Rylaarsdam Lauren, Guemez-Gamboa Alicia
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
Front Cell Neurosci. 2019 Aug 20;13:385. doi: 10.3389/fncel.2019.00385. eCollection 2019.
Autism Spectrum Disorder (ASD) is one of the most prevalent neurodevelopmental disorders, affecting an estimated 1 in 59 children. ASD is highly genetically heterogeneous and may be caused by both inheritable and gene variations. In the past decade, hundreds of genes have been identified that contribute to the serious deficits in communication, social cognition, and behavior that patients often experience. However, these only account for 10-20% of ASD cases, and patients with similar pathogenic variants may be diagnosed on very different levels of the spectrum. In this review, we will describe the genetic landscape of ASD and discuss how genetic modifiers such as copy number variation, single nucleotide polymorphisms, and epigenetic alterations likely play a key role in modulating the phenotypic spectrum of ASD patients. We also consider how genetic modifiers can alter convergent signaling pathways and lead to impaired neural circuitry formation. Lastly, we review sex-linked modifiers and clinical implications. Further understanding of these mechanisms is crucial for both comprehending ASD and for developing novel therapies.
自闭症谱系障碍（ASD）是最常见的神经发育障碍之一，据估计每59名儿童中就有1人受其影响。ASD在遗传上具有高度异质性，可能由遗传和基因变异共同引起。在过去十年中，已经鉴定出数百个基因，这些基因导致了患者经常出现的严重沟通、社会认知和行为缺陷。然而，这些基因仅占ASD病例的10%-20%，并且具有相似致病变异的患者可能被诊断为处于谱系的非常不同水平。在本综述中，我们将描述ASD的遗传格局，并讨论诸如拷贝数变异、单核苷酸多态性和表观遗传改变等遗传修饰因子如何可能在调节ASD患者的表型谱中发挥关键作用。我们还将考虑遗传修饰因子如何改变趋同信号通路并导致神经回路形成受损。最后，我们回顾性连锁修饰因子和临床意义。进一步了解这些机制对于理解ASD和开发新疗法都至关重要。
