Section on Prenatal Genomics and Fetal Therapy, Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD; Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX.
Section on Social Network Methods, Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
Am J Obstet Gynecol. 2024 Feb;230(2):258.e1-258.e11. doi: 10.1016/j.ajog.2023.07.056. Epub 2023 Aug 6.
Down syndrome is associated with several comorbidities, including intellectual disability, growth restriction, and congenital heart defects. The prevalence of Down syndrome-associated comorbidities is highly variable, and intellectual disability, although fully penetrant, ranges from mild to severe. Understanding the basis of this interindividual variability might identify predictive biomarkers of in utero and postnatal outcomes that could be used as endpoints to test the efficacy of future therapeutic interventions.
The main objective of this study was to examine if antenatal interindividual variability exists in mouse models of Down syndrome and whether applying statistical approaches to clinically relevant measurements (ie, the weights of the embryo, placenta, and brain) could define cutoffs that discriminate between subgroups of trisomic embryos.
Three commonly used mouse models of Down syndrome (Dp(16)1/Yey, Ts65Dn, and Ts1Cje) and a new model (Ts66Yah) were used in this study. Trisomic and euploid littermate embryos were used from each model with total numbers of 102 for Ts66Yah, 118 for Dp(16)1/Yey, 92 for Ts65Dn, and 126 for Ts1Cje. Placental, embryonic, and brain weights and volumes at embryonic day 18.5 were compared between genotypes in each model. K-mean clustering analysis was applied to embryonic and brain weights to identify severity classes in trisomic embryos, and brain and placental volumetric measurements were compared between genotypes and classes for each strain. In addition, Ts66Yah embryos were examined for malformations because embryonic phenotypes have never been examined in this model.
Reduced body and brain weights were present in Ts66Yah, Dp(16)1/Yey, and Ts65Dn embyos. Cluster analysis identified 2 severity classes in trisomic embryos-mild and severe-in all 4 models that were distinguishable using a putative embryonic weight cutoff of <0.5 standard deviation below the mean. Ts66Yah trisomic embryos develop congenital anomalies that are also found in humans with Down syndrome, including congenital heart defects and renal pelvis dilation.
Statistical approaches applied to clinically relevant measurements revealed 2 classes of phenotypic severity in trisomic mouse models of Down syndrome. Analysis of severely affected trisomic animals may facilitate the identification of biomarkers and endpoints that can be used to prenatally predict outcomes and the efficacy of treatments.
唐氏综合征与多种合并症相关，包括智力障碍、生长受限和先天性心脏缺陷。唐氏综合征相关合并症的患病率差异很大，尽管智力障碍完全外显，但从轻度到重度不等。了解这种个体间变异的基础可能有助于确定预测宫内和产后结局的生物标志物，这些标志物可用于测试未来治疗干预的疗效。
本研究的主要目的是检查唐氏综合征的小鼠模型中是否存在产前个体间变异性，以及应用统计学方法对临床相关测量值（即胚胎、胎盘和大脑的重量）是否可以定义区分三体胚胎亚组的截止值。
本研究使用了三种常用的唐氏综合征小鼠模型（Dp(16)1/Yey、Ts65Dn 和 Ts1Cje）和一种新模型（Ts66Yah）。每个模型都使用来自三体和同卵双胞胎的胚胎，总数量为 Ts66Yah 为 102，Dp(16)1/Yey 为 118，Ts65Dn 为 92，Ts1Cje 为 126。在每个模型中比较了基因型之间胚胎 18.5 天时的胎盘、胚胎和大脑重量和体积。对胚胎和大脑重量进行 K-均值聚类分析，以确定三体胚胎的严重程度等级，并比较每个品系的基因型和等级之间的大脑和胎盘体积测量值。此外，还检查了 Ts66Yah 胚胎的畸形情况，因为该模型从未检查过胚胎表型。
Ts66Yah、Dp(16)1/Yey 和 Ts65Dn 胚胎的体重和大脑重量均降低。聚类分析在所有 4 种模型中确定了三体胚胎中的 2 种严重程度等级-轻度和重度-可以使用小于平均值 0.5 个标准差的假定胚胎体重截止值来区分。Ts66Yah 三体胚胎发育出先天性异常，这些异常也存在于唐氏综合征患者中，包括先天性心脏缺陷和肾盂扩张。
应用于临床相关测量值的统计学方法揭示了唐氏综合征的 4 种小鼠模型中的 2 种表型严重程度等级。对严重受影响的三体动物的分析可能有助于确定可用于产前预测结局和治疗效果的生物标志物和终点。
