Metabolic Signatures of Cystic Fibrosis Identified in Dried Blood Spots For Newborn Screening Without Carrier Identification
Metabolic Signatures of Cystic Fibrosis Identified in Dried Blood Spots For Newborn Screening Without Carrier Identification
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DOI：
10.1021/acs.jproteome.8b00351
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发表时间：
2019-03-01
影响因子：
4.4
通讯作者：
Britz-McKibbin, Philip
中科院分区：
文献类型：
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作者：
DiBattista, Alicia;McIntosh, Nathan;Britz-McKibbin, Philip
囊性纤维化是一种复杂的多器官疾病，是生命早期受益于治疗干预的最常见的致命遗传病之一。目前，用于无症状CFs检测的新生儿筛查(NBS)依赖于两阶段免疫反应胰蛋白酶原(IRT)和囊性纤维化跨膜传导调节因子(CFTR)突变小组算法，该算法对于识别阳性预测值较低的受影响新生儿是敏感的，但不是特异的。我们首次报告，当使用多段注射-毛细管电泳质谱(MS)作为高通量平台时，从单个直径3.2 mm的干血斑(DBS)冲头中发现一组特定于CF的代谢物，用于从具有质量控制的容量受限/生物库样本中分析非靶向代谢物。这项回顾性病例对照研究设计确定了32种代谢物，包括一系列N-糖化氨基酸、氧化谷胱甘肽二硫化物和烟酰胺，这些代谢物在没有胎粪梗阻的正常出生体重的CF新生儿(n=36)中与胎龄/性别匹配的筛查阴性对照(n=44)相比，在错误发现率调整(q<；0.05)后有差异表达。此外，从DBS提取物中提取的16种代谢物可以区分真正的CF病例和假定筛查阳性携带者，其中一人被确认为CFTR突变和暂时性新生儿高胰蛋白酶原血症新生儿(n=72)，这些新生儿后来被证实未受影响，原因是低汗氯化物(
Cystic fibrosis (CF) is a complex multiorgan disorder that is among the most common fatal genetic diseases benefiting from therapeutic interventions early in life. Newborn screening (NBS) for presymptomatic detection of CF currently relies on a two-stage immunoreactive trypsinogen (IRT) and cystic fibrosis transmembrane conductance regulator (CFTR) mutation panel algorithm that is sensitive but not specific for identifying affected neonates with a low positive predictive value. For the first time, we report the discovery of a panel of CF-specific metabolites from a single 3.2 mm diameter dried blood spot (DBS) punch when using multisegment injection-capillary electrophoresis-mass spectrometry (MS) as a high-throughput platform for nontargeted metabolite profiling from volume-restricted/biobanked specimens with quality control. This retrospective case-control study design identified 32 metabolites, including a series of N-glycated amino acids, oxidized glutathione disulfide, and nicotinamide that were differentially expressed in normal birth weight CF neonates without meconium ileus (n = 36) as compared to gestational age/sex-matched screen-negative controls (n = 44) after a false discovery rate adjustment (q < 0.05). Also, 16 metabolites from DBS extracts allowed for discrimination of true CF cases from presumptive screen-positive carriers with one identified CFTR mutation and transient neonatal hyper-trypsinogenemic neonates (n = 72), who were later confirmed as unaffected due to a low sweat chloride (