What is autism spectrum disorder (ASD)?
Autism spectrum disorder, also known as ASD, is a complex disorder of very early brain development that is approximately four times more common in boys than girls. Different children can be affected in very different ways, ranging from mild to severe, but they share two main categories of symptoms:
Difficulty with social communication and social interactions
Repetitive behaviors and restricted or unusual interests, including sensory symptoms such as heightened sensitivity to noise, touch, or smell
Autism spectrum disorder is a neurodevelopmental condition, meaning it affects the way your child develops and behaves. The number of children being diagnosed with ASD has been increasing since the 1980s, in part because clinicians and families are better able to recognize it.
ASD affects children differently and to varying degrees. An in-depth evaluation by specialists with expertise in child development and behavior can help identify strengths that can be harnessed to help your child learn, as well as skills that they will most need to work on. It’s also important to keep monitoring your child, because the characteristics of their behavior and development may shift as children get older.
Our Research: Identification and functional study of noncoding mutations in autism
The phenotypic and genetic heterogeneity of autism spectrum disorder (ASD) has posed immense clinical and research challenges to understanding the underlying genetic determinants of ASD risk. In the past several years, advancements of sequencing technologies and the availability of large cohorts have led to the discovery of many novel genes contributing to ASD risk, but the vast majority of individuals with ASD still lack a genetic diagnosis.
In this project, Ryan Doan and colleagues will screen for noncoding mutations with the greatest likelihood of impacting gene regulation (i.e., gene promoters, splicing regulators, cis-regulatory elements). Doan’s team will systematically assess underlying mechanisms by which mutations that disrupt transcriptional splicing, gene promoters and enhancers impact ASD risk using both computational predictions and large-scale functional screening. The functional screening approach that will be taken involves measuring gene expression in neuronal cultures using a novel high-throughput massively parallel reporter assay as well as luciferase assays. Interesting candidates arising from these assays will be further investigated through a combination of knock-in cell line and transient transgenic mouse models. This screening approach allows for simultaneous assessment of thousands of promoter mutations. The further incorporation of transcription factor screening and chromatin immunoprecipitation methodologies with this screening approach will allow Doan’s group to elucidate the mechanisms underlying these ASD risk loci.
Together, these data will create the first large-scale genome-wide promoter database of functionally validated mutations with broad importance for both the research and clinical community. Even more, since the coding regions of the impacted genes remain fully intact, this class of mutations represents ideal targets for putative therapeutic attempts. This database of functionally tested mutations will therefore provide an important step toward developing strategies to correct abnormal gene splicing or expression in ASD; such approaches have already shown success in treating other disorders, including spinal muscular atrophy and Duchenne muscular dystrophy.