Pediatric Annals

Special Issue Article 

Updates in Newborn Screening

Farrah Rajabi, MD


Newborn screening in the United States is an important public health measure to provide early detection for specified disorders when early treatment is both possible and beneficial. As technology improves, newborn screening can be offered for many more conditions. In the past 10 years, screening has expanded to include severe combined immunodeficiency, congenital heart disease, lysosomal storage disease, and X-linked adrenoleukodystrophy. This article reviews the current state of newborn screening with updates on recent developments. [Pediatr Ann. 2018;47(5):e187–e190.]


Newborn screening in the United States is an important public health measure to provide early detection for specified disorders when early treatment is both possible and beneficial. As technology improves, newborn screening can be offered for many more conditions. In the past 10 years, screening has expanded to include severe combined immunodeficiency, congenital heart disease, lysosomal storage disease, and X-linked adrenoleukodystrophy. This article reviews the current state of newborn screening with updates on recent developments. [Pediatr Ann. 2018;47(5):e187–e190.]

Newborn screening (NBS) first started in the 1960s to test for phenylketonuria. Since that time, NBS has expanded to become one of the most successful public health initiatives, preventing disability and death not only from metabolic disorders, but also from endocrine disorders, hematologic disorders, immune disorders, cardiac disorders, and pulmonary disorders. Early NBS was dictated by the principles of early disease detection as described by Wilson and Jungner.1 These principles focus on screening for disorders with accepted and readily available treatment, and testing that is acceptable to the population and economical. NBS continues to expand with newer technology in the hope of early treatment and intervention for many more pediatric conditions. DNA-based NBS programs will likely be available soon with technology to obtain DNA from the dried blood spot (DBS), as well as lower cost of genetic testing. As NBS expands into DNA-based technologies, more physicians and patients will need to be educated on the risks and benefits, considering the ethics and implications of genetic testing and diagnosis in the newborn period.

Current Screening

NBS in the United States is dictated by the policies of individual states, so there is a lack of uniformity in testing for disorders at birth around the country. The US Department of Health and Human Services and the American College of Medical Genetics and Genomics (ACMG) recommended conditions for which screening should be mandated. Currently, the recommended uniform screening panel (RUSP) recommends screening for 34 core disorders and 26 secondary disorders.2,3 The majority of the testing is done with the DBS sample; however, screening for critical congenital heart disease and hearing loss occurs as point-of-care testing at the bedside in the newborn nursery. Despite standardized recommendations, individual states ultimately determine what disorders will be screened for so there continues to be variation in testing across the US. More conditions are nominated for consideration as an addition to the RUSP as the preventive health benefits of early diagnosis and treatment become clear. With each new condition nominated to the RUSP, the advisory committee systematically and carefully considers each proposed condition's natural history, testing options allowing short-term follow-up and confirmation, and opportunities for long-term follow-up and treatment. Within the last 10 years, there have been substantial updates to NBS as the list of core disorders on the RUSP expands.3 These expansions have allowed for early detection, which benefit patients, even though secondary findings have also been found with unanticipated results. For example, an acylcarnitine profile done on NBS to identify readily treatable disorders of fatty acid oxidation may secondarily identify more severe disorders with few treatment options, such as ethylmalonic encephalopathy, and more benign disorders that do not usually require intervention, such as 3-methylcrotonyl-CoA carboxylase deficiency.4,5

The primary care provider and the laboratory play critical roles in following up with any abnormal NBS results. The laboratory will usually guide the primary care provider through the next appropriate steps to allow for early treatment and referrals if necessary. The ACMG ACTion sheets are another resource, providing the short-term actions a health professional should follow in communicating with the family and determining the next steps after a positive screening.6 It is important for health professionals to counsel families that screening is not diagnostic in isolation, but that appropriate follow up is required to confirm diagnosis.

Newborn Screening Expansion

NBS for severe combined immunodeficiency (SCID) began in 2008 using assays to detect T-cell receptor excision circles on the DBS and was recommended by the RUSP starting in 2010.7 The clinical course for many patients with immunodeficiency has been altered with additional information about SCID uncovering both a wider phenotypic spectrum and an increased incidence. Additionally, there were unanticipated incidental findings leading to the diagnosis of other disorders associated with T-cell impairment such as chromosome 22q11.2 deletion syndrome, trisomy 21, ataxia telangiectacia, Jacobsen syndrome, and CHARGE syndrome.7.8

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder with a variable presentation including a severe childhood cerebral form associated with rapid neurologic decline and adrenal insufficiency. Early diagnosis and presymptomatic treatment with hematopoeietic stem cell transplantation (HSCT) can prevent adrenal crisis and neurologic deterioration prompting its position as the most recent addition to the RUSP in 2016.9 Screening methods measuring C20-C26 lysophosphatidylcholines by tandem mass spectroscopy on the DBS not only screens for X-ALD, but also can identify female carriers of X-ALD and detect other peroxisomal disorders such as Zellweger syndrome spectrum, acyl-CoA oxidase deficiency, and D-bifunctional protein deficiency.10

Several lysosomal storage disorders (LSDs) have been added to the RUSP with multiple beneficial indications with presymptomatic treatment options. LSDs are rare enough that many practitioners are unfamiliar with their presenting symptoms, leading to delayed diagnosis potentially after patients have suffered irreversible damage.11 Pompe disease, also known as glycogen storage disease type II or acid maltase deficiency, is an autosomal recessive LSD in which a deficiency of acid alpha-glucosidase causes accumulation of glycogen primarily in muscle, skeletal, and cardiac tissue. Pompe disease can present with hypertrophic cardiomyopathy and muscular weakness in infancy, or muscle weakness without cardiac manifestations from early childhood to late adulthood.12 NBS for Pompe disease has been conducted in several programs and was approved for the RUSP in 2015.3 A long-term study of 10 patients with infantile-onset Pompe disease diagnosed by NBS, all of whom were cross-reactive immunologic material-positive, demonstrated high efficacy of early enzyme replacement therapy (ERT).12

Mucopolysaccharidosis (MPS) type 1, also known as Hurler disease, is an autosomal recessive LSD caused by lysosomal alpha-L-iduronidase deficiency. It is a progressive multisystem disorder that ranges from severe infantile presentations with coarsening of facial features, progressive skeletal dysplasia, intellectual disability, and death in childhood from cardiorespiratory failure to attenuated forms with a normal span. Treatment is available with HSCT and ERT, and it was approved for the RUSP in 2016.13

There are disorders that are screened for by individual states even though they are not present on the RUSP; the screens are often added after advocacy from patient and family support groups. These disorders are nominated for the RUSP but may not be recommended because of a lack of supporting new benefit for both screening and treatment. An example is Fabry disease, an X-linked LSD due to deficiency of alpha-galactosidase A, which produces vascular changes expressed by renal and dermatologic disease as well as other organ involvement. ERT may be beneficial but optimal outcome requires that it start before any renal symptoms appear, and there are late-onset disease variants. Although NBS for Fabry disease would lead to early diagnosis, the timing of ERT initiation in a patient identified by NBS remains uncertain since irreversible renal changes may occur presymptomatically.14 Another example is Krabbe disease, a severe neurodegenerative disorder caused by deficiency of galactocerebrosidase. The classic, early-infantile phenotype presents in the first few months of life with irritability, spasticity, developmental delay with subsequent severe deterioration, and death in childhood. There are late onset and milder variants. The treatment is presymptomatic HSCT, although there are significant challenges determining who would benefit.15

The progressive nature of LSD makes early recognition and treatment essential, and NBS is allowing the identification of many more conditions. The incidence of both Pompe disease and Fabry disease has been shown to be much higher than previously thought based on initial data from Illinois.16 As the true incidence of these rare disorders is recognized, there is huge potential to improve understanding of the natural history and variability in presentation. Limitations remain with complicated treatment regimens involving ERT or HSCT, each with its own inherent risks. Screening may identify pseudodeficiency of the enzyme or carrier status, and determining who is affected is critically important before starting any therapy. Pseudodeficiencies for MPS type I and Fabry disease enzymes were detected more often in NBS than true deficiencies.16 Long-term follow-up of NBS for LSD will be essential to truly understand the risks and benefits.

The Future of Newborn Screening

There are two fronts in which NBS has the potential to expand rapidly: genetic testing and new treatment for rare disease. Genetic disorders are on the verge of more treatment options as new therapies for genetic conditions emerge. Rapid diagnosis and available treatment create the ideal candidates for public screening success.

DNA-based NBS programs will soon be seriously considered as cost, efficiency, and accuracy of genetic testing improves.17 Many NBS programs have already added second-tier screening in which the newborn specimen from infants with an initial abnormal screen suggesting cystic fibrosis, galactosemia, or medium chain acyl-CoA dehydrogenase deficiency is subjected to targeted genetic testing. Second-tier genetic testing can reduce the frequency of false-positive results and provide the clinician with more information for the initial clinical evaluation.

Genetic testing options proposed for NBS include next-generation sequencing (NGS) using targeted panel testing, whole-exome sequencing (WES), or whole-genome sequencing (WGS). NGS is a type of high-throughput sequencing that is both faster and more cost-effective than previously used Sanger sequencing, allowing screening of multiple genes in panel testing. NGS is used for WES, which sequences all of the protein-coding genes in the genome, whereas WGS involves sequencing the complete genome. New techniques allow recovery of DNA from the DBS with high coverage for newborn-specific disorders.18 The addition of DNA-based testing to primary NBS could allow diagnosis of conditions that could not be previously identified with a laboratory marker, such as spinal muscular atrophy, Wilson disease, and cystinosis.

Both cost and turnaround time would need to be substantially improved to allow for rapid genetic diagnosis. After genetic testing is obtained, interpretation becomes a major challenge. Any genetic test has four possible results: no variant, disease-causing variant, benign variant, or variant of uncertain significance (VUS). The VUS is a genetic sequence whose association with disease risk is unknown, and it could be benign or pathogenic. It is vital not to overinterpret a VUS result, and thus clinical interpretation and understanding is vital to understand the genetic test results of NBS. A variant found in a gene may not always indicate disease, as the genotype may not necessarily predict the phenotype or the clinical course. Additionally, there would be potential incidental findings with implications for the entire family, revealing reproductive risks, adult-onset conditions, and complex genetic traits.19 Careful consideration will be necessary to ensure that medical decisions and interventions are not based on uncertain or limited information, or incorrect interpretation. Many more genetic specialists, such as medical geneticists and genetic counselors, will be required to handle the immense increase in genetic information. The primary care provider will need to be versed in the nuance of variants of uncertain significance found during genetic screening. The uncertainty of a genetic testing result is a burden to families and must be weighed as a risk of testing.

NBS is currently a public health mandate and does not require an extensive consent process presuming consent unless there is a stated objection, but genetic testing would likely require informed consent with more ethical considerations. An ACMG policy statement from 2012 recommended that WES and WGS not be used as an approach to either prenatal screening or as a first-tier NBS.20 Although there are complex decisions to consider before newborn genetic testing can be implemented, a survey demonstrated high interest in newborn genomic testing among parents of healthy newborns.21 In this study, only 6.4% of the 514 parents surveyed were not at all interested in genomic testing for their newborn, which may be a high number for NBS but remarkably low for an addition as complicated and potentially controversial as genetic testing. In another study of parental attitudes for NBS, when inquiring about possibility of NBS for genetic disorders that manifest in childhood or adulthood, there were mixed results with about one-half preferring the NBS results to prepare for the disease or to advocate for a treatment while others viewed the information as potentially burdensome.22 A 2014 survey of genetics professionals found that 86.5% of the 113 respondents felt WGS should not currently be used in NBS, but 75.7% foresee its future use.23 Consensus recommendations from groups of physicians have stated that any publicly funded universal NBS using genetic methods should be limited to disease that can be diagnosed in the newborn period and effectively treated or prevented in childhood. Furthermore, presently, our understanding and ability to interpret genomic variants does not justify the use of WES or WGS in NBS.24


NBS continues to provide early diagnosis with important early intervention and treatment. As NBS expands, the medical infrastructure will need to be in place to provide both providers and patients with education. There are exciting opportunities from the early identification of rare disorders to allowing early institution of treatment to change the course of rare disease in childhood. More long-term follow up is required to fully understand the risks and benefits of expanded NBS.


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Farrah Rajabi, MD, is a Staff Physician, Division of Genetics and Genomics, Boston Children's Hospital; and an Instructor, Harvard Medical School.

Address correspondence to Farrah Rajabi, MD, 300 Longwood Avenue, Boston, MA 02115; email:

Disclosure: The author has no relevant financial relationships to disclose.


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