Autism spectrum disorder (ASD), also known as autism, is a class of neurodevelopmental disorders, the main clinical characteristics of social disorders and repetitive stereotyped behavior, the incidence of about 0.29% in China. Developmental delays or intellectual disabilities (ID/DD) are the most common comorbidities of autism2. Researchers often refer to people with autism who have no ID/DD symptoms as high-functioning autism, and those who have comorbidity with developmental retardation or intellectual disability as low-functioning autism. At present, there are relatively few large-scale genome-wide and whole-exon genetic studies on autism in China, and there are no large-scale genetic studies on autism in other countries in East Asia.

On July 7, 2023, the Center of Excellence in Brain Science and Intelligent Technology of the Chinese Academy of Sciences/Songjiang Research Institute of Shanghai Jiao Tong University School of Medicine, Researcher Qiu Zilong's team, and Director Li Fei of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine cooperated in the international well-known journal Biological The research paper entitled "Discovery and validation of novel genes in a large Chinese ASD cohort", published in the journal Psychiatry, reports for the first time a large-scale whole-exon genetics study of autism in China.

Li Fei, director of Shanghai Key Laboratory of Environment and Child Health of the Ministry of Education and Department of Developmental Behavior and Child Care, Xinhua Hospital Affiliated to Shanghai Jiao Tong University College of Medicine, collected thousands of autism cases over the years. The team conducted detailed behavioral assessments and IQ developmental quotient tests for patients, and classified high-functioning and low-functioning autism in detail. Based on these important clinical data, the research team conducted a whole-exome sequencing study on 772 Chinese autism core families collected from Xinhua Hospital, and combined with the 369 Chinese autism core coefficient data reported by the team from Shanghai Mental Health Center, a total of 22 high-confidence autism candidate genes (FDR<0.1) were identified. It contains nine new autism candidate genes that have not been found in European and American autism genetics studies (Figure A, new candidate genes in red font). In this study, we also integrated these findings with the largest published database of emerging mutations in autism to obtain whole-exome significance for 4,27 genes (FDR<0.1, Figure B), indicating that autism susceptibility genes in China are significantly different from those found in European and American populations. This result further enriches the list of candidate genes for human autism and demonstrates the importance of conducting research on autism genetics in populations with different genetic backgrounds for a comprehensive understanding of the basis of autism genetics.

The research team also collaborated with Professor Wang Xiaoqun from Beijing Normal University/Institute of Biophysics of Chinese Academy of Sciences, and combined with the single cell sequencing Atlas of the human embryonic cerebral cortex, 5,6, found that newly mutated genes in high-functioning autistic people are richly expressed in a class of human-specific neuroprecursors, which may further develop into deep cortical neurons. The gene with the new mutation in low-functioning autism is enriched in another class of neural precursor cells (Figure D). This result demonstrates potential differences in genetics and pathogenesis between the two groups of patients.

Finally, the researchers combined mouse genetic and behavioral studies to verify the important function of a new autism candidate gene, SLC35G1, in mouse social behavior. Compared to wild-type mice, Slc35g1 heterozygous mice exhibited an autism-like phenotype.

This study is another achievement of the collaborative team of Zilong Qiu and Fei Li in the field of autism genetics research, which provides a new way to comprehensively understand the genetic structure of autism, explain the characteristics of high-functioning autism, and further improve the intervention program of autism core phenotype. It is worth mentioning that in order to integrate the basic and clinical strength of autism research in China, researchers Li Fei and Qiu Zilong initiated the establishment of the "Yangtze River Delta Autism Research Center" on April 8, 2023. The lead author of this work and the lead author of related articles, Professor Du Yasong, are both members of the Yangtze River Delta Autism Research Center. It is expected that the Yangtze River Delta Autism Research Center will continue to integrate the clinical resources of major hospitals to conduct characteristic autism research and promote the clinical diagnosis and treatment of autism.

Zilong Qiu, a researcher at the Center for Excellence in Brain Science and Intelligent Technology, Chinese Academy of Sciences/Songjiang Research Institute, Shanghai Jiao Tong University School of Medicine, and Fei Li, Director of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, are co-corresponding authors of the paper. Dr. Wang Jincheng, Center of Excellence in Brain Science and Intelligent Technology, Chinese Academy of Sciences; Yu Juehua, Researcher, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; Wang Mengdi, PhD student, Institute of Biophysics, Chinese Academy of Sciences; Zhang Lingli, Young Researcher, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; Yang Kan, a young researcher from Xinhua Hospital of Shanghai Jiao Tong University School of Medicine, is the co-first author of the paper. Dr. Du Xiujuan from Xinhua Hospital of Shanghai Jiao Tong University School of Medicine, Researcher Jinyu Wu from Wenzhou Medical University and Professor Wang Xiaoqun from Beijing Normal University participated in the study. The research was supported by Zhejiang Jiahang Charity Foundation, National Natural Science Foundation of China, Strategic Pilot Science and Technology Project of Chinese Academy of Sciences, Shanghai Major Science and Technology Project, Shanghai Municipal Health Commission Collaborative Innovation Project, and Guangdong Province Key Areas Research and Development Plan. The partner of whole exome sequencing is Shanghai Xuzhenda Biotechnology Co., LTD.

Original link:

https://doi.org/10.1016/j.biopsych.2023.06.025

In Figure A, the Manhattan chart of 1141 new mutations in autism was analyzed using the TADA model.

Figure B shows FDR before and after database combination.

Figure C, mutation statistics of two groups of people with autism.

Figure D is a hierarchical clustering tree of major cell types in the single cell sequencing atlas of the human embryonic cerebral cortex.

Reference

1 Zhou, H. et al. Prevalence of Autism Spectrum Disorder in China: A Nationwide Multi-center Population-based Study Among Children Aged 6 to 12 Years. Neurosci Bull 36, 961-971, doi:10.1007/s12264-020-00530-6 (2020).

2 Mottron, L. A radical change in our autism research strategy is needed: Back to prototypes. Autism Res 14, 2213-2220, doi:10.1002/aur.2494 (2021).

3 Yuan, B. et al. Identification of de novo mutations in the Chinese ASD cohort via whole-exome sequencing unveils brain regions implicated in autism. Neurosci Bull doi: 10.1007/s12264-023-01037-6. (2023).

4 Zhou, X. et al. Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes. Nat Genet 54, 1305-1319, doi:10.1038/s41588-022-01148-2 (2022).

5 Fan, X. et al. Spatial transcriptomic survey of human embryonic cerebral cortex by single-cell RNA-seq analysis. Cell Res 28, 730-745 (2018).

6 Fan, X. et al. Single-cell transcriptome analysis reveals cell lineage specification in temporal-spatial patterns in human cortical development. Sci Adv 6, eaaz2978 (2020).