Massively parallel characterization of non-coding de novo mutations in autism spectrum disorder

Congcong Chen; Songwei Guo; Yanan Shi; Xinyu Gu; Ziye Xu; Yingjia Chen; Yayun Gu; Na Qin; Yue Jiang; Juncheng Dai; Yuanlin He; Xiao Han; Yan Liu; Zhibin Hu; Xiaoyan Ke; Cheng Wang

doi:10.1016/j.jgg.2025.07.008

Massively parallel characterization of non-coding de novo mutations in autism spectrum disorder

doi: 10.1016/j.jgg.2025.07.008

Congcong Chen^a,b,d,
Songwei Guo^c,
Yanan Shi^c,
Xinyu Gu^c,
Ziye Xu^c,
Yingjia Chen^c,
Yayun Gu^a,b,
Na Qin^a,
Yue Jiang^a,
Juncheng Dai^a,
Yuanlin He^a,b,
Xiao Han^b,e,
Yan Liu^b,e,
Zhibin Hu^a,b,e,
Xiaoyan Ke^f, ,,
Cheng Wang^a,b,d, ,

a. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China;
b. State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China;
c. Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, Jiangsu 211166, China;
d. The Second People's Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu 213003, China;
e. State Key Laboratory of Reproductive Medicine (Suzhou Centre), The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Innovation Center of Suzhou Nanjing Medical University, Suzhou, Jiangsu 215000, China;
f. Child Mental Health Research Center, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China

基金项目:

This work was supported by the National Natural Science of China (82322032 and 82221005), the Outstanding Youth Foundation of Jiangsu Province (BK20220050), the National Key Research & Development (R&D) Program of China (2024YFC2706800 and 2021YFC2700600), the Major Project of Changzhou Medical Center (CZKY1040101), the Major Project of Taizhou Clinical Medical College (TZKY20240003), the Major Program of Gusu School (GSKY20210102) and the China Postdoctoral Science Foundation (2024M760296).

详细信息

通讯作者:
Xiaoyan Ke,E-mail:kexiaoyan@njmu.edu.cn

Cheng Wang,E-mail:cheng_wang29@njmu.edu.cn

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出版历程
- 收稿日期: 2025-02-16
- 录用日期: 2025-07-22
- 修回日期: 2025-07-19
- 网络出版日期: 2025-07-29

Massively parallel characterization of non-coding de novo mutations in autism spectrum disorder

Congcong Chen^a,b,d,
Songwei Guo^c,
Yanan Shi^c,
Xinyu Gu^c,
Ziye Xu^c,
Yingjia Chen^c,
Yayun Gu^a,b,
Na Qin^a,
Yue Jiang^a,
Juncheng Dai^a,
Yuanlin He^a,b,
Xiao Han^b,e,
Yan Liu^b,e,
Zhibin Hu^a,b,e,
Xiaoyan Ke^{f
, ,},
Cheng Wang^{a,b,d
, ,}

a. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China;
b. State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China;
c. Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, Jiangsu 211166, China;
d. The Second People's Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu 213003, China;
e. State Key Laboratory of Reproductive Medicine (Suzhou Centre), The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Innovation Center of Suzhou Nanjing Medical University, Suzhou, Jiangsu 215000, China;
f. Child Mental Health Research Center, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China

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摘要

摘要: Autism spectrum disorder (ASD) is a neurodevelopmental disorder where de novo mutations play a significant role. Although coding mutations in ASD have been extensively characterized, the impact of non-coding de novo mutations (ncDNMs) remains less understood. Here, we integrate cortex cell-specific cis-regulatory element annotations, a deep learning-based variant prediction model, and massively parallel reporter assays to systematically evaluate the functional impact of 227,878 ncDNMs from Simons Simplex Collection (SSC) and Autism Speaks MSSNG resource (MSSNG) cohorts. Our analysis identifies 238 ncDNMs with confirmed functional regulatory effects, including 137 down-regulated regulatory mutations (DrMuts) and 101 up-regulated regulatory mutations (UrMuts). Subsequent association analyses reveal that only DrMuts regulating loss-of-function (LoF) intolerant genes rather than other ncDNMs are significantly associated with the risk of ASD (Odds ratio = 4.34; P = 0.001). A total of 42 potential ASD-risk DrMuts across 41 candidate ASD-susceptibility genes are identified, including 12 recognized and 29 unreported genes. Interestingly, these noncoding disruptive mutations tend to be observed in genes extremely intolerant to LoF mutations. Our study introduces an optimized approach for elucidating the functional roles of ncDNMs, thereby expanding the spectrum of pathogenic variants and deepening our understanding of the complex molecular mechanisms underlying ASD.
- Autism spectrum disorder /
- Non-coding de novo mutations /
- Massively parallel reporter assay /
- High-throughput screening /
- Loss-of-function intolerant gene
Abstract: Autism spectrum disorder (ASD) is a neurodevelopmental disorder where de novo mutations play a significant role. Although coding mutations in ASD have been extensively characterized, the impact of non-coding de novo mutations (ncDNMs) remains less understood. Here, we integrate cortex cell-specific cis-regulatory element annotations, a deep learning-based variant prediction model, and massively parallel reporter assays to systematically evaluate the functional impact of 227,878 ncDNMs from Simons Simplex Collection (SSC) and Autism Speaks MSSNG resource (MSSNG) cohorts. Our analysis identifies 238 ncDNMs with confirmed functional regulatory effects, including 137 down-regulated regulatory mutations (DrMuts) and 101 up-regulated regulatory mutations (UrMuts). Subsequent association analyses reveal that only DrMuts regulating loss-of-function (LoF) intolerant genes rather than other ncDNMs are significantly associated with the risk of ASD (Odds ratio = 4.34; P = 0.001). A total of 42 potential ASD-risk DrMuts across 41 candidate ASD-susceptibility genes are identified, including 12 recognized and 29 unreported genes. Interestingly, these noncoding disruptive mutations tend to be observed in genes extremely intolerant to LoF mutations. Our study introduces an optimized approach for elucidating the functional roles of ncDNMs, thereby expanding the spectrum of pathogenic variants and deepening our understanding of the complex molecular mechanisms underlying ASD.
- Autism spectrum disorder /
- Non-coding de novo mutations /
- Massively parallel reporter assay /
- High-throughput screening /
- Loss-of-function intolerant gene

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Massively parallel characterization of non-coding de novo mutations in autism spectrum disorder

doi: 10.1016/j.jgg.2025.07.008

通讯作者:
Xiaoyan Ke,E-mail:kexiaoyan@njmu.edu.cn

Cheng Wang,E-mail:cheng_wang29@njmu.edu.cn

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Massively parallel characterization of non-coding de novo mutations in autism spectrum disorder

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Massively parallel characterization of non-coding de novo mutations in autism spectrum disorder

doi: 10.1016/j.jgg.2025.07.008

通讯作者: Xiaoyan Ke,E-mail:kexiaoyan@njmu.edu.cn Cheng Wang,E-mail:cheng_wang29@njmu.edu.cn

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Massively parallel characterization of non-coding de novo mutations in autism spectrum disorder

计量

出版历程

目录

通讯作者:
Xiaoyan Ke,E-mail:kexiaoyan@njmu.edu.cn

Cheng Wang,E-mail:cheng_wang29@njmu.edu.cn