Tandem mass spectrometry (MS MS) and simple fluorometric assays are currently used in newborn screening programs to detect inborn errors of metabolism (IEM). The aim of the study was to evaluate the clinical utility of exome sequencing as a second-tier screening method to assist clinical diagnosis of newborn. The findings demonstrate that gene testing is a useful method to help verify newborns positive for an IEM and guide specific biochemical confirmatory testing. In order to improve the current standard of care, the study advocates second-tier gene testing for all newborns with a suspected IEM. By this approach, clinicians will be more empowered with informative genetic and biochemical results, allowing them to reach a definitive clinical diagnosis and, where appropriate, administer early treatments of the newborn to manage the disease symptoms over a lifetime.