Newborn Screening Research Sponsored by the NIH: From Diagnostic Paradigms to Precision Therapeutics

Abstract

Newborn screening (NBS) is a successful public health initiative that effectively identifies pre-symptomatic neonates so that treatment can be initiated before the onset of irreversible morbidity and mortality. Legislation passed in 2008 has supported a system of state screening programs, educational resources, and an evidence-based review process to add conditions to a recommended universal newborn screening panel (RUSP). The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, has promoted NBS research to advance legislative goals by supporting research that will uncover fundamental mechanisms of disease, develop treatments for NBS disorders, and promote pilot studies to test implementation of new conditions. NICHD’s partnerships with other federal agencies have contributed to activities that support nominations of new conditions to the RUSP. The NIH’s Newborn Sequencing In Genomic Medicine and Public Health (NSIGHT) initiative funded research projects that considered how genomic sequencing could be integrated into NBS and its ethical ramifications. Recently, the workshop, “Gene Targeted Therapies: Early Diagnosis and Equitable Delivery,” has explored the possibility of expanding NBS to include genetic diagnosis and precision, gene-based therapies. Although hurdles remain to realize such a vision, broad engagement of multiple stakeholders is essential to advance genomic medicine within NBS.

1. Introduction

Today, newborn screening (NBS) programs throughout the United States serve as an example of a successful mandatory public health program that has improved the lives of thousands of infants over the past 50 years. In fact, state-based NBS programs began in the 1970s after the seminal work of Robert Guthrie, who developed a bacterial inhibition assay to identify elevated levels of phenylalanine in dried blood spots (DBS) from neonates with phenylketonuria (PKU). States soon began screening for conditions where early intervention with available therapies could improve health and long-term outcomes. But as NBS programs grew throughout the United States (U.S.), it became clear that there was a great deal of variability in the quality of screening tests and the number of conditions screened for in the different state NBS laboratories. In 2006, an initial uniform newborn screening panel was proposed in an effort led by the American College of Medical Genetics (ACMG) with input from an expert panel and under the direction of the Health Resources and Services Administration (HRSA) (Watson et al., 2006). The Newborn Screening Saves Lives Act (NBSSLA), passed in 2008 and reauthorized in 2014, codified an advisory committee to establish guidelines for newborn screening in every state, to ensure that the approximately 4 million babies born each year in the U.S. have access to diagnostic screening and life-saving treatments for otherwise deadly or severely disabling conditions. This federal legislation also authorized the National Institutes of Health (NIH) to carry out, coordinate, and expand research in NBS. However, NBS research had already found a place among a variety of NIH institutes, as research into conditions such as PKU, sickle cell disease, hearing loss, and other neonatal disorders had been undertaken for many years. Bringing the NIH focus on NBS research under the auspices of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) allowed there to be a singular concentration on NBS research that could serve in a coordinating role across the NIH, and provide resources and tools to investigators as well as the other federal entities supporting NBS (Urv & Parisi, 2017).

This review will provide an overview of NBS research from the perspective and mission of the NIH, then describe the NBS-relevant resources available to investigators. A summary of the federal agencies and their engagement in support of condition nominations and NBS implementation is followed by a description of the Newborn Sequencing In Genomic Medicine and Public Health (NSIGHT) program developed to explore the use of genomic sequencing in the newborn period, and the current state of gene-targeted therapies for personalized treatment approaches, concluding with a look to the future.

2. Newborn Screening Saves Lives Act and the NIH mandate

The Public Health Service Act, Title XI, § 1109 (42 U.S.C. 300b-10; https://www.congress.gov/110/plaws/publ204/PLAW-110publ204.htm), also known as the NBSSLA, was passed in 2008 (P.L. 110–204) and established grant programs to expand the ability of state and local public health agencies to provide screening, counseling, and services for newborns and children with heritable disorders, to assist in education and training of health care professional and laboratory personnel in NBS and new technologies, and to develop educational programs on NBS for families and patient advocacy groups. It established, among other things, a federal advisory committee (“Advisory Committee on Heritable Disorders in Newborns and Children” or ACHDNC) to establish guidelines based on a formal advisory process that would recommend conditions to be added to the Recommended Uniform Newborn Screening Panel (RUSP). The RUSP was initially composed of 29 core conditions, along with 25 secondary conditions that could be detected when screening for the core conditions but for which treatments or natural history are lacking; this list has been amended to 36 core conditions and 26 secondary, with mucopolysaccharidosis type II added to the RUSP by the Secretary of the Department of Health and Human Services (HHS) in August 2022 (see https://www.hrsa.gov/advisory-committees/heritable-disorders/index.html for an updated list of conditions). The ACHDNC provides a mechanism for soliciting nominations for the RUSP and a process for formal evidence review of those conditions (https://www.hrsa.gov/advisory-committees/heritable-disorders/condition-nomination). As part of that legislation, the NIH was mandated to “continue carrying out, coordinating, and expanding research in newborn screening (to be known as `Hunter Kelly Newborn Screening Research Program’).” This legislation was later amended by the Newborn Screening Saves Lives Reauthorization Act of 2014 (P.L. 113–240; https://www.congress.gov/bill/113th-congress/house-bill/1281/text) to include data for NBS conditions under review by the ACHDNC. The four elements under the purview of NIH are described in Figure 1, along with several mechanisms used to support these goals (see also next section). In 2009, the NICHD, one of 27 institutes and centers within the NIH, officially launched its NBS research program under the auspices of the Hunter Kelly Newborn Screening Research Program (https://www.nih.gov/news-events/news-releases/nih-newborn-screening-research-program-named-memory-hunter-kelly). Hunter Kelly, who was the son of Buffalo Bills National Football League quarterback Jim Kelly, had Krabbe disease, a devastating neurodegenerative disorder from which he ultimately succumbed at the age of 8.5 years. His extended family had been advocates for NBS and were present at the launch of the program.

Figure 1.

Elements of the Hunter Kelly Newborn Screening Research Program as outlined in the Newborn Screening Saves Lives Act (NBSSLA) of 2007 and its 2014 reauthorization and NICHD mechanisms used to achieve its goals. The four articulated NIH responsibilities under the NBSSLA are described in the gray boxes. Funding mechanisms and programs used to address the goals are indicated underneath the elements.

ACHDNC, Advisory Committee for Heritable Disorders in Newborns and Children; IDIQ, Indefinite Delivery, Indefinite Quantity; NBS, newborn screening; PARs, Program Announcement with special Review.

*Dedicated NBS PARs include Innovative Therapies and Clinical Studies/Tools for Screenable Disorders and Natural History of Disorders Identifiable by Newborn Screening

One of the challenges of NBS is the fact that each state has distinct legal and administrative policies that guide how and when a condition is added to its NBS panel and its own public health program that administers the screening and follow-up of screen-positive infants in that state. It also takes time for each state to validate the screening assay and develop follow-up protocols for a new condition added to the RUSP. Thus, although there is now a recommended panel of 36 conditions on the RUSP, not all states have adopted every recommended condition, and certainly not in a uniform manner. As one example, one state, Wisconsin, started screening for severe combined immunodeficiency (SCID) in 2008, SCID was added to the RUSP in 2010, and it took until December 2018 for all 50 U.S. states to launch screening programs for the disorder (https://primaryimmune.org/news/all-50-states-now-screening-newborns-severe-combined-immunodeficiency-scid), in part because the technology required a DNA-based assay for T-cell receptor excision recombination circles (TRECs) using quantitative polymerase chain reaction (PCR), a novel technology for many state screening laboratories (Puck & Gennery, 2021). In contrast, Spinal Muscular Atrophy (SMA) was added to the RUSP in June 2018, and by July 2022, 47 states were screening for the condition, representing 97% of all newborns in the U.S. (https://www.curesma.org/newborn-screening-for-sma/). Protocols for screening for SMA have been facilitated by the technology developed for SCID, as the two disorders can be evaluated in the same multiplex PCR assay (Taylor et al., 2015). Furthermore, each state sets its own policies regarding length of retention of DBS and availability of these for use in research. Hence, NBS researchers may have a challenging time navigating the different NBS practices and policies among states and identifying the best strategies for diagnosing newborns, understanding the natural history of new conditions, and developing treatments for them. And because these conditions are so rare, ascertainment of affected infants from multiple states, sometimes over several years, may be necessary to achieve an adequate-sized cohort for treatment trials. Of the over 7000 rare diseases, only a fraction currently has available treatments that can be lifesaving.

As part of the NBS research mission, the NICHD has maintained an active portfolio of grants, contracts, and small business awards addressing a variety of aspects of screening, diagnosis, and treatment for NBS conditions, or those with the potential to be screened in the newborn setting but for which screening is not (yet) currently recommended (so called “screenable disorders”). Overall, over 130 projects have been funded by NICHD between 2005–2020 that address newborn or prenatal screening. During this time, NICHD also published funding opportunity announcements (FOAs) to stimulate focused support of NBS research, and the number of projects awarded in response to these FOAs is summarized in Table 1. NICHD published an initial suite of program announcements with special review considerations (PARs), to allow such applications to be reviewed together by a panel with NBS expertise, in 2006 and subsequently renewed through 2024, for the “development of novel screening platforms and/or therapeutic interventions for potentially fatal or disabling conditions that have been identified through newborn screening, as well as for “high priority” genetic conditions where screening may be possible in the near future” (https://grants.nih.gov/grants/guide/pa-files/PAR-21-353.html). These allowed for classic 5-year research project grants (R01 mechanism), 2-year exploratory or developmental grants (R21 mechanism), or 2-year small grants with defined scope requiring limited funding (R03 mechanism). These generated significant numbers of awards across all mechanisms, with the 5-year R01s being particularly popular.

Table 1.

Summary of newborn screening projects awarded by NICHD from 2006–2020 in response to Funding Opportunity Announcements and small business and contract announcements

NBS Projects Awarded by NICHD in Response to NIH Funding Opportunity Announcements (FOAs)
Mechanism
Year	Natural History of Disorders Identifiable by Newborn Screening (R01)	Innovative Therapies and Tools for Screenable Disorders in Newborns (R01)†	Innovative Therapies and Tools for Screenable Disorders in Newborns (R21)‡	Innovative Therapies and Tools for Screenable Disorders in Newborns (R03)§	Small Business (SBIR/STTR) Projects	Pilot Contracts (Conditions)¶	Total funded per year
2006	-	-	-	-	2	2	4
2007	-	4	-	-	4	1	9
2008	-	6	2	-	3	2	13
2009	-	14	5	-	4	-	23
2010	-	16	5	2	6	3	32
2011	2	11	1	3	3	2	22
2012	2	9	-	1	9	2 (X-ALD, SMA, DMD)	23
2013	2	7	1	2	6	-	18
2014	2	6	1	2	3	3 (Pompe)	17
2015	1	5	-	-	-	3 (MPS I)	9
2016	-	4	1	1	3	2 (X-ALD)	11
2017	1	4	2	3	4	3 (SMA)	17
2018	2	4	3	2	6	-	17
2019	3	3	3	-	8	1 (PUCD)	18
2020	2	2	2	1	6	1 (HCU)	14
FOA numbersǁ	RFA-HD-10-019, PAR-16-061, PAR-18-090, reissued as PAR-21-115	PAR-06-060, PAR-07-184, PAR-10-230, PAR-14-270, PAR-18-689, reissued as PAR-21-353	PAR-06-342, PAR-10-232, PAR-14-269, PAR-18-691, reissued as PAR-21-355	PAR-06-341, PAR-10-231, PAR-14-271, PAR-18-690, reissue as PAR-21-354

This was a search of NICHD’s internal funding database, so does not include NBS-related funding from other NIH institutes and centers, including the National Institute on Deafness and Other Communication Disorders (NIDCD), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Institute of Neurological Disorders and Stroke (NINDS), each of which has participated in these PARs during some cycles. Note that each year includes type 1 (new) awards as well as type 5 (noncompeting continuation) awards, or those that were initially issued in earlier years.

DMD, Duchenne Muscular Dystrophy; HCU, Homocystinuria and related disorders; MPS I, Mucopolysaccharidosis type I; PAR, Program Announcement with special review considerations, in this case reviewed as a group; Pompe, Pompe disease; PUCD, Proximal Urea Cycle Disorders; RFA, Request for Applications; SBIR, Small Business Innovation Research; STTR, Small Business Technology Transfer; SMA, Spinal Muscular Atrophy; X-ALD, X-linked adrenoleukodystrophy

^†Initial PAR-06-060 and PAR-07-184 were entitled, “Innovative Therapies and Clinical Studies for Screenable Disorders (R01),” and most recent PAR-21-353 is entitled, “Innovative Screening Approaches and Therapies for Screenable Disorders in Newborns (R01 - Clinical Trial Optional)”

^‡Initial PAR-06-342 was entitled, “Innovative Therapies and Clinical Studies for Screenable Disorders (R21),” and most recent PAR-21-355 is entitled, “Innovative Screening Approaches and Therapies for Screenable Disorders in Newborns (R21 - Clinical Trial Optional)”

^§Initial PAR-06-341 was entitled, “Innovative Therapies and Clinical Studies for Screenable Disorders (R03),” and most recent PAR-21-354 is entitled, “Innovative Screening Approaches and Therapies for Screenable Disorders in Newborns (R03 - Clinical Trial Optional)”

^¶Contracts for specific pilot conditions under the IDIQ (Indefinite Deliverables, Indefinite Quantity) were awarded starting in 2012

^ǁNote that the first 2 numbers in a FOA name represent the first fiscal year that awards can be made under that announcement and that most PARs last for 3 years

NBS paradigms originally considered the criteria proposed by Wilson and Jungner (Wilson & Jungner, 1968) for assessing the validity of a screening program for public health purposes, but the needs of NBS were such that these criteria were abandoned in favor of an evidence review process that evaluated three main criteria: (1) the condition had to be identified within 24–48 hours after birth prior to symptom onset, (2) the screening test had to have appropriate sensitivity and specificity, and (3) there were demonstrated benefits of early detection, intervention, and treatment. Ultimately, the ACHDNC adopted a revised decision matrix in 2013 that rated the strength of net benefit of screening along with an evaluation of the feasibility and readiness of states to add a condition to their panels (Kemper et al., 2014; Urv & Parisi, 2017; Watson et al., 2006). An assessment of the magnitude and certainty of the net benefit of early screening and treatment requires knowledge of the natural history of a condition, but since NBS identifies rare disorders, an understanding of the progression of disease is often limited or incomplete. To address this gap, NICHD issued a request for applications (RFA) in 2010 to support studies of the natural history of disorders screenable in the newborn period; two projects were funded in total, to collect longitudinal data on infants diagnosed with SMA or Inborn Errors of Metabolism (IEM). The natural history studies for SMA have been seminal in building the evidence base for the eventual nomination of SMA to be added to the RUSP (see Swoboda, Lessons Learned from Pilots of Spinal Muscular Atrophy (SMA), this issue); for IEMs, these studies created a core set of long-term follow-up data for many IEMs on the RUSP that can be accessed through the Newborn Screening Translational Research Network (see section below). Other awards have enhanced the understanding of conditions as diverse as sex chromosome trisomies, succinic semialdehyde dehydrogenase deficiency, and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) retinopathy.

NIH grant awards issued to commercial entities, either through the Small Business Innovation Research (SBIR; R43 and R44 mechanisms) or Small Business Technology Transfer (STTR; R41 and R42 mechanisms) programs, represent projects with an ultimate goal of commercialization. A healthy handful of such awards has propelled development of screening platforms for conditions such as fragile X syndrome, sex chromosome disorders, and cyanotic heart disease via pulse oximetry. Several have leveraged digital microfluidics platforms using small droplets of blood to facilitate table-top or bedside screening for neonatal disorders such as hypoglycemia, hyperbilirubinemia, or conventional RUSP conditions such as galactosemia, PKU, and lysosomal storage disorders (LSDs); adaptation of this technology can also be used for DNA sequencing-based analyses (Millington et al., 2010). Commercialization and FDA authorization of a microfluidics platform for a panel of four LSDs has facilitated adoption of these conditions into state newborn screening programs (Millington et al., 2018).

Contracts are another mechanism used by NIH/NICHD to stimulate NBS research, typically with specified deliverables within a limited time frame. To address the NBSSLA mandate of supporting pilot studies for NBS conditions recommended by the ACHDNC and to ensure these conditions are ready for nationwide implementation, beginning in 2014, the NICHD issued a series of indefinite delivery/indefinite quantity (“IDIQ”) requests for proposals to establish a pool of contracted states and laboratories to pilot the implementation of screening for new conditions recently added, or likely to be nominated for addition, to the RUSP. This mechanism allows for increased flexibility and ease of awarding new task orders because this type of contract provides for an indefinite quantity of newborn screens during a fixed period of time. These contracts have included pilots by one or more screening programs to screen for Pompe disease, mucopolysaccharidosis type I (MPS I), X-linked adrenoleukodystrophy (X-ALD), SMA, proximal urea cycle disorders (PUCD), and homocystinuria (HCU) and related conditions (Table 1). Currently, one state is performing a pilot of mucopolysaccharidosis type II (MPS II). A new disorder to pilot is selected by NICHD every 1–2 years, with the goal of screening at least 100,000 infants (initially only 50,000) in order to identify at least one newborn with the targeted condition accurately and efficiently and establish a treatment plan for true positive cases. The ultimate goal is to compete pilots that will support the collection of data to inform the ACHDNC evidence-based review for recently nominated conditions to the RUSP. Two articles in this issue describe the experiences by at least one group (See Wilcox, Georgia State Spinal Muscular Atrophy (SMA) newborn screening experience: screening assay performance and early clinical outcomes; and Wilcox, Newborn screening for proximal urea cycle disorders: results from the Georgia State pilot study, this issue) and provide valuable “real-world experiences” to inform the adoption and implementation of new conditions for NBS by other states. Importantly, these contracts have allowed laboratories to “test out” and validate technology platforms, assays, and algorithms for new conditions as well as confirmatory testing, diagnosis, and initiation of therapy to demonstrate the benefits of screening on a population-wide basis. In several cases, these contracts have facilitated development of post-analytic tools to refine cutoffs, elucidated strategies to address false positive cases due to enzyme pseudodeficiency, and identified improved approaches to confirmatory testing (Hall, Li, et al., 2020; Hall, Sanchez, et al., 2020; Kucera et al., 2021; Lee et al., 2020; Taylor et al., 2019; Taylor & Lee, 2019; Thorsen et al., 2021).

3. NICHD Resources: The Newborn Screening Translational Research Network (NBSTRN)

Beginning in 2008, the NICHD awarded a contract to the ACMG to support NBS researchers through the Newborn Screening Translational Research Network (NBSTRN), which serves as a centralized infrastructure to promote, facilitate, coordinate, and enhance NBS research (Figure 1) (Lloyd-Puryear et al., 2019). As described previously, the heterogeneity among the NBS public health programs with regard to specific conditions screened, DBS retention, and policies around informed consent requirements for research makes research in NBS challenging. The NBSTRN provides tools and resources in a secure environment for researchers conducting research in NBS and other rare diseases with neonatal onset. Resources developed in the first decade of the NBSTRN included access to tools for the analytical and clinical validation of screening tests by state screening programs (the “Region 4 Stork” information technology (IT) system (R4S) housed at the Mayo Clinic for clinical and NBS laboratory improvement); a web-based, “virtual” repository of over 3 million dried blood spots (VRDBS) to facilitate researcher access to samples housed in state NBS laboratories from population controls as well as from individuals known to have NBS conditions; an analytical and clinical data capture tool for the collection, analysis, sharing, and reporting of longitudinal laboratory and clinical data on newborn-screened individuals (the “Longitudinal Pediatric Data Resource” or LPDR); and resources to support awareness of and research on the ethical, legal, and social implications (ELSI) related to state and federal policies governing informed consent for DBS research (the “ELSI Advantage” function) (Lloyd-Puryear et al., 2019). NBSTRN also provides tools for researchers such as informed consent templates, support for disease registries, information about state NBS policies, and consultations for pilot studies. The LPDR has provided a resource for investigators to access case report form generators and a mechanism for collating data on the conditions under study (Brower et al., 2021). Additional requirements during the second 5-year funding cycle beginning in 2013 included development of common data elements (CDEs; see https://cde.nlm.nih.gov/cde/search?q=newborn%20screening) for NBS conditions and maintenance of a data repository to securely house genomic data, such as variant call files from genome and exome sequencing, and phenotypic data from subjects in the LPDR. The R4S system for collecting laboratory-based information from state programs and establishing cutoffs by comparing with the results of other states and international partners is now subsumed by the Collaborative Laboratory Integrative Reports (CLIR) project (Hall, Wittenauer, et al., 2020). Several of the work products of the NBSTRN have been developed by its working groups, and in particular, the Bioethics and Legal Workgroup has developed a platform to address ELSI questions (“Ask ELSA!”) and integrate key ELSI questions into pilot studies (Goldenberg et al., 2019).

During its most recent funding period, beginning in 2018, the NBSTRN revamped its resources and released a new version of its website that launched in February 2021 (https://nbstrn.org/) and included 3 curated knowledgebases (Figure 2):

• NBS Virtual Repository of States, Subjects & Samples (NBS-VR) provides state-level views of screening panels, polices, and procedures; estimated number of subjects available by condition; details about DBS retention time and storage conditions; and racial distributions of births

• NBS Conditions Resource (NBS-CR) is an interactive resource to learn more about conditions that are part of, or candidates for, nationwide screening

• ELSI Advantage is a resource about the ethical, legal, and social issues (ELSI) related to NBS, NBS research, and NBS pilot studies

Figure 2.

Core functions of the Newborn Screening Translational Research Network (NBSTRN). The NBSTRN provides 3 newly created knowledgebases to assist investigators with understanding the framework of NBS across conditions and states and address their ethical, legal, and social issues (left large box). Researchers can participate in a variety of collaboration tools and activities and forums (middle large box). The Longitudinal Pediatric Data Resource (LPDR) provides a suite of data tools to collect, analyze, visualize, and share genomic and phenotypic data for NBS project (right large box).

dbGaP, database of Genotypes and Phenotypes; ELSI, ethical, legal, and social issues; NBS, newborn screening.

Collaboration resources for researchers are also a core function of the new NBSTRN, as is the LPDR (Figure 2). The LPDR remains a cornerstone of the resource, supporting over 350 registered users on its redesigned interface, coordinating the development of over 24,000 core and disease-specific CDEs, and hosting data from 23 longitudinal projects, including data from 118 rare genetic diseases and over 8800 participants, as well as multi-state pilots that collectively screened over 1.2 million births. NBSTRN also served as the de facto data coordinating center for the four Newborn Sequencing In Genomic Medicine and Public Health (NSIGHT) projects and is now coordinating their genomic dataset deposition into the NIH database of Genotypes and Phenotypes (dbGaP; see later section) (Brower et al., 2021).

4. Partnerships with other Federal agencies: Road to the RUSP

The efforts of the NIH to promote NBS research is not the only federal activity that promotes advances in NBS. In fact, although NIH (and specifically NICHD’s) role has been focused on research to develop the evidence base for the development and piloting of new screening paradigms as well as new therapies and interventions, several other agencies within the Department of HHS also support NBS activities as outlined in the NBSSLA. As illustrated in “The Road to the RUSP” (Figure 3), several activities typically need to occur before a new condition can be nominated to the RUSP. There is preparatory work that takes place years or sometimes decades before a condition is ready for adoption into a public health screening setting, and the NIH role is often one that supports the scientific research to understand the basic mechanisms of disease, learn about its natural history, study animal models of the condition, develop and pilot screening assays to detect the disorder, and develop interventions and treatments for the condition. Many of these research activities are funded through NIH FOAs and supported by the NBSTRN. Since many of the conditions are associated with IEMs, treatments often rely on either dietary interventions such as medical foods or formulas that minimize the intake of nutrients that can lead to build-up of toxic metabolites (e.g., low protein or phenylalanine-free formulas for PKU), or ingestion of compounds that can bind or eliminate those toxic metabolites (e.g., nitrogen scavengers such as sodium phenylbutyrate that combine with glutamine for excretion of ammonia that bypasses the urea cycle). Enzyme replacement therapy has become a mainstay of therapy for many of the lysosomal storage disorders and related disorders so that the defective enzyme can be provided to critical target tissues to prevent the build-up of storage material in lysosomes (e.g., Pompe disease); stem cell transplantation is also an option for some disorders where blood-based hematopoietic stem cells can correct the metabolic defects in critical tissues (e.g., for MPS I). More recently, gene-targeted therapies have been developed for some disorders to replace, correct, or repair a defective gene and rescue the defect (e.g., SMA). In addition to NIH support for research, foundations and patient organizations may fund some of this early-stage research, along with the Centers for Disease Control and Prevention (CDC). CDC often supports research that helps develop and validate screening assays, it provides resources for pilot studies, and it also develops quality assurance (QA) and proficiency testing materials to be used by the states to ensure accurate NBS. Both CDC and the Agency for Healthcare Research and Quality (AHRQ) contribute to epidemiological and health services research and surveillance that are critical to understand the public health magnitude of the condition. A screening assay must be approved by the Food and Drug Administration (FDA) through its Center for Devices and Radiological Health (CDRH). In addition, availability of a safe and effective therapy is a crucial requirement for adding a new condition to the RUSP, and most new therapeutics are typically submitted to the FDA for review and approval—to the Center for Drug Evaluation and Research (CDER) for medications, and to the Center for Biologics Evaluation and Research (CBER) for gene therapy-based treatments.

Figure 3.

The Road to the RUSP with federal agency support. The circles above the black funnel represent preparatory work prior to submission of a nomination package for a new condition to the ACHDNC. The 8 arrow-bars underneath represent the steps in considering, approving, and implementing a new condition that has been nominated to the ACHDNC and approved.

ACHDNC, Advisory Committee on Heritable Disorders in Newborns and Children; AHRQ, Agency for Healthcare Research and Quality; CDC, Centers for Disease Control and Prevention; Epi, epidemiological; FDA, Food and Drug Administration; HHS, U.S. Department of Health and Human Services; HRSA, Health Resources and Services Administration; NBS, Newborn Screening; NIH, National Institutes of Health; NSMBB, Newborn Screening and Molecular Biology Branch; RUSP, Recommended Uniform Screening Panel; Secretary, Secretary of HHS; QA, Quality Assurance; TA, Technical Assistance.

Pilot studies are critical to gather real-world evidence of whether the assay is reliable, accurate, and sensitive in a study performed in a population-based screening environment (see Swoboda, Lessons Learned from Pilots of Spinal Muscular Atrophy (SMA), and Gruber, A Pilot of Duchenne Muscular Dystrophy: An Algorithm for Carrier Females, this issue, for details of sample pilot studies employed for this purpose). Validation of the screening test, the availability of confirmatory testing, and a prospective, population-based pilot study are all requirements for a RUSP nomination (https://www.hrsa.gov/advisory-committees/heritable-disorders/frequently-asked-questions). In reality, a confirmed positive case identified through a pilot study has been a necessary requirement for a nomination to be successful. For each disorder, these studies can require decades of research investment, commitment of investigators and clinicians who specialize in the disorder, and partnerships with advocacy groups and patients themselves to gather sufficient evidence to submit a successful nomination package to HRSA, which provides technical assistance and oversees the nomination review process by the ACHDNC. The nomination form has recently been updated and is available on the HRSA ACHDNC webpage (https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp/nominate.html).

Once a nomination is received by HRSA under the ACHDNC, a multi-step process ensues to review the nomination, and if approved, to conduct a rigorous, evidence-based review for the nominated condition (https://www.hrsa.gov/sites/default/files/hrsa/advisory-committees/heritable-disorders/rusp/Nominate-condition/rusp-nomination-review-process.pdf). This formal external review determines if the benefits outweigh the harms of screening for the condition with an emphasis on the health benefits to the newborn being screened, as well as an assessment of the public health system impact and the readiness and feasibility of states to include the condition in their screening programs. The Committee uses a decision matrix (https://www.hrsa.gov/advisory-committees/heritable-disorders/decision-matrix) to guide its final decision on whether to recommend that the condition be added to the RUSP. If the committee votes to recommend addition to the RUSP, the recommendation is sent to the Secretary of HHS who makes the final decision.

Once the condition is formally added to the RUSP, this does not mean that states will adopt and implement the condition immediately; many steps may be required to facilitate adoption of a new NBS condition, and this can vary by state and screening program. The NBS Quality Assurance Program within the Newborn Screening and Molecular Biology Branch (NSMBB) at CDC provides Technical Assistance (TA) and Quality Assurance (QA) materials to state NBS programs and more than 80 countries to ensure the accuracy of newborn screening. HRSA also provides TA and supports development of quality measures and a resource (NewSTEPs; https://www.newsteps.org/) that allows states to track outcomes and compare quality indicators with one another. Finally, CDC and HRSA often provide assistance in the form of grants and cooperative agreements for implementing new conditions within state public health programs and resources for continuous improvement. HRSA has developed clinician and family education materials for RUSP conditions (https://newbornscreening.hrsa.gov). The ACMG also provides ACTion (ACT) Sheets for medical providers who may see newborns with a positive screen for these conditions to inform clinical decision making.

5. Genomic Sequencing in Newborns: The NSIGHT Program developed by NHGRI and NICHD

The NBS research community has been the beneficiary of a fruitful collaboration between the NICHD and the National Human Genome Research Institute (NHGRI). In 2010, the two institutes, along with the NIH Office of Rare Diseases Research (ORDR), sponsored a workshop entitled, “Newborn Screening in the Genomic Era: Setting a Research Agenda” to define the technical considerations for conducting genomic sequencing on samples from DBS, explore the value that genomic sequencing could add to NBS, and address the ELSI-related issues for such a paradigm shift in NBS (see https://www.nichd.nih.gov/sites/default/files/about/meetings/2010-retired/Documents/Newborn_Research_Agenda.pdf for meeting summary). The development of massively parallel sequencing technologies in the 2000s enabled, for the first time, large-scale genomic sequencing at lower cost and greater throughput, with potential to be applied to newborns. While the possibilities and promise of applying genomic sequencing modalities in newborns, especially those with devastating or life-threatening conditions, is more broadly accepted today, when the workshop was held, there was a great deal of concern about the use of this technology and its potential to lead to “designer babies” or a dystopian world similar to the premise of the movie “GATTACA,” where a person’s fate was sealed by their genetic makeup at birth. In 2010, the RUSP had just been created after the Secretary of HHS accepted the ACHDNC recommendation to adopt 29 core and 25 secondary conditions that have serious health implications in newborns if not identified and treated efficiently, but the majority of states were not screening for nearly that many conditions. At that time, the screening of all of these conditions, with the exception of cystic fibrosis (CF) and hearing loss, relied on biochemical, metabolic, and/or enzymatic assays, many based on tandem mass spectrometry (MS/MS). The only DNA-based analysis was performed by states that utilized PCR-based targeted mutation panels for pathogenetic variants in the CFTR gene as secondary screening for CF. Two FOAs released in 2012 emerged from concepts developed through workshop deliberations: a PAR for “Methods Development for Obtaining Comprehensive Genomic Information from Human Specimens that are Easy to Collect and Store (R43/R44)” (https://grants.nih.gov/grants/guide/pa-files/PAR-13-203.html); and an RFA for “Genomic Sequencing and Newborn Screening Disorders (U19)” (https://grants.nih.gov/grants/guide/rfa-files/rfa-hd-13-010.html). The latter RFA had the purpose of supporting projects that addressed one or more of the following research questions:

• For disorders currently screened for in newborns, how can genomic sequencing replicate or augment known newborn screening results?

• What knowledge about conditions not currently screened for in newborns could genomic sequencing of newborns provide?

• What additional clinical information could be learned from genomic sequencing relevant to the clinical care of newborns?

Each project responding to the RFA was required to have 3 components:

1. Acquisition and analysis of genomic datasets that expand considerably the scale of data available for analysis in the newborn period;

2. Clinical research that will advance understanding of specific disorders identifiable via newborn screening through promising new DNA-based analysis; and

3. Research related to the ELSI of the possible implementation of genomic sequencing of newborns.

The four U19 awards, funded in 2013 and completed in 2019, were the basis for the Newborn Sequencing In Genomic Medicine and Public Health (NSIGHT) program (https://www.genome.gov/Funded-Programs-Projects/Newborn-Sequencing-in-Genomic-Medicine-and-Public-Health-NSIGHT), the initiative jointly funded by NICHD and NHGRI that explored the implications, challenges, and opportunities associated with the possible use of genomic sequence information in the newborn period (Berg et al., 2017) (Table 2).

Table 2.

Overview of the four funded Newborn Sequencing In Genomic Medicine and Public Health (NSIGHT) projects.

	Brigham and Women’s Hospital/Boston Children’s Hospital/Baylor College of Medicine	Rady Children’s Hospital and Children’s Mercy Hospital	University of California, San Francisco	University of North Carolina at Chapel Hill
Title of Project	Genome Sequence-Based Screening for Childhood Risk and Newborn Illness (“BabySeq”)	Clinical and Social Implications of 2-day Genome Results in Acutely III Newborns	Sequencing of Newborn Blood Spot DNA to Improve and Expand Newborn Screening (“NBSeq”)	NC NEXUS, North Carolina Newborn Exome Sequencing for Universal Screening
Cohort under study	Sick newborns (ICUs) and Healthy newborns (well nursery)	Sick newborns (NICU), some trios	De-identified DBS from California NBS program; Newborn DBS from consented individuals with PID	Children with known NBS conditions Healthy newborns (prenatal ascertainment)
Biospecimens	Whole blood/saliva	Whole blood	DBS from NBS biobank	Cheek swabs
Sequencing approach	WES	Rapid WGS	WES	WES
Return of results—primary findings	Diagnostic findings (if NICU/clinical indications); highly penetrant childhood-onset or treatable conditions (all)	Diagnostic or likely diagnostic findings	No ROR for NBS cohort; clinical confirmation offered for likely pathogenic variants in PID cohort	Diagnostic findings (affected cohort); Childhood-onset, medically actionable conditions (all)
Return of results—secondary findings	Carrier status for childhood-onset conditions and selected PGx	Incidental genetic disorders if life-threatening in childhood	None	Parents randomly assigned to decision group can choose: childhood-onset, non-medically actionable; carrier status-recessive conditions; adult-onset medically actionable conditions
ELSI project	Surveys of parents and MDs to assess impact of genomic sequencing	Surveys of parents and MDs to assess impact of genomic sequencing	Focus groups with parents of PID patients; healthy pregnant women; OBs and pediatricians	Metric to determine medical actionability; electronic decision aid to set parental preferences
References	Ceyhan-Birsoy et al, 2017; Ceyhan-Birsoy et al, 2019; Pereira et al., 2021	Willig et al., 2015; Kingsmore et al., 2019; Dimmock et al, 2020; Cakici et al, 2020	Adhikari, Gallagher et al., 2020; Adhikari, Curry et al., 2020; Woerner et al., 2021	Lewis et al., 2016; Milko et al., 2018; Milko et al., 2019; Roman et al., 2020; Moultrie et al., 2020

Data derived from the NSIGHT Program website (https://www.genome.gov/Funded-Programs-Projects/Newborn-Sequencing-in-Genomic-Medicine-and-Public-Health-NSIGHT) and (Berg et al., 2017).

DBS, dried blood spots; ICU, intensive care unit; MD, medical doctor; NBS, newborn screening; NICU, neonatal intensive care unit; OB, obstetricians; PGx, pharmacogenomics; PID, primary immunodeficiency; ROR, return of results; WES, Whole Exome Sequencing; WGS, Whole Genome Sequencing

Two of the NSIGHT projects enrolled a specialized population of newborns: ill neonates in the intensive care unit (ICU). In an initial study of 35 infants performed at Children’s Mercy Hospital in Kansas City, results suggested that rapid whole genome sequencing (rWGS) could be performed as a first-tier diagnostic test in inpatient infants, with diagnosis provided in 57%, and changes in treatment or management in 65%, including initiation of palliative care when appropriate (Willig et al., 2015). In a subsequent study at Rady Children’s Hospital, this team performed a randomized control trial of rWGS or rapid whole exome sequencing (rWES) to identify potential genomic variants that could explain the neonate’s constellation of features, and ultra-rapid whole genome sequencing (urWGS) was employed for those critically ill or unstable (Kingsmore et al., 2019). Of the 1248 babies admitted to the ICU, 578 (46%) of whom had unknown conditions, 313 infants were enrolled within 96 hours of admission to one of the genomic modalities. The analytic performance of rWGS was superior to that of rWES in identification of pathogenic or likely pathogenic (P/LP) variants, but the overall diagnostic yield was similar for both, 19–20%, as was the time to obtain a result (~ 11 days). In contrast, urWGS had a higher diagnostic yield (46%) and the shortest time to result (median 4.6 days), important in medically unstable infants, and in those in whom a genetic diagnosis was likely to impact immediate management (Kingsmore et al., 2019). In these studies, the perception of clinicians caring for these infants was that rapid genome sequencing was clinically useful for 77% of infants, whether they received positive or negative test results, and especially when genomic sequencing results led to a change in management (reported for 28% of infants) (Dimmock et al., 2020); comparable positive perceptions were reported by parents whose ill infants had received rapid genomic sequencing—they had been adequately consented, understood the results, and denied regret or harm from the study (Cakici et al., 2020). This pioneering work highlights the value of rWGS, which can return results in a few days, in comparison with targeted gene panels that may take weeks if not months for completion and may not yield a definitive diagnosis. This approach is transforming care for infants in the ICU setting, and as shown by one study of the use of rWGS in 5 tertiary-care children’s hospitals in California receiving Medicaid services, demonstrated clinical utility and reduced net healthcare expenditures (Dimmock et al., 2021). In the other NSIGHT Project study evaluating ill neonates based in Boston, WES had limited impact on diagnosis, but the cohort only included 32 newborns in the ICU (Ceyhan-Birsoy et al., 2019).

Two of the projects explored the utility and value of sequencing in healthy newborns. The Boston-based Genome Sequence-Based Screening for Childhood Risk and Newborn Illness (“BabySeq”) Project and the North Carolina Newborn Exome Sequencing for Universal Screening (“NC NEXUS”) Project, both proposed and developed panels of genes that could be tested in newborns due to the early age of onset and medical actionability of a P/LP variant. The BabySeq project identified a panel of 954 genes with strong evidence for childhood-onset disorders or associated with highly penetrant disease (Ceyhan-Birsoy et al., 2017). Of their cohort of newborns sequenced, including healthy newborns and those in the Neonatal Intensive Care Unit (NICU), 15/159 had a P/LP variant not associated with their underlying condition, for a yield of 9.4% (Ceyhan-Birsoy et al., 2019). In addition, 88% of newborns had at least one recessive carrier variant that could have implications for other family members, and 5% of neonates had an atypical pharmacogenomic variant that could impact metabolism of medications. The NC NEXUS project identified a panel of 466 genes determined to be of childhood onset and medically actionable based on a semi-quantitative approach evaluating severity and penetrance of pathogenic mutations, efficacy and acceptability of interventions, and strength of evidence (Milko et al., 2019). The North Carolina cohort also consisted of healthy infants and those diagnosed with an IEM or hearing loss, and 3.7% had P/LP variants (Roman et al., 2020). For those infants whose parents requested it, the number of carrier findings ranged from 1–7 variants, for an average of 1.8 per individual. In both projects, the yield of genomic sequencing was small but not insignificant, and suggested that larger sample sizes would be valuable to confirm these results. The targeted lists of genes generated by these groups provide a potential framework to consider additional genetic disorders for NBS in the future.

Both the NC NEXUS Project and the Sequencing of Newborn Blood Spot DNA to Improve and Expand Newborn Screening (“NBSeq”) Project in California compared the results of WES with traditional methods using MS/MS to determine how sequencing compared to conventional NBS. Both groups found that sequencing-based technologies detected 88% of infants with known NBS disorders (Adhikari, Gallagher, et al., 2020; Roman et al., 2020). In the NBSeq project, WES had a sensitivity of 88% and specificity of 98.4%, compared to 99.0% and 99.8%, respectively, for MS/MS, in a large collection of screen-positive and control samples from the California state screening program (Adhikari, Gallagher, et al., 2020). This finding suggests that genomic sequencing is unlikely to replace traditional detection methods at least in the near-term; however, sequencing results can be employed as a 2^nd or 3^rd tier approach with MS/MS to decrease false positive and increase specificity of the screen. Combining WES with MS/MS may also improve the sensitivity of screening to identify some infants with certain NBS conditions (Adhikari, Currier, et al., 2020). Moreover, WES-based approaches may also identify some infants with forms of NBS conditions not ascertained by traditional methods and identify new genetic causes for classical NBS conditions, attesting to its potential as at least an adjunct to conventional NBS approaches (Woerner et al., 2021).

The ELSI projects pursued by the NSIGHT program provided insights into some potential ethical challenges to the use of WES or WGS in mandatory public health NBS programs. The BabySeq Project explored the psychosocial impact of newborn genomic sequencing on families through a randomized clinical trial of return of newborn genomic sequencing results vs. standard NBS results plus a family history report, and found that there were no persistent negative effects on families, even those that received a monogenic disease risk finding (Pereira et al., 2021). However, the recruitment rates for the study were low (concerns about privacy and insurance discrimination as well as the burden of participation were cited as reasons for declining) and skewed towards parents with a higher educational level that were not representative of the general U.S. population (Tarini, 2021). In addition, the team struggled with the return of a result of an adult-onset-only condition (a pathogenic BRCA2 variant in a newborn that predisposed adult family members to breast and/or ovarian cancer), which raised issues related to informed consent, the child’s best interests vs. those of the extended family, and the potential need for cascade testing of other at-risk family members (Holm et al., 2019). The NC NEXUS project developed an evidence-based and validated online tool to support parental informed decision-making about the use of genomic testing in NBS that was piloted among families enrolling in the enhanced NBS project and explored issues of informed consent and decisional regret (Lewis et al., 2016; Milko et al., 2018). In focused interviews with current or expecting parents, 91% indicated they would definitely want genomic sequencing for their newborn if offered, but they were less definitive about receiving information that was not medically actionable, related to adult onset conditions, or revealed carrier status (Moultrie et al., 2020). In general, for the studies that sequenced healthy newborns, the number of prospectively tested infants was small, and including larger and more diverse populations of infants and their parents will be important to confirm these preliminary findings. In fact, one of the projects is doing just that, by engaging community partners to enroll a larger and more representative cohort of 500 new babies in BabySeq2 in order to determine the utility and impact of genomic sequencing in newborns (https://www.genomes2people.org/research/babyseq/). Overall, bioethicists associated with these projects agreed that while genomic sequencing may be justified and have clinical utility in specific contexts (such as for symptomatic newborns), and targeted sequencing panels may be reasonable to identify specific conditions included on NBS panels such as the RUSP, widespread genomic sequencing for newborns was premature (Johnston et al., 2018).

Throughout the course of this program, the NBSTRN served as a coordinating center for the NSIGHT projects and has served as the data repository for sequencing data from 3 of them; it has deposited these genomic datasets into dbGaP for broader data sharing and distribution.

6. New paradigms for newborn screening

Although the current process for adding conditions to the RUSP has effectively added 7 new conditions since the original panel was proposed in 2006 and adopted in 2010 (an eighth, guanidinoacetate methyltransferase or GAMT deficiency, was recommended for RUSP addition by the ACHDNC in May 2022 and is awaiting the HHS Secretary’s final decision), there are a number of conditions (at least 8 according to the HRSA website; https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp/previous-nominations.html) that have not been recommended for addition to the RUSP. The reasons vary, but for some, the evidence of benefit of screening has not been firmly established, the pilot has not prospectively identified a true positive case, or the timing of NBS was not optimal for the identification of the infantile condition (such as hyperbilirubinemia, which often peaks several days after a newborn is discharged from the hospital). Several conditions were nominated 2 or 3 times before finally being approved for addition to the RUSP. Among the estimated 7000 rare diseases, a subset presents in the neonatal period, and a smaller subset has available treatments; nonetheless, it will take a very long time before all of the eligible conditions have had a chance for review by the ACHDNC. Clearly, the NBS system needs new strategies for updating screening panels, pursuing pilot studies, and potentially considering groups of disorders together. One novel approach is an infant screening program termed “Early Check,” led by a team at Research Triangle Park, Inc. (RTI) in partnership with the North Carolina state screening program, to provide the infrastructure to identify conditions for which there have been significant advances in treatment options, but require a large-scale, population-based study to test benefits, risks, and feasibility (Bailey et al., 2019). This strategy obtains informed consent postnatally from families to take an extra punch from the DBS for testing conditions such as fragile X syndrome, DMD, and others that are ideally identified in the newborn period but not as time-critical as the other conditions on the RUSP (Kucera et al., 2021).

Another team is taking a different approach to pilot the screening of a flexible panel of an additional 14 LSDs in several birthing hospitals in New York City by using imbedded study coordinators to obtain informed consent from new parents at each site (Wasserstein et al., 2019; Wasserstein et al., 2021). The creative funding for this program, known as “ScreenPlus,” includes NICHD sources as well as a number of industry partners engaged in developing treatments for several of these LSD conditions. In addition, the project will explore some of the ELSI issues associated with this expanded pilot study, particularly since it is likely to identify infants with later-onset, untreatable, and uncertain forms of the conditions.

The availability of new therapeutics and patient group advocacy efforts collectively may overwhelm the current NBS system with nominations and threaten the public acceptance of a mandatory public health program such as NBS (McCandless & Wright, 2020). Given the explosion of gene therapies projected to be approved by the FDA in the next decade, there is a great need to anticipate the best strategies for modernizing the NBS system, and a systematic feedback process involving panels of NBS stakeholders (Andrews et al., 2022) and a survey completed by NBS experts (Bailey et al., 2021) explored some of these challenges and solutions. Potential solutions included establishing mechanisms for cross-state data coordination for new disorders, creating public-private partnerships to support funding for NBS expansion, and creating a network of regional screening laboratories to support these efforts.

7. Gene-Targeted Therapies Workshop

In June 2021, the NIH, led by the National Center for Advancing Translational Sciences (NCATS) in conjunction with NICHD and the National Institute of Neurological Disorders and Stroke (NINDS), sponsored a workshop entitled, “Gene Targeted Therapies: Early Diagnosis and Equitable Delivery (GTT-EDED; https://events-support.com/events/Gene-Targeted_Therapies_June_2021). The premise of the workshop was the recognition that the development of precision therapies has the potential to provide treatments to many individual and unique genetic conditions quickly and efficiently. In fact, it is theoretically possible to correct up to about 89% of all known pathogenic human genetic variants using gene-targeted approaches, such as oligonucleotide therapies, virus-mediated gene replacement, and somatic genome editing (https://www.advancedsciencenews.com/delivering-crispr-gene-editing-therapy-whats-holding-us-back/)(Anzalone et al., 2019). Given the promise of individualized therapies using common gene vectors and therapeutic platforms, there is the potential to intervene pre-symptomatically to achieve the best outcomes, and the newborn period affords an opportunity to treat prior to the onset of irreversible disease manifestations. Thus, the purpose of this workshop was to push the boundaries of what might be feasible to implement such gene-targeted therapies in the future, while addressing the very real concerns related to efficiency, cost-effectiveness, and equitable distribution to all at-risk infants. To accomplish these goals, workshop organizers brought together a group of stakeholders representing the biomedical research, regulatory, clinical practice, public health, industry, government, and advocacy communities, and including the general public, to consider new gene-based approaches to screening, diagnosis, and treatment now that the costs of WES and WGS have fallen significantly to make these sequencing-based approaches feasible. Held just over 10 years after the NICHD-NHGRI joint workshop on Newborn Screening in the Genomic Era, this workshop considered these three themes: (1) The “who, what, and when” of optimal diagnosis and treatment for new conditions using these approaches; (2) The infrastructure and approaches needed so that this “genome-first approach” could inform traditional NBS; and (3) The economic and ethical implications of ensuring that such technologies and access to treatments are equitably distributed to all individuals.

One of the major ideas that emerged from that meeting was the concept of moving away from “one disease at a time” paradigms of NBS to consideration of gene-targeted platforms that could address groups of diseases, particularly monogenic disorders caused by a number of pathogenic genomic variants. With the recognition that rare genetic diseases are a significant cause of infant mortality and lifelong morbidity and economic burden in the U.S. (Yang et al., 2022), approaches to diagnosis would need to be comprehensive, efficient, and build on the egalitarian model of NBS—every infant is screened, regardless of race, sex, place of residence, and socioeconomic status. A “sequencing-first approach” could consider, as a starting point, a panel of all established disease-associated genomic variants for which treatments are available, much as several NSIGHT projects proposed. However, there are significant financial implications to such a change in screening paradigms, and costs for under-resourced NBS public health laboratories to implement such strategies, including investments in new equipment and staff responsible for interpretation of genomic variant data and return of results, are considerable (Woerner et al., 2021).

On the other hand, platforms to develop gene-targeted therapies for classes of genetic diseases are already under development, and some are used as treatments for NBS conditions, such as two of the therapies available for SMA: the antisense oligonucleotide (ASO) therapy nusinersen (Spinraza) and the gene replacement therapy Zolgensma (Jablonka et al., 2022). Customizable “n of 1” treatments have been brought to fruition in under a year for specific variant-based disorders such as neuronal ceroid lipofuscinosis (Kim et al., 2019), and non-profit groups such as the n-Lorem Foundation have pledged to facilitate this process regardless of a family’s ability to pay (Crooke, 2022). Federal legislation and the FDA have demonstrated a willingness to support these approaches through the Orphan Drug Act and approval of genomic therapeutics such as RNA-based therapies (Yu & Tu, 2022). Nonetheless, ensuring population-wide access to gene-based diagnostics and therapeutics has not always been successful, and requiring equitable distribution from the beginning, as well as effective public-private partnerships, would be necessary to ensure that this laudable goal could be accomplished.

8. Conclusions: Looking toward the Future

NICHD has made a clear commitment to NBS research and addressing legislative priorities in the NBSSLA, as evidenced by its long-standing support of FOAs, programs, and resources through the Hunter Kelly Newborn Screening Research Program. In its partnerships with other federal agencies, NIH has promoted research that can support the nomination of new conditions to be added to the RUSP. And the joint NHGRI-NICHD program that examined the use of genomic technologies in newborns provided provocative pilot data regarding the feasibility and logistic and ethical challenges of such an approach in NBS and newborn medicine. The remaining question is, “What is next?” How will NIH resources and research investments continue to stimulate cutting-edge research in NBS? Can the approach to single treatable conditions be expanded to include a group of conditions for which early interventions are the mainstay of treatment? Could NBS expand to include conditions where the “diagnostic odyssey” might be alleviated even if specific treatments are not (yet) available, potentially providing knowledge that can inform quality of life for the child and family members? The ethical implications of NBS expansion approaches need to be considered carefully, and under NIH’s current mandate to increase diversity across NIH communities (https://www.nih.gov/ending-structural-racism/unite), issues of equity and justice take on even more importance. In order for inclusion of genome-based testing strategies into NBS to succeed, there is a critical need to increase trust from underrepresented communities so that they feel comfortable having their newborn’s genome sequenced, and so that families do not opt out of all of NBS, thereby sabotaging its effectiveness as a universal public health strategy. Past experience has shown that groups that fear governmental collection of genetic data may pursue lawsuits that result in the destruction of valuable DBS samples and result in tightened restrictions on their use in research (“Newborn bloodspot retention reinstated in Minnesota: practice expected to benefit larger newborn screening studies, public health, disease research,” 2014). NBS, lauded as one of the ten most significant public health achievements in the U.S. between 2001–2010 by the CDC (“Ten great public health achievements--United States, 2001–2010,” 2011), will cease to be such an exemplar if it is not distributed equitably. We are at an inflection point, and the future is promising, but next steps need to be considered carefully, and public/parental/stakeholder engagement will be crucial to increasing the acceptability of WGS in testing newborns. Truly, we have come full circle with the potential to use population-based screening to diagnose individual genetic disease, with the hope that precision therapies will be available to treat all impacted newborns.