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.

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

“…WES was therefore concluded to be insufficiently sensitive or specific as a general primary NBS test for IEM. The NC NEXUS study was performed in a smaller cohort and found similar results (54).…”

“…Analysis was blinded to phenotype, and analyzed genes included those with childhood-onset medically actionable disorders (NBS-NGS, 466 genes, all subjects) and those with diagnostic findings (affected subjects, additional indication-based genes analyzed). This project included randomization to an arm in which parents could decide whether to learn additional information from the genomic analysis including low or no actionability childhood-onset conditions, high actionability adult-onset conditions, and carrier status for recessive disorders ( 54 ). The NBSeq project performed exome sequencing retrospectively on DNA obtained from dried blood spots of cases with known IEM diagnosed through conventional newborn screening in California.…”

“…The NC NEXUS project found that NBS-NGS was 88% sensitive for cases with an abnormal newborn screen for an IEM and 18% sensitive for the hearing loss cohort ( 54 ). Four individuals had abnormal NBS-NGS results not identified by other methods, including female heterozygote status for OTC deficiency in a child with PKU and heterozygous status for a known pathogenic variant in LDLR causing autosomal dominant familial hypercholesterolemia in a child with a known family history of this.…”

“…Four individuals had abnormal NBS-NGS results not identified by other methods, including female heterozygote status for OTC deficiency in a child with PKU and heterozygous status for a known pathogenic variant in LDLR causing autosomal dominant familial hypercholesterolemia in a child with a known family history of this. Two children in the hearing loss cohort had additional clinically relevant findings, one with a variant in DSC2 causing autosomal dominant arrhythmogenic right ventricular dysplasia and one with two variants in the gene associated with factor XI deficiency ( 54 ). These findings addressed the second aim of the NSIGHT consortium.…”

Select Ethical Aspects of Next-Generation Sequencing Tests for Newborn Screening and Diagnostic Evaluation of Critically Ill Newborns

“…It is proposed that the primary benefits of early genetic diagnosis in these patients include both the rapid implementation of targeted interventions that may decrease morbidity, as well as the rapid identification of likely futile intensive care in the course of what may otherwise be a protracted diagnostic approach during, which parents may experience "inappropriate hope" or "needless guilt." Meanwhile, secondary benefits may include guiding parents regarding the risk of recurrence in future children as well as possible overall healthcare cost reductions [1,27].…”