Newborn screening for neurodevelopmental diseases: Are we there yet?

Abstract

In the US, newborn screening (NBS) is a unique health program that supports health equity and screens virtually every baby after birth, and has brought timely treatments to babies since the 1960's. With the decreasing cost of sequencing and the improving methods to interpret genetic data, there is an opportunity to add DNA sequencing as a screening method to facilitate the identification of babies with treatable conditions that cannot be identified in any other scalable way, including highly penetrant genetic neurodevelopmental disorders (NDD). However, the lack of effective dietary or drug-based treatments has made it nearly impossible to consider NDDs in the current NBS framework, yet it is anticipated that any treatment will be maximally effective if started early. Hence there is a critical need for large scale pilot studies to assess if and how NDDs can be effectively screened at birth, if parents desire that information, and what impact early diagnosis may have. Here we attempt to provide an overview of the recent advances in NDD treatments, explore the possible framework of setting up a pilot study to genetically screen for NDDs, highlight key technical, practical, and ethical considerations and challenges, and examine the policy and health system implications.

FIGURE 1

Trade‐off between sensitivity and PPV in reporting results. In individuals with monogenic cause of NDDs, the approach of reporting only Pathogenic and Likely Pathogenic variants will have high PPV but modest sensitivity, as some true positives are currently classified as VUSs. On the other hand, including VUS in the report will lead to high sensitivity but low PPV. Resolving VUS in the future, by improved computational and experimental tools and learning systems, is the key to improve sensitivity while maintaining high PPV.

FIGURE 2

Infrastructure to support efficient implementation of sequencing based newborn screening nationwide. A small number of regional sequencing centers makes it easier to achieve uniform test performance. A national data center makes data curation and processing more efficient with the benefit of centralized continuous improvements from a more diverse and balanced representation of the US population while leveraging geographically scattered expertise.