The neonatal screening of ~4 million newborns each year in the United States leads to the diagnosis of over 1 in 294 infants with a genetic condition that allows for early identification of infants who may have a risk of serious and/or life-threatening disease that can be mitigated by early diagnosis and treatment. This session will describe innovative efforts to leverage the newborn screening (NBS) system to realize the promise of genomics to screen, diagnose, treat, and manage disease and to do so in a responsible way.

Each speaker represents a unique stakeholder group and because NBS occurs in an unselected population, the discussion of ideas and solutions will take into consideration the diverse representation and perspectives of the ACMG audience. NBS is the largest public health genetic program and has the potential to improve population health in an equitable manner. This unselected cohort allows equitable access to screening, regardless of race/ethnicity, geography, economic or educational status. With population-based NBS there is the chance to help advance disease understanding using genomic sequencing of all newborns to better understand the full phenotypic range, identify resiliency factors, and assess social determinants of health that impact outcome after the diagnosis.

Speaker 1 will introduce these topics, describe the current system of NBS in the United States, and begin to make the case for genomic sequencing of all newborns. This talk with serve as an introduction to the session and describe the public health goals of newborn screening, the infrastructure supporting newborn screening, the Recommended University Screening Panel (RUSP), and the criteria that are used to assess nominations for addition to the RUSP. We will review the additions to NBS since its inception and how recent pilot studies can inform future pilot studies, nominations, and additions to the panel. We will then consider the addition of sequencing as a platform for future screening and what conditions could be screening using sequence data and how input from families and pediatricians is shaping considerations of what to include on a sequencing-based panel. We will also discuss how early diagnosis can be a stimulus to developing therapies and how NBS and treatments will likely co-evolve as was the case for spinal muscular atrophy.

Speaker 2 describes the challenges and offers solutions to sequencing-based NBS expansion given that the capacity to expand NBS is variable, and nationwide adoption takes many years. They will highlight that the current approach is unsustainable and unresponsive to the rapid advances in screening and diagnostic technologies, the emergence of novel therapies, and the expectations of the public (or families/advocates). This presentation assesses the current state of Newborn Screening systems in light of the rapid emergence of highly promising treatment modalities for rare disorders that would benefit from NBS and diagnosis prior to the onset of symptoms. This situation emphasizes the imminent need for scalable screening and diagnostic methodologies. Successful and rapid implementation of sequencing and bioinformatics tools applied in high diagnostic yield populations has established sequencing as such scalable methodology and stresses the need for programmatic development efforts and accelerated adoption. Variants of unknown significance (VOUS) are often cited as reason of limited utility of sequencing applications as primary, second tier or diagnostic modalities.

Speaker 3 will provide an overview of the research infrastructure available to help realize the promise of population-based NBS.  For over a decade, the American College of Medical Genetics and Genomics (ACMG) has led the Newborn Screening Translational Research Network (NBSTRN). Use cases exploring the use of genomic sequencing of newborns that leverage the NBSTRN research infrastructure and contributed to a better understanding of the etiology, pathophysiology, and phenotypic heterogeneity of NBS conditions will be presented. With population-based newborn screening, there is the chance to help advance disease understanding using genomic sequencing of all newborns to better understand the full phenotypic range, identify resiliency factors, and assess social determinants of health that impact outcomes after the diagnosis. To realize the full promise of genomic newborn screening will require the engagement of all stakeholders, gathering data during and after newborn screening, and iterating to improve the process.