Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, 2200 Children's Way, Nashville, TN, 37232, USA.
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Orphanet J Rare Dis. 2024 Nov 14;19(1):427. doi: 10.1186/s13023-024-03423-3.
The number of known inherited metabolic diseases (IMDs) has been expanding, and the rate of diagnosis is improving with the development of innovative approaches including next generation sequencing (NGS). However, a substantial proportion of IMDs remain undetected by traditional diagnostic approaches. We aim to highlight the spectrum of IMDs diagnosed by the Undiagnosed Diseases Network (UDN) and to learn from the UDN diagnostic processes that were able to detect IMDs.
We conducted a retrospective analysis of 757 UDN participants diagnosed from 2015 until 2023 using the cohort database, which were divided into a cohort with IMDs (n = 194; 27%) and a cohort whose phenotypes were not explained by an IMD (n = 563; 73%), based on the International Classification of Inherited Metabolic Disorders (ICIMD). Then, we divided the causes of the metabolic 194 diagnoses into seven groups that included all the ICIMD categories. We inspected which clinical and laboratory approaches contributed to a final UDN diagnosis. We also present a UDN case example from each group to highlight the diagnostic yields that resulted from combining newer diagnostic approaches in the UDN and illustrate potential pitfalls of current NGS methods.
These 194 cases of IMDs included examples from 21/25 (84%) of the ICIMD categories. Of the UDN subjects 164/194 (85%) were diagnosed with IMDs through NGS.
The spectrum of IMDs detected in the UDN cohort is large and growing and appropriate use of newer multiple diagnostic approaches should further increase diagnosis of IMDs that are presently missed by the traditional laboratory screening methods.
随着包括下一代测序（NGS）在内的创新方法的发展，已知的遗传性代谢疾病（IMD）的数量不断增加，诊断率也在提高。然而，传统诊断方法仍有相当一部分 IMD 未被发现。我们旨在强调未确诊疾病网络（UDN）诊断的 IMD 谱，并从能够检测 IMD 的 UDN 诊断过程中吸取经验。
我们使用队列数据库对 2015 年至 2023 年期间通过 UDN 诊断的 757 名参与者进行了回顾性分析，根据国际遗传性代谢疾病分类（ICIMD）将这些参与者分为 IMD 组（n=194，27%）和其表型不能用 IMD 解释的组（n=563，73%）。然后，我们将 194 例代谢诊断的原因分为七个组，包括所有的 ICIMD 类别。我们检查了哪些临床和实验室方法有助于最终的 UDN 诊断。我们还从每个组中提供了一个 UDN 病例示例，以突出展示在 UDN 中结合使用新的诊断方法所带来的诊断收益，并说明当前 NGS 方法的潜在陷阱。
这 194 例 IMD 病例包括 21/25（84%）ICIMD 类别的示例。在 UDN 受试者中，有 164/194（85%）通过 NGS 诊断为 IMD。
UDN 队列中检测到的 IMD 谱很大且在不断增加，适当使用新的多种诊断方法应该会进一步增加目前传统实验室筛查方法错过的 IMD 的诊断率。
