Simons Simplex Collection Genetics Consortium (SSCGC)
There is substantial evidence that a significant portion of autism is caused by mutations that alter copy number for genomic regions and for the genes in these regions. These copy number variation (CNV) mutations are usually recent in origin in a family and often are de novo in the child and not present in the parents.
Although these mutations could mediate their effect through regions outside of protein coding genes such as microRNAs and regulatory sequences, the majority of the CNV mutations probably produce their harmful effects through altered levels of expression of dosage-sensitive protein coding genes. In the case of gene deletions causing autism, it is virtually certain that loss of function point mutations in these same genes would cause autism as well.
For these reasons, it is logical to focus genomic copy number analysis on protein coding genes, and even more specifically on each of the exons for such genes. This has the advantage of detecting smaller CNVs that involve only one gene or even one or a few exons within a gene.
Preliminary results demonstrate the feasibility of designing an Agilent oligonucleotide array with 1 million features using six oligos per exon (three oligos using both strands) for >95% of the exons in the genome. Preliminary results also show the feasibility of detecting small CNVs not detected by existing genome-wide arrays that will be used for the initial studies of the Simons Simplex Collection (SSC) of autism families.
This pilot project will examine 100 trios (patient and parents) from the SSC. The number of de novo events per trio and the genic location of these events will be determined. Inherited CNVs in the patients will be compared to those occurring in the non-transmitted chromosomes of the parents, to the results of the study of the same families using Nimblegen and Illumina arrays, and to available databases where feasible.
Relevance of the project to IDDRC mission:
Autism is one of the most common causes of serious childhood disabilities, and this project is directly involved in efforts to identify genetic and epigenetic causes of autism.