Autism: New Mutations, Genes, and Pathways

In this lecture, Evan Eichler, PhD, will summarize his laboratory’s recent finding regarding the discovery of rare, large copy number variants (CNVs) and their contribution to autism spectrum disorder (ASD) and intellectual disability (ID). His team’s analysis of more than 2500 children with ASD and 30,000 children with ID suggests that between 8 and 14 percent of disease is caused by deletions and duplications of large segments of the genome involving multiple genes. These mutations can be either inherited or found in the parents of children depending on the size of the event. Dr. Eichler will present evidence from exome and molecular inversion probe sequencing of more than 2000 parent-child trios with sporadic autism and show how these data may be used to pinpoint novel genes underlying CNV burden as well as provide insight into new pathways. Re-contact and follow-up of patients with the same de novo mutation shows, in some cases, striking similarities with respect to the phenotype. In other cases, Dr. Eichler’s group finds that some of the same “disease-causing” mutations can manifest very differently and, in particular, be more severe if they occur on a background of other compounding mutations. They also find that both de novo mutations and inherited SNV and CNV mutations are contributing to simplex autism. They predict that the overall burden of rare and private gene-disruptive mutations will correlate with different outcomes. Dr. Eichler and his colleagues propose that the early development of the brain is particularly sensitive to the timing and expression of many different genes and that multiple genetic perturbations within specific pathways can lead to disease with varying severity.