Exome/Genome-Wide Testing in Newborn Screening: A Proportionate Path Forward

Abstract

Population-based newborn screening (NBS) is among the most effective public health programs ever launched, improving health outcomes for newborns who screen positive worldwide through early detection and clinical intervention for genetic disorders discovered in the earliest hours of life. Key to the success of newborn screening programs has been near universal accessibility and participation. Interest has been building to expand newborn screening programs to also include many rare genetic diseases that can now be identified by exome or genome sequencing (ES/GS). Significant declines in sequencing costs as well as improvements to sequencing technologies have enabled researchers to elucidate novel gene-disease associations that motivate possible expansion of newborn screening programs. In this paper we consider recommendations from professional genetic societies in Europe and North America in light of scientific advances in ES/GS and our current understanding of the limitations of ES/GS approaches in the NBS context. We invoke the principle of proportionality—that benefits clearly outweigh associated risks—and the human right to benefit from science to argue that rigorous evidence is still needed for ES/GS that demonstrates clinical utility, accurate genomic variant interpretation, cost effectiveness and universal accessibility of testing and necessary follow-up care and treatment. Confirmatory or second-tier testing using ES/GS may be appropriate as an adjunct to conventional newborn screening in some circumstances. Such cases could serve as important testbeds from which to gather data on relevant programmatic barriers and facilitators to wider ES/GS implementation.

Prospects for Expansion of Universal Newborn Screening in Bulgaria: A Survey among Medical Professionals

“…First, NBS promotes the early diagnosis and onset of treatment, resulting in improved health outcomes and prognosis [ 28 ]. Second, the continuing advances in medical science and health technologies lead to better and cheaper NBS tools [ 43 ]. Third, NBS is also associated with important indirect savings due to reductions in productivity losses and consumption of public services [ 44 ].…”

Call to Action for Advancing Equitable Genomic Newborn Screening

“…Scaling up gNBS to the population level requires examining condition prevalence within populations, the benefits and challenges of different genomic technologies, and the type of information obtained. Selecting appropriate variants is particularly challenging in the constantly evolving genomic landscape, as empirical knowledge about variants and their health implications changes over time [17]. Genomic NBS can also identify variants of uncertain significance (VUS), variants associated with adult-onset conditions, and carrier status in individuals for whom early detection offers no health benefits but may affect reproductive choices.…”

“…Another important consideration is whether to report previously selected variants or all identified variants and then determine their effects [18]. The latter approach will identify many VUS, creating prognostic uncertainty [17, 18]. Additionally, limited clinical phenotype data may be available when gNBS is scaled up to the population level, creating difficulties in determining the clinical relevance of results [19].…”

“…Genomic NBS can also identify variants in individuals from minoritized and underrepresented populations whose genomes do not align with the current reference genome, rendering results of questionable utility [17, 19] and creating greater inequities in who benefits from NBS [6]. Although knowledge of diverse genomes is expanding rapidly, developing comprehensive understanding of these genomes will take time, further limiting the applicability of gNBS results for individuals from minoritized and underrepresented populations [19].…”

“…We believe that the rapid evolution of genomic science, limited size of the genetic counseling workforce, and implementation of population-wide gNBS require flexible and innovative approaches to education and counseling. One proposed approach is online education, potentially combined with artificial intelligence (AI), to augment education provided by genetic counselors [17, 28, 29]. However, exclusively online education may not be appropriate in all countries and for all populations [6].…”