RNA Expression Patterns in Autism

Autism Spectrum Disorder (ASD) is a disorder that is likely caused by the interaction of genetic predispositions and environmental triggers that coalesce at a sensitive period of development to lead to the spectrum of behaviors which includes autism, pervasive developmental disorder – not otherwise specified (PDD-NOS), Asperger’s disorder and Rett’s disorder. Our working hypothesis of this project is that ASD is likely caused by the interplay between genetic predisposition and environmental factors that leads to the observed developmental neurological disability and that experience through neuronal activity affects a gene expression program.  This in turn meditates the process of synaptic development, maturation, refinement and connectivity, the basic processes that shapes the maturation of connections in the brain. Autism could result from either a genetic alteration in that signaling network or alternatively there could be and environmental insult that perturbs that normal experience dependant synaptic development. Despite extensive research into the genetics behind autism the underlying molecular cause remains elusive. Such an understanding of the underlying genetic mechanism will be needed to improve diagnosis, to decipher the interplay between environment and genetics, and lead to rational approaches to therapy.  This lack of success is somewhat surprising given the high heritability for autism and the numerous linkage studies in ASD families. The lack of molecular genetic understanding of the disorder begs for new and different approaches to the problem.  To decipher the underlying basis of autism we plan to approach the problem with novel and somewhat speculative approaches outlined below in our aims.

Aim 1: The establishment of whole genome transcriptome in individuals with ASD, and their parents, by using peripheral blood lymphocytes, and the comparison of  these patterns to control individuals in an attempt to establish characteristic profiles of expression to molecularly phenotype individuals with ASD.

Hypothesis: Analogous to expression profiles in cancer we believe that there are differences in gene expression in the peripheral blood of individuals with ASD compared to controls that are reproducible, and that will provide not only a “signature” for ASD, opening the possibility of a diagnostic test for ASD but also will pave the way to the discovery of biochemical pathways modulated by primary genetic defect and stratify patients and families for genetic and therapeutic studies.

Aim 2: Robust re-sequencing of candidate genes prioritized by bioinformatic means in large cohorts of ASD individuals and controls.

Hypothesis: Prior genetic linkage studies implicate multiple loci to be involved in ASD, therefore we anticipate multiple genes to harbor mutations with ASD. We hypothesize that ASD is likely caused by different mutations in the same gene or related ones, rather than a common variant.  Such mutations can only be detected by sequencing both coding and non-coding regulatory elements in large numbers of ASD individuals and controls.

Aim 3: Look for minor or aberrant splice forms of transcripts expressed in late stage neuronal development, which might play a role in disease pathogenesis.

Hypothesis: The low penetrance and variant phenotypes in monozygotic twins in ASD may indicate an alternate epigenetic pathological mechanism.  Minor perturbations of splice forms could have negative impact on neuronal development leading to developmental disorders such as ASD.  Recent work in disorders such as myotonic dystrophy has shown that perturbation in splicing machinery can have dominant effects on genes other than the primary defect.  The epigenetic influence on splicing in neurons might be most predominant in chromosomal rearrangements and might explain the high incidence of ASD in the many different chromosomal disorders.