autism and the most profound language deficits of any participant. Another child with autism and epilepsy had both an inherited deletion putting him at risk for epilepsy and a de novo mutation of a gene associated with epilepsy, SCN1A. These two cases support the 'multi-hit' theory of autism – that a combination of mutations in the same pathway is necessary to cause severe autism or related disorders. The authors note that the study supports the role of de novo mutations as a major genetic contributor to autism and demonstrates the great potential of whole exome sequencing to identify candidate genes.

–IACC 2011 Summary of Advances in ASD Research


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