Figure 4

Investigational algorithm for IEM using metabolomics testing. Individuals identified through NBS programs or those with specific IEM features are diagnosed by selected targeted assays and confirmed through gene sequencing. In some cases, WES complemented by functional studies, such as enzyme activity measurement, may be required. Individuals with non-specific IEM phenotypes investigated through broad-spectrum targeted metabolomics prior to further investigation through gene panels. In some cases, WES may be warranted with complementary functional studies. Individuals with broad, non-specific (non-IEM), neurometabolic phenotypes investigated by WES as a front-line investigation. It is possible that such patients may benefit from GUM analysis when VUS are discovered by WES, requiring validation. In addition to metabolomics testing, functional characterization studies (such as enzyme activity measurement or flux studies) should be utilized, where appropriate³¹.