Diagnosis of inborn errors of metabolism through massive DNA sequencing: benefits and limitations

Inborn errors of metabolism (IEM) are inherited disorders resulting from genetic defects in proteins involved in breakdown or storage of fatty acids, carbohydrates and proteins. Collectively, IEM encompasses approximately 1000 different disorders and can affect up to 1 in 2000 births. While biochemical newborn screening programs have been successfully applied to early identify newborns with treatable IEM conditions and to reduce their associated morbidity and mortality, the great majority of known IEM are not recognizable through biochemical screening. In recent years, next generation DNA sequencing technologies (including sequencing of gene panels, exome sequencing, and genome sequencing) has revolutionized the genetic diagnosis of monogenic diseases, including IEM. Here, we present a narrative review with selected bibliography to show a general landscape about the current status of NGS-based IEM diagnosis as well as its intrinsic limitations. NGS can detect newborns with metabolic diseases that may otherwise be clinically unrecognized until symptoms start. Importantly, a subgroup of these newborns will benefit from individualized medical management.