Mobile Menu

Whole-exome sequencing as a tool to detect inborn errors of metabolism

A study published in Nature Medicine has demonstrated the potential of whole-exome sequencing (WES) in detecting inborn errors of metabolism (IEMs) in newborns.

IEMs are a class of rare genetic disorders that arise from an enzyme defect in biochemical and metabolic pathways. Public newborn screening (NBS) programmes have been essential in detecting rare and treatable conditions like IEMs.

With ongoing technological advancements and declining costs, genomic sequencing is now regularly used for diagnosis of rare disorders and has been proposed for all newborns to personalise medicine. The recent launch of the genetics service in NHS Wales called WINGS is an example of this. This service will provide whole-genome sequencing to critically ill newborns and infants who have suspected rare genetic disorders.

Whole-exome sequencing in NBS programmes

In this study, researchers from the University of California quantified the performance of WES. They determined the potential use of WES in primary NBS programmes for identifying IEMs. They also compared WES to the current NBS approach using tandem mass spectrometry (MS/MS).

The team were able to use samples from the California Department of Public Health Biobank. This consists of dried blood spots from nearly 4.5 million infants tested for IEM between July 2005 and December 2013. As a result, the team analysed 1,190 high-quality exomes from 805 IEM-affected individuals and 385 MS/MS false positives. The analysis was based on 78 genes associated with 48 IEMS that researchers currently use in NBS programmes in California.

The team found that WES had an overall sensitivity of 88% and specificity of 98.4% compared to 99.0% and 99.8%, respectively for MS/MS. These results demonstrated that WES alone was insufficiently sensitive or specific as the primary NBS method for identifying IEMs. However, researchers found that WES complemented MS/MS in NBS testing. They found that when used in collaboration with MS/MS, WES could reduce false-positive results, help resolve cases quicker and, in some cases, provide a more appropriate diagnosis.

Image credit: Baby photo created by –

More on these topics

Genetics. Sequencing / IEM / WES