Lo Hsiao-Fan, Hong Mingi, Krauss Robert S
Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
Front Cell Dev Biol. 2021 Dec 22;9:795194. doi: 10.3389/fcell.2021.795194. eCollection 2021.
Many common developmental disorders are thought to arise from a complex set of genetic and environmental risk factors. These factors interact with each other to affect the strength and duration of key developmental signaling pathways, thereby increasing the possibility that they fail to achieve the thresholds required for normal embryonic patterning. One such disorder, holoprosencephaly (HPE), serves as a useful model system in understanding various forms of multifactorial etiology. Genomic analysis of HPE cases, epidemiology, and mechanistic studies of animal models have illuminated multiple potential ways that risk factors interact to produce adverse developmental outcomes. Among these are: 1) interactions between driver and modifier genes; 2) oligogenic inheritance, wherein each parent provides predisposing variants in one or multiple distinct loci; 3) interactions between genetic susceptibilities and environmental risk factors that may be insufficient on their own; and 4) interactions of multiple genetic variants with multiple non-genetic risk factors. These studies combine to provide concepts that illuminate HPE and are also applicable to additional disorders with complex etiology, including neural tube defects, congenital heart defects, and oro-facial clefting.
许多常见的发育障碍被认为源于一系列复杂的遗传和环境风险因素。这些因素相互作用，影响关键发育信号通路的强度和持续时间，从而增加了它们无法达到正常胚胎模式所需阈值的可能性。一种这样的疾病，全前脑畸形（HPE），在理解各种形式的多因素病因方面是一个有用的模型系统。对HPE病例的基因组分析、流行病学研究以及动物模型的机制研究揭示了风险因素相互作用产生不良发育结果的多种潜在方式。其中包括：1）驱动基因和修饰基因之间的相互作用；2）寡基因遗传，即每个亲本在一个或多个不同位点提供易感性变异；3）遗传易感性与单独可能不足的环境风险因素之间的相互作用；4）多个遗传变异与多个非遗传风险因素的相互作用。这些研究共同提供了阐明HPE的概念，也适用于具有复杂病因的其他疾病，包括神经管缺陷、先天性心脏病和口腔颌面部裂。
