标题：Modeling-based prediction tools for preimplantation genetic testing of mitochondrial DNA diseases: estimating symptomatic thresholds, risk, and chance of success
中文标题：基于模型的胚胎植入前遗传学检测线粒体DNA疾病的预测工具: 估计发病阈值、风险和成功机会
引用信息：
Ji D, Zhang N, Zou W, Zhang Z, Marley JL, Liu Z, Liang C, Shen L, Liu Y, Liang D, Su T, Du Y, Cao Y. Modeling-based prediction tools for preimplantation genetic testing of mitochondrial DNA diseases: estimating symptomatic thresholds, risk, and chance of success. J Assist Reprod Genet. 2023 Sep;40(9):2185-2196. doi: 10.1007/s10815-023-02880-2. Epub 2023 Jul 13. PMID: 37439868; PMCID: PMC10440331.
摘要：
Purpose:Preimplantation genetic testing (PGT) has become a reliable tool for preventing the germline transmission of mitochondrial DNA (mtDNA) variants. However, procedures are not standardized across mtDNA variants. In this study, we aim to estimate symptomatic thresholds, risk, and chance of success for PGT for mtDNA pathogenic variant carriers.
Methods:We performed a systematic analysis of heteroplasmy data including 455 individuals from 187 familial pedigrees with the common m.3243A>G, m.8344A>G, or m.8993T>G pathogenic variants. We applied binary logistic regression for estimating symptomatic thresholds of heteroplasmy, simplified Sewell-Wright formula and Kimura equations for predicting the risk of disease transmission, and binomial distribution for predicting minimum oocyte numbers.
Results:We estimated the symptomatic thresholds of m.8993T>G and m.8344A>G as 29.86% and 16.15%, respectively. We could not determine a threshold for m.3243A>G. We established models for mothers harboring common and rare mtDNA pathogenic variants to predict the risk of disease transmission and the number of oocytes required to produce an embryo with sufficiently low variant load. In addition, we provide a table allowing the prediction of transmission risk and the minimum required oocytes for PGT patients with different variant levels.
Conclusion:We have established models that can determine the symptomatic thresholds of common mtDNA pathogenic variants. We also constructed universal models applicable to nearly all mtDNA pathogenic variants which can predict risk and minimum numbers for PGT patients. These models have advanced our understanding of mtDNA disease pathogenesis and will enable more effective prevention of disease transmission using PGT.
中文摘要：
目的: 胚胎植入前遗传学检测(PGT)已成为预防线粒体脱氧核糖核酸(mtDNA)变异种系传播的可靠工具。然而，在线粒体 DNA 变异中，检测程序并没有标准化。在这项研究中，我们的目的是评估线粒体 DNA 致病性变异携带者 PGT 的发病阈值、风险和成功机会。
方法: 对187个家系的455个个体进行异质性资料的系统分析，共有 m. 3243A > G，m. 8344A > G，或 m. 8993T > G 致病变异。我们使用二元 Logit模型来估计异质性的症状阈值，使用简化的 Sewell-Wright 公式和 Kimura 方程来预测疾病传播的风险，使用二项分布来预测最小的卵母细胞数量。
结果: 8993T > G 和8344A > G 的症状阈值分别为29.86% 和16.15% 。我们无法确定 m. 3243A > G 的阈值。我们为携带常见和罕见 mtDNA 致病变异的母亲建立了模型，以预测疾病传播的风险和产生具有足够低变异负荷的胚胎所需的卵母细胞数量。此外，我们提供了一个表格，允许预测传播风险和不同水平的 PGT 患者所需的最低卵母细胞。
结论: 我们已经建立了可以确定常见线粒体 DNA 致病变异体发病阈值的模型。我们还构建了适用于几乎所有线粒体 DNA 致病变异的通用模型，可以预测 PGT 患者的风险和最小数量。这些模型提高了我们对线粒体 DNA 疾病发病机制的认识，并将能够使用 PGT 更有效地预防疾病传播。
原文链接：
https://link.springer.com/article/10.1007/s10815-023-02880-2
