Copy number variation, exome sequencing and the variability in neurological disease

Abstract

We present a detailed study of the genomes of children with developmental delay compared to adult controls and show that as much as 14% of paediatric disease, including autism, epilepsy and intellectual disability, 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. I will present evidence from exome sequencing of over 200 parent–child trios with sporadic autism and show how these data may be used to pinpoint novel genes underlying copy number variation (CNV) burden as well as provide insight into new pathways. We find 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. We predict that the overall burden of rare and private severe mutations will correlate with different outcomes ranging from autism, intellectual disability and epilepsy. We 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.