Identifying Autism Susceptibility Genes By High-Throughput Chip Resequencing (Principle Investigator)
The four-fold excess of affected males with autism and genetic linkage findings strongly suggests a role for X-linked genes. Approximately 20% of patients with Fragile X syndrome, a disorder cause by a trinucleotide repeat sequence at FMR1, exhibit symptoms consistent with the DMS IV diagnosis of autism. In spite of this evidence for the role of FMR1 as a cause or genetic modifier contributing to autism, the gene has not been comprehensively resequenced in any large patient populations. We are conducting high-throughput, highly accurate microarray-based resequencing of a 270kb X chromosome region that includes the FMR1 and FMR2 genes among a large collection of male affected sibpairs (cases) from the Autism Genetic Resource Exchange (AGRE) sample collection and controls. Developing methods and analyzing the dense resequencing datasets we produce is also a goal of this project. Our ultimate aim is to identify genetic variants that either cause or act as susceptibility alleles in the development of autism.
Resequence All Unique X Chromosome Exons to Identify Genetic Variants Contributing to Autism Susceptibility (Project 2)
This project is part of a larger program project grant obtained in collaboration with Dr. Stephen T. Warren. The goals of project aims to either identify of rule out X-linked coding genetic variants as contributing factors to autism susceptibility. The goals of this proposal are (1) Comprehensively resequence all unique exons on the X chromosome in 330 males with autism (~ 703 MB of total DNA sequence generated) using samples obtained from the Simons Simplex Collection, (2) Functionally annotate and determine the extent of DNA sequence conservation for all rare and common genetic variants discovered. Usingin silico analysis, we will prioritize genetic variants observed relative to potential autism susceptibility, and (3) Using a ranked list of prioritized X-chromosome SNPs, we will develop simple, high-throughput genotyping assays and assess a larger collection of autism samples derived from the remainder of the Autism Genetic Resource Exchange (AGRE) collection and samples obtained through the Simons Simplex ascertainment effort.
Resequencing the FMR1 Gene To Identify Novel Mutations Causing Mental Retardation.
This project, carried out in collaboration with Dr. Stephen T. Warren’s laboratory, aims to perform comprehensive resequencing in male patients with unexplained mental retardation to identify novel mutations in FMR1.