Matthew MacDonald, Bernie Devlin and Kathryn Roeder plan to leverage the most recent genomic results and integrate them with a wealth of high-quality proteome and transcriptome data to achieve a deeper understanding of how different classes of genetic susceptibility and different ASD risk genes converge on overlapping biological networks critical to ASD.

Autism is a highly polygenic disorder in which multiple classes of genetic variation — ranging from common variants with small effects to highly penetrant copy number variants and de novo exonic variants — contribute to risk. Growing evidence suggests an interplay between rare and common variants. Hyejung Won, Kristen Brennand and Nan Yang aim to study the biological underpinning of how common and rare variants interact to contribute to ASD risk.

Missense variants are a class of genetic variants that contribute to autism risk, but predicting the impact of individual variants remains challenging and limits return of meaningful genetic results. In this study, Yufeng Shen, Brian O’Roak and Jacob Michaelson aim to substantially improve interpretation of missense variants in autism risk genes using experimental, machine learning and biophysical approaches. The results of the study are expected to improve yield in clinical diagnosis and advance our understanding of how these genetic variants increase autism risk.

Hundreds of human genes involved in dozens of different molecular and cellular mechanisms are associated with an increased risk of autism, though it is unclear how these disparate genetic factors all seem to lead to the same core set of characteristics. In the current project, Michael F. Wells aims to discover points of biological convergence across nearly a dozen high-confidence autism risk genes through human-derived stem cell-based screens. Findings from these studies could improve drug discovery efforts by identifying dysfunctional gene networks and cellular phenotypes that are shared across different genetic risk profiles.

Genetic studies have identified a large number of genes that increase the risk for autism. Many of these risk genes function to regulate the genome in the developing brain. Anne West aims to identify common regulatory mechanisms used by many ASD risk genes that may explain convergent effects on gene regulation during neurodevelopment.

Marta Biagioli and colleagues intend to provide further proof of the efficacy of RNA therapy, proposing SINEUP technology as a new RNA-based tool for the treatment of genetic ASDs. Her lab intends to share validated SINEUP reagents with the ASD community so that SINEUP therapeutic properties could be further analyzed to streamline the development of these molecules to the clinic.

To advance our understanding of the epigenetic contribution to autism, Zhaolan (Joe) Zhou aims to test a hypothesis that the transcription of broad enhancer-like chromatin domain (BELD) genes is particularly sensitive to mutations in chromatin genes and that deregulation of those BELD genes underlies the pathogenesis of autism. The ultimate goal is to provide a foundation to identify possible points of biological convergence and promote mechanism-based therapeutic development.

The tremendous genotypic and phenotypic diversity in ASD has made it extremely challenging to pinpoint causal mechanisms, distinguish the effects of individual genetic variants, stratify patients into subtypes and develop treatments. In the current project, Randall J. Platt plans to profile patient-specific CHD8 variants in human-derived stem cells and induced neurons. The overall aim is to functionally dissect CHD8 mutations and help prioritize convergent/divergent mechanisms for future studies.

A key challenge in translating ASD risk variant discovery to novel therapeutics has been how the functionally diverse genes, once perturbed, converge to confer high risk for ASD. Fikri Birey seeks to take on this challenge by aiming to chart the multi-dimensional phenotypic landscape of ASD risk using a human cellular model of the developing cerebral cortex (mid-to-late gestational stage) and state-of-the-art cellular and molecular assays.