Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Baylor Genetics, Houston, Texas.
JAMA Netw Open. 2021 Jul 1;4(7):e2114155. doi: 10.1001/jamanetworkopen.2021.14155.
Recent advances in newborn screening (NBS) have improved the diagnosis of inborn errors of metabolism (IEMs); however, many potentially treatable IEMs are not included on NBS panels, nor are they covered in standard, first-line biochemical testing.
To examine the utility of untargeted metabolomics as a primary screening tool for IEMs by comparing the diagnostic rate of clinical metabolomics with the recommended traditional metabolic screening approach.
DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study compares data from 4464 clinical samples received from 1483 unrelated families referred for trio testing of plasma amino acids, plasma acylcarnitine profiling, and urine organic acids (June 2014 to October 2018) and 2000 consecutive plasma samples from 1807 unrelated families (July 2014 to February 2019) received for clinical metabolomic screening at a College of American Pathologists and Clinical Laboratory Improvement Amendments-certified biochemical genetics laboratory. Data analysis was performed from September 2019 to August 2020.
Metabolic and molecular tests performed at a genetic testing reference laboratory in the US and available clinical information for each patient were assessed to determine diagnostic rate.
The diagnostic rate of traditional metabolic screening compared with clinical metabolomic profiling was assessed in the context of expanded NBS.
Of 1483 cases screened by the traditional approach, 912 patients (61.5%) were male and 1465 (98.8%) were pediatric (mean [SD] age, 4.1 [6.0] years; range, 0-65 years). A total of 19 families were identified with IEMs, resulting in a 1.3% diagnostic rate. A total of 14 IEMs were detected, including 3 conditions not included in the Recommended Uniform Screening Panel for NBS. Of the 1807 unrelated families undergoing plasma metabolomic profiling, 1059 patients (58.6%) were male, and 1665 (92.1%) were pediatric (mean [SD] age, 8.1 [10.4] years; range, 0-80 years). Screening identified 128 unique cases with IEMs, giving an overall diagnostic rate of 7.1%. In total, 70 different metabolic conditions were identified, including 49 conditions not presently included on the Recommended Uniform Screening Panel for NBS.
These findings suggest that untargeted metabolomics provided a 6-fold higher diagnostic yield compared with the conventional screening approach and identified a broader spectrum of IEMs. Notably, with the expansion of NBS programs, traditional metabolic testing approaches identify few disorders beyond those covered on the NBS. These data support the capability of clinical untargeted metabolomics in screening for IEMs and suggest that broader screening approaches should be considered in the initial evaluation for metabolic disorders.
最近新生儿筛查（NBS）的进展提高了先天性代谢缺陷（IEM）的诊断水平；然而，许多潜在可治疗的 IEM 并未被纳入 NBS 检测，也未被纳入标准的一线生化检测中。
通过比较临床代谢组学与推荐的传统代谢筛查方法，评估非靶向代谢组学作为 IEM 初级筛查工具的效用。
设计、设置和参与者：这项横断面研究比较了来自 1483 个无关家庭的 4464 个临床样本（2014 年 6 月至 2018 年 10 月）和来自 1807 个无关家庭的 2000 个连续血浆样本（2014 年 7 月至 2019 年 2 月）的数据，这些样本是在一家美国病理学家协会和临床实验室改进修正案认证的生化遗传学实验室进行的血浆氨基酸、血浆酰基肉碱谱和尿液有机酸的靶向代谢组学筛查（分析于 2019 年 9 月至 2020 年 8 月进行）。
在美国的一家遗传检测参考实验室进行的代谢和分子检测以及每位患者的可用临床信息被评估以确定诊断率。
在扩展的 NBS 背景下，评估了传统代谢筛查与临床代谢组学分析的诊断率。
在传统方法筛查的 1483 例病例中，912 例患者（61.5%）为男性，1465 例（98.8%）为儿科患者（平均[标准差]年龄，4.1[6.0]岁；范围，0-65 岁）。共发现 19 个 IEM 家族，诊断率为 1.3%。共检测到 14 种 IEM，包括 3 种未包含在 NBS 推荐的统一筛查面板中的疾病。在进行血浆代谢组学分析的 1807 个无关家庭中，1059 例患者（58.6%）为男性，1665 例（92.1%）为儿科患者（平均[标准差]年龄，8.1[10.4]岁；范围，0-80 岁）。筛查发现 128 例 IEM 患者，总诊断率为 7.1%。共发现 70 种不同的代谢疾病，包括 49 种目前不在 NBS 推荐的统一筛查面板中的疾病。
这些发现表明，与传统的筛查方法相比，非靶向代谢组学提供了 6 倍更高的诊断率，并确定了更广泛的 IEM 谱。值得注意的是，随着 NBS 项目的扩展，传统的代谢检测方法除了 NBS 涵盖的疾病外，很少能识别出其他疾病。这些数据支持临床非靶向代谢组学在 IEM 筛查中的能力，并表明在代谢障碍的初始评估中应考虑更广泛的筛查方法。
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