基于MS/MS和UP-MMCA的新生儿甲基丙二酸血症二阶筛查新方法构建与临床应用研究

甲基丙二酸血症（MMA）是我国常见的严重威胁新生儿生命健康的有机酸血症代谢病。目前的串联质谱筛查（MS/MS）存在假阳性率高且易漏诊，高通量且低成本的基因筛查方法对于新生儿MMA精准治疗具有重要意义。我们前期实验显示基于通用引物的多重熔解曲线分析（UP-MMCA）可以解决多重实时PCR基因分型的技术瓶颈，满足新生儿代谢病基因筛查需求。本项目拟构建基于UP-MMCA的快速准确、经济高效、高通量的新生儿MMA基因筛查新技术，可同时检测MMACHC和MMUT基因30种突变。然后将上述基因筛查方法与MS/MS筛查联合构建经济高效的新生儿MMA二阶筛查新策略，并通过“决策分析”模型，对比三种筛查策略（未筛查，常规筛查，本项目筛查方法）的成本效益，从卫生经济学角度阐明基于MS/MS和UP-MMCA的二阶筛查新方法用于新生儿MMA疾病筛查的优势。本项目有望为我国新生儿代谢病二阶筛查提供方法学与实践参考。

Methylmalonic acidemia (MMA) is a common inborn error of organic acid metabolism that seriously threaten newborn's health and lives in China. The tandem mass spectrometry (MS/MS) has been widely used to screen for metabolic disorders in neonates, but with a high false positive rate. Therefore, a high-throughput and low-cost genetic screening assay is of great significance for the precise treatment of MMA. The preliminary experiments proved that the universal primers-based multiplex melting curve analysis (UP-MMCA) can well meet the needs of genetic screening for neonatal metabolic diseases. In this study, we will develop a novel UP-MMCA-based MMA genetic screening assay with low-cost and high-throughput, which can simultaneously detect 30 mutations in MMACHC gene and MMUT gene. Then we combine this with MS/MS screening assay to develop a cost-effective second-tier screening strategy, as well as perform the cost-effectiveness analysis for this clinical study. The study could be expected to provide a methodological reference for the second-tier screening for neonatal metabolic disorders in China.