新生儿异戊酸血症串联质谱法与相关基因突变检测的价值研究

目的　了解福建省泉州地区新生儿异戊酸血症（isovaleric acidemia, IVA）串联质谱法与相关基因突变检测情况。方法　2019 年1 月～ 2020 年12 月，泉州地区共有151 917 例新生儿进行串联质谱遗传代谢病筛查，异戊酰基肉碱(isovalerylcarnitine, AISO-C5 ) 浓度升高的筛查样本应用MassARRAY 技术进行IVD 基因突变筛查，IVA 疑似样本采用高通量测序技术诊断。结果　研究期间共有132 例新生儿表现为浓度升高，采用传统筛查规则需召回132 例新生儿，召回复查阳性人数20 例，1 例确诊为IVA 患者，IVA 的阳性预测值为0.76%。此外，3 例新生儿被诊断为2- 甲基丁酰辅酶A 脱氢酶缺乏症（2-methylbutyryl-CoA dehydrogenase deficiency，2-MBAD）患者。联合应用基因突变筛查后，仅5 例新生儿结果异常，基因诊断证实4 例新生儿为IVA 携带者，1 例新生儿为IVA 患者，因此IVA 的阳性预测值提高至20%。所有患者的新生儿筛查和召回复查结果均显示AISO-C5 浓度升高。1 例IVA 患者携带IVD 基因c.499A > G(p.M167V) 和c.1208A > G（p.Y403C）复合杂合突变，3 例2-MBAD 患者均携带ACADSB 基因c.1165A > G (p.M389V)纯合突变。结论　联合应用MassARRAY 技术进行IVD 基因突变筛查可以有效排除AISO-C5 升高的假阳性标本，提高阳性预测值，明显提高IVA 的新生儿筛查效率。

Study on the Value of Tandem Mass Spectrometry and Related Gene Mutation Detection in Neonates with Isovaleric Acidemia

Objective　To investigate the value of tandem mass spectrometry and related gene mutation detection of neonates with isovaleric acidemia (IVA) in Quanzhou of Fujian Province. Methods　From January 2019 to December 2020, a total of 151 917 newborns in Quanzhou were screened for inherited metabolic diseases by tandem mass spectrometry (MS/MS). Newborns with elevated levels of isovalerylcarnitine (AISO-C5 ) were subjected to IVD gene mutation screening using MassARRAY assay, and suspected patients were diagnosed by second-generation sequencing. Results　During the study period, 132 newborns with elevated AISO-C5 levels had to be recalled by conventional MS/MS screening, of which 20 were still positive when recalled, and one patient was confirmed as IVA. The positive predictive value of IVA was 0.76%. In addition, three neonates were diagnosed with 2-methylbutyryl-CoA dehydrogenase deficiency (2-MBAD). After the application of mutation screening, only 5 newborns had abnormal genetic screening results, and the genetic analysis confirmed that four newborns were IVA carriers and one patient newborn was IVA, so the positive predictive value of IVA was increased to 20%. The NBS results showed that all patients with increased concentrations of AISO-C5 , and the AISO-C5 concentration was still elevated during recall. The IVA patient carried the compound heterozygous mutation of c.499A > G (p.P167V) and c.1208A >G (p.Y403C) in the IVD gene, and all three 2-MBAD patients carried the homozygous mutation of c.1165A > G (p.M389V) in the ACADSB gene. Conclusion　The application of MassARRAY assay for IVD gene mutation screening could effectively eliminate AISO-AISO-C5 false positive samples and increase the positive predictive value, thus significantly improved the efficiency of newborn screening for IVA.