Kim Soo-Whee, An Joon-Yong
Department of Integrated Biomedical and Life Science, Korea University, Seoul, Republic of Korea; L-HOPE Program for Community-Based Total Learning Health Systems, Korea University, Seoul, Republic of Korea.
Department of Integrated Biomedical and Life Science, Korea University, Seoul, Republic of Korea; L-HOPE Program for Community-Based Total Learning Health Systems, Korea University, Seoul, Republic of Korea; School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Republic of Korea.
Mol Cells. 2025 Aug;48(8):100248. doi: 10.1016/j.mocell.2025.100248. Epub 2025 Jun 26.
Autism spectrum disorder (ASD) is a neurodevelopmental condition with a complex genetic basis. Large-scale whole-exome sequencing and whole-genome sequencing studies, with increasing sample sizes and improved ancestral diversity, have significantly advanced the discovery of ASD-associated genes. In addition to identifying coding variants, whole-genome sequencing has facilitated the detection of risk noncoding variants in regulatory elements such as enhancers, promoters, and untranslated regions, prompting experimental validation of their functional impact on neurodevelopment. A deeper understanding of ASD genetic liability has revealed the interplay between rare and common variants. Moreover, genetic liability varies by sex and phenotype profile, underscoring the complexity of ASD's genetic architecture. While the clinical application of these genomic insights remains in early stages, progress has been made in gene-based therapeutic development, the interpretation of noncoding risk variants, and the use of polygenic score for risk stratification. In this review, we summarize key findings from large-scale genomic studies, explore the role of coding and noncoding variants in ASD, and discuss emerging opportunities for translating these discoveries into clinical practice.
自闭症谱系障碍（ASD）是一种具有复杂遗传基础的神经发育疾病。随着样本量的增加和祖先多样性的改善，大规模全外显子组测序和全基因组测序研究显著推进了与ASD相关基因的发现。除了识别编码变异外，全基因组测序还促进了对调控元件（如增强子、启动子和非翻译区）中风险非编码变异的检测，促使对它们对神经发育的功能影响进行实验验证。对ASD遗传易感性的更深入理解揭示了罕见变异和常见变异之间的相互作用。此外，遗传易感性因性别和表型特征而异，突出了ASD遗传结构的复杂性。虽然这些基因组见解的临床应用仍处于早期阶段，但在基于基因的治疗开发、非编码风险变异的解释以及使用多基因评分进行风险分层方面已取得进展。在本综述中，我们总结了大规模基因组研究的关键发现，探讨了编码和非编码变异在ASD中的作用，并讨论了将这些发现转化为临床实践的新机遇。
