Identification of de novo Mutations in the Chinese Autism Spectrum Disorder Cohort via Whole-Exome Sequencing Unveils Brain Regions Implicated in Autism

 Bo Yuan3  · Mengdi Wang5  · Xinran Wu6  · Peipei Cheng2  · Ran Zhang3  · Ran Zhang2  · Shunying Yu2  · Jie Zhang6  · Yasong Du2  · Xiaoqun Wang4  · Zilong Qiu1,3
1 Songjiang Research Institute, Songjiang Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China 
2 Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China 
3 Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Chinese Academy of Sciences, Shanghai 200032, China 
4 Beijing Normal University, Beijing 100875, China 
5 Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China 
6 Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China


Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors. Although hundreds of ASD risk genes, implicated in synaptic formation and transcriptional regulation, have been identified through human genetic studies, the East Asian ASD cohorts are still under-represented in genome-wide genetic studies. Here, we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin. Using a joint-calling analytical pipeline based on GATK toolkits, we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants, as well as de novo copy number variations containing known ASD-related genes. Importantly, combined with single-cell sequencing data from the developing human brain, we found that the expression of genes with de novo mutations was specifically enriched in the pre-, post-central gyrus (PRC, PC) and banks of the superior temporal (BST) regions in the human brain. By further analyzing the brain imaging data with ASD and healthy controls, we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls, suggesting the potential structural deficits associated with ASD. Finally, we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas, the insula, as well as the frontal lobes in ASD patients. This work indicated that combinatorial analysis with genome-wide screening, single-cell sequencing, and brain imaging data reveal the brain regions contributing to the etiology of ASD.

Autism; Cohorts; Whole-exome sequencing; Single-cell sequencing