Principles of Genomic Newborn Screening Programs

Abstract

IMPORTANCE Genomic newborn screening (gNBS) may optimize the health and well-being of children and families. Screening programs are required to be evidence based, acceptable, and beneficial. OBJECTIVES To identify what has been discovered following the reporting of the first gNBS pilot projects and to provide a summary of key points for the design of gNBS. EVIDENCE REVIEW A systematic literature review was performed on April 14, 2021, identifying 36 articles that addressed the following questions: (1) what is the interest in and what would be the uptake of gNBS? (2) what diseases and genes should be included? (3) what is the validity and utility of gNBS? and ( 4) what are the ethical, legal, and social implications? Articles were only included if they generated new evidence; all opinion pieces were excluded. FINDINGS In the 36 articles included, there was high concordance, except for gene disease inclusion, which was highly variable. Key findings were the need for equitable access, appropriate educational materials, and informed and flexible consent. The process for selecting genes for testing should be transparent and reflect that parents value the certainty of prediction over actionability.Data should be analyzed in a way that minimizes uncertainty and incidental findings. The expansion of traditional newborn screening (tNBS) to identify more life-threatening and treatable diseases needs to be balanced against the complexity of consenting parents of newborns for genomic testing as well as the risk that overall uptake of tNBS may decline. The literature reflected that the right of a child to self-determination should be valued more than the possibility of the whole family benefiting from a newborn genomic test. CONCLUSIONS AND RELEVANCEThe findings of this systematic review suggest that implementing gNBS will require a nuanced approach. There are gaps in our knowledge, such as the views of diverse populations, the capabilities of health systems, and health economic implications. It will be essential to rigorously evaluate outcomes and ensure programs can evolve to maximize benefit.

Medical Evaluation of Unanticipated Monogenic Disease Risks Identified through Newborn Genomic Screening: Findings from the BabySeq Project

“…The BabySeq Project is a series of randomized controlled trials of whole exome sequencing (WES) in newborns from the newborn nursery (NBN) or intensive care unit (ICU) who were randomized to conventional care plus family history assessment and genetic counseling alone or with WES. Detailed methodology for the study design and recruitment can be found elsewhere 1,2 . In brief, parents and newborns from the well-baby nursery at Brigham and Women’s Hospital (BWH) and parents and sick newborns from the neonatal intensive care unit and other intensive care units (NICU/ICUs) at BWH, Boston Children’s Hospital (BCH), and Massachusetts General Hospital (MGH), were approached, consented, and enrolled into the study regardless of the absence or presence of a specific phenotype.…”

“…Recent advances in the clinical deployment of genome-scale sequencing now make it possible to determine an infant’s complete genome sequence shortly after birth, enabling the identification of deleterious variants associated with monogenic disorders along with other health-related traits 1 . Genomic sequencing as a screening tool in newborns is being explored 2 and supplementary genomic screening panels are now offered by several commercial laboratories 3 , but there are a number of evidentiary, ethical, and cost concerns that must be considered 1,4-7 .…”

Developing a National Newborn Genomes Program: An Approach Driven by Ethics, Engagement and Co-design

“…This may be done through the expansion of genomic and/or other technologies, and by reviewing the evidence required to incorporate conditions in screening programs in the context of a national publicly-funded health system ( Genetic Alliance UK, 2022 ). Other genomic population screening research initiatives have taken place or are underway internationally, and highlight the importance of equitable access, managing expectations and uncertainties, and ensuring a robust consent process ( Screen4care, 2022 ; Holm et al, 2018 ; Roman et al, 2020 ; Downie et al, 2021 ). However, there remains a relative lack of empirical evidence about the benefits and harms of these programs, particularly in the long term.…”

“…Despite these advantages, the use of WGS in newborn screening at a national health system level is a novel approach and limitations remain, particularly when testing asymptomatic rather than pre-symptomatic individuals. For example, it will be important to minimize feedback of information that is uncertain or not clinically useful, and the burden this may place on families and health systems ( Nuffield Council on Bioethics, 2017 ; Biesecker et al, 2021 ; Downie et al, 2021 ). The sensitivity, specificity, positive and negative predictive values would be expected to vary for each condition depending on its prevalence, ability to distinguish pathogenic from benign variants, and ability to detect known and unknown pathogenic variants ( Hagenkord et al, 2020 ; Marshall et al, 2020 ).…”

Feasibility of Screening for Chromosome 15 Imprinting Disorders in 16 579 Newborns by Using a Novel Genomic Workflow

“…The advent of new genetic technologies and potential therapies has led to renewed interest in newborn screening for rare disorders, 7 including genetically determined neurodevelopmental disorders for which early detection may benefit affected newborns and their families. Individuals affected by PWS, AS, or Dup15q may benefit from newborn screening followed by early targeted interventions that may become available in the next 5 years.…”