Public health newborn screening (NBS) programs provide population-scale ascertainment of rare, treatable conditions that require urgent intervention. Tandem mass spectrometry (MS/MS) is currently used to screen newborns for a panel of rare inborn errors of metabolism (IEMs)^1,2,3,4. The NBSeq project evaluated whole-exome sequencing (WES) as an innovative methodology for NBS. We obtained archived residual dried blood spots and data for nearly all IEM cases from the 4.5 million infants born in California between mid-2005 and 2013 and from some infants who screened positive by MS/MS, but were unaffected upon follow-up testing. WES had an overall sensitivity of 88% and specificity of 98.4%, compared to 99.0% and 99.8%, respectively for MS/MS, although effectiveness varied among individual IEMs. Thus, WES alone was insufficiently sensitive or specific to be a primary screen for most NBS IEMs. However, as a secondary test for infants with abnormal MS/MS screens, WES could reduce false-positive results, facilitate timely case resolution and in some instances even suggest more appropriate or specific diagnosis than that initially obtained. This study represents the largest, to date, sequencing effort of an entire population of IEM-affected cases, allowing unbiased assessment of current capabilities of WES as a tool for population screening.

公共卫生新生儿筛查 (NBS) 计划可在人群范围内查明需要紧急干预的罕见、可治疗的疾病。串联质谱 (MS/MS) 目前用于筛查新生儿一组罕见的先天性代谢错误 (IEM) ^1,2,3,4。NBSeq 项目将全外显子组测序 (WES) 评估为 NBS 的创新方法。我们获得了 2005 年中期至 2013 年期间在加利福尼亚州出生的 450 万婴儿以及一些经 MS/MS 筛查呈阳性但在后续检测中未受影响的婴儿的几乎所有 IEM 病例的存档残留干血点和数据。WES 的总体敏感性为 88%，特异性为 98.4%，而 MS/MS 的总体敏感性和特异性分别为 99.0% 和 99.8%，尽管各个 IEM 的有效性有所不同。因此，单独使用 WES 的敏感性或特异性不足以作为大多数 NBS IEM 的主要筛选。然而，作为对 MS/MS 筛查异常的婴儿的二次检测，WES 可以减少假阳性结果，促进及时解决病例，在某些情况下甚至可以提出比最初获得的诊断更合适或更具体的诊断。这项研究代表了迄今为止对受 IEM 影响的整个人群进行的最大规模的测序工作，从而可以对 WES 作为人群筛查工具的当前能力进行公正的评估。