南京医科大学王铖团队的最新研究提出了自闭症谱系障碍中非编码新生突变的大规模平行表征。这一研究成果发表在2025年7月28日出版的国际学术期刊《遗传学报》上。

该研究团队整合了皮层细胞特异性顺式调控元件注释、基于深度学习的变异预测模型和大规模并行报告者分析，系统地评估了来自Simons Simplex Collection （SSC）和Autism Speaks MSSNG资源（MSSNG）队列的227878个ncDNMs的功能影响。他们的分析鉴定出238个具有功能性调控作用的ncDNMs，包括137个下调调控突变（DrMuts）和101个上调调控突变（UrMuts）。

随后的关联分析显示，只有调节功能丧失（LoF）不耐受基因的DrMuts而不是其他ncDNMs与ASD风险显著相关(优势比= 4.34；P = 0.001)。共鉴定出42个潜在的ASD风险基因，涉及41个候选ASD易感性基因，其中包括12个已识别的基因和29个未报道的基因。有趣的是，这些非编码破坏性突变往往出现在对LoF突变极度不耐受的基因中。他们的研究引入了一种优化的方法来阐明ncDNMs的功能作用，从而扩大了致病变异的范围，加深了他们对ASD复杂分子机制的理解。

据了解，自闭症谱系障碍（ASD）是一种神经发育障碍，其中新生突变起着重要作用。虽然编码突变在ASD中已经被广泛表征，但非编码新生突变（ncDNMs）的影响仍然知之甚少。

附：英文原文

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

Author: Xiaoyan Ke f, Cheng Wang a b d

Issue&Volume: 2025/07/28

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.

DOI: 10.1016/j.jgg.2025.07.008

Source: https://www.sciencedirect.com/science/article/abs/pii/S167385272500205X