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Updated: Sep 13, 2025

A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia

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Published on: June 15, 2011

在自闭症谱系障碍中对非编码de novo突变进行大规模并行表征

Congcong Chen¹, Songwei Guo², Yanan Shi²

¹Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; 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.

Journal of genetics and genomics = Yi chuan xue bao

|July 30, 2025

概括

影响不能容忍功能丧失的基因的非编码新基因突变 (ncDNMs) 与自闭症谱系障碍 (ASD) 风险有关. 这项研究确定了特定的ncDNMs和候选基因,改善了对ASD的理解.

科学领域:

遗传学遗传学是一个
神经发育障碍神经发育障碍
基因组医学是基因组医学.

背景情况:

自闭症谱系障碍 (ASD) 是一种复杂的神经发育状况,具有重要的遗传成分.
虽然在ASD中编码de novo突变得到了很好的研究,但对非编码de novo突变 (ncDNMs) 的作用不太了解.
了解ncDNMs对于全面了解ASD病原体至关重要.

研究的目的:

系统地评估在ASD队列中大量的ncDNMs的功能影响.
为了确定与ASD风险相关的特定ncDNMs.
扩大对ASD病原性变体的理解.

主要方法:

整合皮质细胞特异性的调节元素注释.
基于深度学习的变体预测模型的应用.
使用来自西蒙斯简单集合 (SSC) 和MSSNG队列的ncDNMs的大规模并行报告员分析的验证.

主要成果:

确定了238个功能验证的ncDNMs,包括137个下调调节的调节突变 (DrMuts) 和101个上调调节的调节突变 (UrMuts).
发现调节功能丧失 (LoF) 不耐受基因的DrMuts与ASD风险显著相关 (OR=4.34,P=0.001).
在41个候选基因中发现了42个潜在的ASD风险DrMuts,其中包括29个新型基因,通常在对LoF高度不耐受的基因中.

结论:

开发了一种优化的方法来功能性地评估ncDNMs.
证明了特定的ncDNMs,特别是LoF不耐受基因中的DrMuts,有助于ASD风险.
扩大了已知的ASD相关变体的谱,并提供了对潜在分子机制的见解.

关键词:

自闭症谱系障碍自闭症谱系障碍高通量选的高通量选功能丧失不容忍基因的功能丧失.大规模并行记者测试.非编码的de novo突变

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Autism Spectrum Disorder

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