Corrigan Rachel R, Mashburn-Warren Lauren M, Yoon Hyojung, Bedrosian Tracy A
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA; email:
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA.
Annu Rev Pathol. 2025 Jan;20(1):13-32. doi: 10.1146/annurev-pathmechdis-111523-023528. Epub 2025 Jan 2.
Research efforts over the past decade have defined the genetic landscape of somatic variation in the brain. Neurons accumulate somatic mutations from development through aging with potentially profound functional consequences. Recent studies have revealed the contribution of somatic mosaicism to various brain disorders including focal epilepsy, neuropsychiatric disease, and neurodegeneration. One notable finding is that the effect of somatic mosaicism on clinical outcomes can vary depending on contextual factors, such as the developmental origin of a variant or the number and type of cells affected. In this review, we highlight current knowledge regarding the role of somatic mosaicism in brain disorders and how biological context can mediate phenotypes. First, we identify the origins of brain somatic variation throughout the lifespan of an individual. Second, we explore recent discoveries that suggest somatic mosaicism contributes to various brain disorders. Finally, we discuss neuropathological associations of brain mosaicism in different biological contexts and potential clinical utility.
过去十年的研究工作已经明确了大脑中体细胞变异的基因图谱。从发育到衰老，神经元积累体细胞突变，这可能会产生深远的功能影响。最近的研究揭示了体细胞嵌合现象在各种脑部疾病中的作用，包括局灶性癫痫、神经精神疾病和神经退行性疾病。一个值得注意的发现是，体细胞嵌合现象对临床结果的影响可能因背景因素而异，例如变异的发育起源或受影响细胞的数量和类型。在这篇综述中，我们重点介绍了关于体细胞嵌合现象在脑部疾病中的作用以及生物学背景如何介导表型的当前知识。首先，我们确定个体一生中大脑体细胞变异的起源。其次，我们探讨了表明体细胞嵌合现象与各种脑部疾病有关的最新发现。最后，我们讨论了不同生物学背景下大脑嵌合现象的神经病理学关联以及潜在的临床应用价值。
