父亲年龄相关的生殖系突变在子代神经发育障碍中的研究进展

Advanced paternal age-related germline mutations in the offspring with neurodevelopmental disorders:An update

由于社会经济的高速发展以及人们生育观念的改变,高龄生育呈持续迅速上升趋势。然而生育时父亲高龄可能引发潜在的子代健康问题,尤其可能会增加神经发育障碍(NDDs)的发病风险。与年龄增长相关的自由基损伤会造成男性生殖系统乃至精子细胞在DNA水平和(或)表观遗传修饰等方面的改变并发生累积,最终导致子代NDDs发病风险增加。本文综述了与父亲高龄相关的子代NDDs流行病学、生殖系从头突变(DNMs)、NDDs相关突变基因选择性累积以及表观遗传修饰变异。NDDs涉及的病因复杂多样,但目前针对父亲年龄增加所致子代NDDs的研究大多局限于单一因素,未来应深入探讨多种机制的协同作用,为子代NDDs及其他与父亲高龄有关的疾病进一步研究和诊疗提供指导依据。

With the rapid development of social economy and changed concept of reproduction,childbirth at an advanced age is on a steadily upward trend.However,advanced paternal age(APA)at conception may lead to potential health problems and increase the risk of neurodevelopmental disorders(NDDs)in the offspring.Aging-related free radical damage can cause changes and accumulation in the DNA level and/or epigenetic modifications of the male reproductive system and even spermatozoa,ultimately increasing the risk of NDDs in the offspring.This article reviews the epidemiology of NDDs,de novo mutations in the germline,selective accumulation of NDDs-related mutations,and epigenetic modifications,which are all associated with APA.The causes of NDDs are complicated and diversified,while current studies on APA-induced NDDs in the offspring are mostly restricted to univariate approaches.In-depth explorations are required into the multi-mechanism synergistic effects to provide some evidence for the diagnosis,treatment and further studies of NDDs and other APA-related disorders in the offspring.