An Age-Based Framework for Evaluating Genome-Scale Sequencing Results in Newborn Screening

Abstract

To assess the performance of a standardized age-based metric for scoring clinical actionability to evaluate conditions for inclusion in newborn screening (NBS), and compare it with the results from other contemporary methods. The North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) study developed an age-based, semi-quantitative metric (ASQM) to assess the clinical actionability of gene-disease pairs and classify them with respect to age of onset or timing of interventions. This categorization was compared with the gold standard Recommended Uniform Screening Panel (RUSP) and other methods to evaluate gene-disease pairs for newborn genomic sequencing. We assessed 822 gene-disease pairs, enriched for pediatric onset of disease and suspected actionability. Of these, 466 were classified as having childhood onset and high actionability, analogous to conditions selected for the RUSP core panel. Another 245 were classified as having childhood onset and low to no actionability, 25 were classified as having adult onset and high actionability, 19 were classified as having adult onset and low to no actionability, and 67 were excluded due to controversial evidence and/or prenatal onset. This study describes a novel method to facilitate decisions about the potential use of genomic sequencing for newborn screening. These categories may assist parents and physicians in making informed decisions about the disclosure of results from voluntary genomic sequencing in children.