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.

In the current project, Zeynep Coban Akdemir plans to improve the classification of protein truncating variants, which account for a significant proportion of pathogenic variants. The goal is to enhance predictive models and tools to classify these variants by utilizing multi-omics approaches and functional characterizations. The overall aim is to increase the accuracy of diagnosing ASD in individuals undergoing genome-wide sequencing and ultimately lead to the development of new targeted therapies.

Multiple studies, including genetics, have implicated mitochondrial dysfunction among the many factors affecting the risk of developing autism-related symptoms. However, it has been challenging to link polygenic influencers of autism spectrum disorder (ASD) risk from population studies to relative mitochondrial energetic weakness in individuals. This study attempts to use previous large-scale genetic studies of ASD to create a mitochondrial polygenic function score, then to apply this score to the Simons Simplex Collection. LCLs from individuals at either end of the genetic mitoPFS spectrum will then be assayed for their mitochondrial energetic function. A validated mitoPFS, and blood-based assay for mitochondrial energetics itself, would be an invaluable tool for identifying ASD individuals for clinical trials involving mitochondrial therapeutics.

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.

Many individuals with autism carry novel mutations in transcription factors, which are critical regulatory proteins. In the current project, Max Staller plans to investigate the functional consequences of mutations in activation domains, the regions of transcription factors that activate target genes.