Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project

Abstract

Newborn screening (NBS) was established as a public health program in the 1960s and is crucial for facilitating detection of certain medical conditions in which early intervention can prevent serious, life-threatening health problems. Genomic sequencing can potentially expand the screening for rare hereditary disorders, but many questions surround its possible use for this purpose. We examined the use of exome sequencing (ES) for NBS in the North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) project, comparing the yield from ES used in a screening versus a diagnostic context. We enrolled healthy newborns and children with metabolic diseases or hearing loss (106 participants total). ES confirmed the participant's underlying diagnosis in 15 out of 17 (88%) children with metabolic disorders and in 5 out of 28 (∼18%) children with hearing loss. We discovered actionable findings in four participants that would not have been detected by standard NBS. A subset of parents was eligible to receive additional information for their child about childhood-onset conditions with low or no clinical actionability, clinically actionable adult-onset conditions, and carrier status for autosomal-recessive conditions. We found pathogenic variants associated with hereditary breast and/or ovarian cancer in two children, a likely pathogenic variant in the gene associated with Lowe syndrome in one child, and an average of 1.8 reportable variants per child for carrier results. These results highlight the benefits and limitations of using genomic sequencing for NBS and the challenges of using such technology in future precision medicine approaches.

Keywords: exome sequencing; hearing loss; inborn errors of metabolism; newborn screening; pathogenic.

Figure 1

Number of Carrier Findings for NC NEXUS Participants that Were Randomized into the Experimental Group and Elected to Receive Carrier Findings Number of carrier findings is represented on the x axis and the number of NC NEXUS participants is represented on the y axis.

Figure 2

Variants in HFE, SERPINA1, GALT, and RBM8A Were the Most Frequently Observed Carrier Findings Variants/predicted protein changes and genes in which they are located are represented on the x axis. Total number of carrier findings in the NC NEXUS study is represented on the y axis.