"Background" Newborn screening (NBS) is a state-based public health program that screens
babies for a panel of over 30 conditions. It is estimated that about 12,500 newborns each
year in the United States are identified with one of the conditions screened in NBS, with
each child receiving the benefit of early treatment. For inclusion in newborn screening
there must be evidence that pre-symptomatic treatment is more effective than treatment
after clinical presentation. Most conditions proposed for newborn screening are rare,
however, and researchers have difficulty identifying sufficient numbers of babies to test
the benefits of pre-symptomatic identification and treatment. This lack of data is
central to challenges that the U.S. Department of Health and Human Services Advisory
Committee on Heritable Disorders in Newborns and Children (ACHDNC) faces when making
federal recommendations to states on which conditions should be included in newborn
screening programs. ACHDNC is often asked to consider conditions for inclusion in newborn
screening for which there is limited evidence of the natural history, prevalence, and
especially about the benefit of early treatment.
"Rationale" That evidence gap, especially in the rare disease context, makes it important
to develop and test a system to efficiently generate high-quality data about conditions
that have the potential to be candidates for state newborn screening. The Early Check
program will address this gap through screening newborns for a carefully selected panel
of conditions, offered under a research protocol with biological maternal permission,
except in cases where there is a transfer or loss of custody. In cases with a
transfer/loss of custody, a legal guardian can grant permission for the infant to join
Early Check. Early Check will identify pre-symptomatic infants with rare disorders,
accelerate the acquisition of data on the early natural history of rare disorders, and
demonstrate the feasibility of a statewide program to offer voluntary opt-in newborn
screening for a panel of conditions not currently included in states' standard newborn
screening. Further, Early Check will facilitate the public health 'on-boarding' of
conditions that are ultimately recommended for state newborn screening programs.
The initial panel of conditions screened in the Early Check program will change over the
course of the study. Previously screened conditions have included spinal muscular
dystrophy (SMA), fragile X syndrome (FXS), and Duchenne muscular dystrophy (DMD) and
related neuromuscular conditions that result in increased levels of creatine kinase
(CK-MM). SMA has an approved treatment, nusinersen, which has been demonstrated to
improve outcomes in infants with infantile-onset SMA. In addition, infants with a shorter
disease duration compared to a longer disease duration had improved outcomes after the
start of treatment with nusinersen, suggesting that earlier identification of SMA would
benefit affected infants. There is also an approved gene therapy, Zolgensma, for SMA. FXS
does not have an approved treatment, although there is evidence that early behavioral
intervention services may improve outcomes. Given that the diagnosis of FXS is made on
average after the child is three years old, early identification through the screening of
newborns may provide benefit to the child. These conditions are rare; SMA has an
estimated incidence of 1 in ~10,000, DMD has an estimated incidence of 1 in 4000-5000
males, and FXS has an estimated incidence of 1 in ~4,000 males and 1 in ~4,000-6,000
females. We also completed a sub-study with a secondary permission process that offers
mothers the choice to obtain additional data about the gene that causes FXS:
specifically, whether the infant has a premutation in the gene, which has an uncertain
impact on the infant's learning and development. This uncertainty is the reason why
premutation results are offered separately under a sub-study. DMD causes progressive
inflammation, fibrosis, and muscle fiber degradation, and weakness. DMD has traditionally
been treated with physical therapy, corticosteroids, and ACE inhibitors to delay the
progression of skeletal muscle and cardiac damage. In 2016, the FDA approved Eteplirsen
(Exondys, 51) a promising treatment for a subset of patients with DMD. In 2017 the FDA
approved Emflaza, a corticosteroid also known as deflazacort. In 2019 the FDA approved
Vyondys 53 and in 2020 the FDA approved Viltepso for mutations amenable to exon 53
skipping. Early diagnosis allows for treatments that might work best if used
presymptomatically.
The current screening panel includes 182 genes for rare conditions that are highly
actionable by age 2. An optional secondary panel includes 32 genes that are less
actionable, or for which there are treatments under trial, with an additional optional
third panel that screens for genetic risk for Type 1 Diabetes.
For a wide range of rare disorders there is evidence that a delayed diagnosis (i.e., the
frequently-described diagnostic odyssey as parents search for a diagnosis) can have
negative health outcomes on children who miss out on treatments or interventions and on
families who experience negative psychosocial impact
In the future, Early Check will continue to integrate new conditions to the screening
platform as science advances and funding is secured, and conditions may be removed from
the screening platform as associated research questions are answered and/or conditions
achieve inclusion in state newborn screening programs (as was the case with SMA and FXS).
The overall research question is whether Early Check is an effective onboarding program
to inform newborn screening policy decision-making.
Early Check will also provide the infrastructure to facilitate translational research
studies and clinical trials. A dilemma in research in rare diseases is a lack of
sufficient numbers of presymptomatic patients. New treatments are being developed for
rare diseases at a rapid pace. Presymptomatic treatment often has the best potential for
effective treatment. Currently, early identification and intervention is based on the
prenatal or early diagnosis of a sibling of a patient with known disease, which greatly
limits the numbers of presymptomatic patients available for trials. Newborn screening has
the greatest potential to identify presymptomatic infants. Ultimately the research
program should more rapidly advance understanding of diseases and treatments, reducing
the length of time for appropriate conditions to be added to the recommended panel for
inclusion in state newborn screening programs, and provide early identification of
affected newborns.
Overall, this project will provide important information about the success of Early Check
to feasibly and acceptably implement a large scale, electronically-mediated research
approach to accurately identify affected infants. Results of the research activities and
the ongoing quality assessment will be used to inform the most efficient and judicious
translation of expanded newborn screening into public health in ways that maximize
benefit and minimize potential risk of harm to children and families.