The Use of Whole Genome and Exome Sequencing for Newborn Screening: Challenges and Opportunities for Population Health

Abstract

Newborn screening (NBS) is a population-based program with a goal of reducing the burden of disease for conditions with significant clinical impact on neonates. Screening tests were originally developed and implemented one at a time, but newer methods have allowed the use of multiplex technologies to expand additions more rapidly to standard panels. Recent improvements in next-generation sequencing are also evolving rapidly from first focusing on individual genes, then panels, and finally all genes as encompassed by whole exome and genome sequencing. The intersection of these two technologies brings the revolutionary possibility of identifying all genetic disorders in newborns, allowing implementation of therapies at the optimum time regardless of symptoms. This article reviews the history of newborn screening and early studies examining the use of whole genome and exome sequencing as a screening tool. Lessons learned from these studies are discussed, along with technical, ethical, and societal challenges to broad implementation.

Keywords: newborn screening; next-generation sequencing; recommended uniform screening panel; whole exome sequencing; whole genome sequencing.

Figure 1

Newborn screening paradigms. Newborn screening progressed from one marker for each disease (left) to multiplex testing with multiple markers identified from a single test (right) broadening the scope of initial screening tests and significantly increasing the differential diagnosis of a positive newborn screen.

Figure 2

A typical genomic analysis pipeline in the context of newborn screening (NBS). Among all the variants observed in the newborn DNA sequence, only those occurring in previously identified NBS genes are considered further. Within NBS genes, rare variants are prioritized over common variants. A combination of curated pathogenic variant databases and computational prediction tools is utilized to assign variant pathogenicity and screen for individuals who carry such variants. For NBS, the pipeline will need to demonstrate both a high sensitivity (screen positive almost all newborns with disease) and a high specificity (screen negative almost all newborns without disease).