胎儿基因纯合突变的基因杂合子孕母，是否合适大剂量补充叶酸？

首先，这不是病例贴，只是在翻看孩子的一道高三生物试题引发的思考。

题目的疑问是最后一个空（附图的红框），到底是按一般人群补充0.4-1.0mg，还是4.0mg？可以查询到2种参考答案，分别是按一般人群和按NTDs生育史人群推荐用量。

如果附图答案正确，底层逻辑是不是这样：虽然胎儿纯合突变，但孕母非纯合，体内仍然正常转化四氢叶酸供胎儿发育，额外大量补充的叶酸可能只是从肾排泄出去（参考Crider KS, et al. Folic Acid and the Prevention of Birth Defects: 30 Years of Opportunity and Controversies. Annu Rev Nutr. 2022 Aug 22;42:423-452. )，不过此文章在“NTDs危险因素”关于 MTHFR基因突变的影响“里有表述 Both maternal and fetal MTHFR C677T polymorphisms have been implicated as significant risk factors for NTDs”（提及胎儿基因突变增加NTDS风险）。然而，此观点的参考文献(Tsang BLet al Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. Am J Clin Nutr. 2015 Jun;101(6):1286-94)以及其中3篇相关引用文献（Yan L, et al. Association of the maternal MTHFR C677T polymorphism with susceptibility to neural tube defects in offsprings: evidence from 25 case-control studies. PLoS ONE 2012;7:e41689. Zhang T, et al, Genetic variants in the folate pathway and the risk of neural tube defects: a meta-analysis of the published literature. PLoS ONE 2013;8:e59570. Yadav U, et al. Polymorphisms in folate metabolism genes as maternal risk factor for neural tube defects:an updated meta-analysis. Metab Brain Dis 2015;30(1):7–24.）并没有印证孕母杂合子胎儿纯合突变情况下增加NTDS风险。

另外一种答案的理由是“胎儿基因纯合突变，所以符合‘NTD生育史‘，故推荐4.0mg’’”。

请问各位是否有兴趣讨论一下？