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Newborn screening (NBS) is a population-based public health program with the aim to detect conditions, mostly genetics, which can lead to serious morbidity and mortality. When detected early in life, these conditions can be acted upon to significantly reduce long-term disability and prevent premature death. With many breakthroughs happening in the understanding of the inheritance of genetic disorders, NBS traces its origin to the early-mid 20th century. In 1902, Dr. Archibald Garrod coined the term “Inborn Errors of Metabolism.” He demonstrated that alkaptonuria (black urine disease), an inborn error of metabolism, transmits in a typical Mendelian recessive manner.1 In 1934, Dr. Asbjørn Følling used a ferric chloride test to demonstrate the presence of “ketone bodies” in the urine of two mentally retarded siblings.2 It was discovered that the “ketone bodies” were phenylpyruvic acid that would accumulate in the blood and urine of patients with a defect in phenylalanine metabolism.3 The disease was named phenylketonuria (PKU) and led to the development of the “ferric chloride wet diaper test.”4 From the 1930s to several decades thereafter, the ferric chloride test was used to screen for PKU.
Though the ferric chloride test allowed the presumptive diagnosis of PKU, there was no treatment for the disease. In 1953, Dr. Horst Bickel in collaboration with Dr. Louis Woolf, developed a low-phenylalanine diet for the treatment of PKU.5,6 In 1961, this was followed by another big step towards systematic newborn screening when Dr. Robert Guthrie developed a dried blood spot bacterial inhibition test for the screening of PKU.7 Blood collection on a filter paper was very convenient and the test was fairly accurate and easy to perform in a laboratory. In 1961, the National Association for Retarded Children began a public campaign to support PKU Screening. In 1962, the Child Health Bureau sponsored a study for PKU screening. The study, which enrolled 400,000 infants in 29 states, was a success and demonstrated the possibility of newborn screening for PKU.8 Despite the opposition by some groups based on the questions about the test’s validity, extent of treatment, and unknown outcomes, the National Association for Retarded Children successfully lobbied for mandatory newborn screening.8 By 1965, 27 states mandated newborn screening for PKU, and many others gave their public health departments the power to decide. Realizing the benefits of NBS, over the years, the number of NBS programs have increased immensely in the United States and across the globe. In most developed and many developing countries, newborn screening is now mandatory. In fact, in the United States, newborn screening is the largest public health program screening for over 4 million babies every year. It is one of the most effective and equitable public health programs that has been proven to save and improve lives.
The progress of newborn screening didn’t stop at screening for PKU. In the 1970s, screening for congenital hypothyroidism was added to many newborn screening programs.9 As Guthrie and colleagues developed bacterial inhibition assays for maple syrup urine disease and classic galactosemia in the 1980s, these disorders were added to many newborn screening programs. In the 1990s, screening for hemoglobinopathies and congenital adrenal hyperplasia was added by many newborn screening programs. Until this time, the addition of new disorders to newborn screening was based on the principle of one test for one disease. The development of tandem mass spectrometry (MS/MS) screening in the early 1990s to 2000s revolutionized newborn screening and led to the rapid expansion of metabolic disorders included in newborn screening. Mass spectrometry changed the paradigm from one test for one disorder to one test for multiple disorders. With tandem mass spectrometry, a single analysis from a dry bloodspot (DBS) could screen for over 50 metabolic disorders.10 These disorders include amino acidemias, organic acidemias, and fatty acid oxidation defects. During this rapid expansion, it was noted that there was no uniform approach to the addition of disorders to the newborn screening. Some states were screening only a few conditions and others were screening for more than 50. In 2002, the federal Health Resources and Services Administration's (HRSA) designated the American College of Medical Genetics (ACMG) to develop uniform guidelines for newborn screening. In 2006, the American College of Medical Genetics (ACMG) published guidelines for the selection of disorders to be included in newborn screening. This list of selected conditions was referred to as the Recommended Uniform Screening Panel (RUSP).11 Based on several evidence-based criteria of scoring, 29 core conditions were assigned to RUSP. In addition, 25 conditions could be identified while screening for the 29 core conditions; these were referred to as secondary conditions. Since 2006, several other conditions have been added to RUSP. Currently, RUSP has 37 core conditions (including bedside screening for hearing loss and critical congenital heart disease) and 26 secondary conditions. The current list of conditions in RUSP can be found on the Health Resources and Services Administration (HRSA) website.12
Though tandem mass spectrometry, microfluidics, and other technologies are being used to screen most disorders, the use of DNA sequencing of individual genes or panel of genes is increasingly being used as first-tier or second-tier genetic testing in NBS. The disorders for which DNA sequencing is widely used include cystic fibrosis, spinal muscular atrophy and severe combined immunodeficiency. The whole exome sequencing and whole genome sequencing has been proposed for newborn screening.13,14 Limitations of genetic testing include high cost, identification of carriers, and the detection of a large number of DNA variants of uncertain clinical significance. Undoubtedly, as the cost comes down and there is a better understanding of DNA variants, the use of genetic testing in NBS will increase.
In conclusion, newborn screening has been the largest and one of the most successful public health programs. Over the decades, NBS has and will continue to expand as advances in technology and treatment occur.
1. History of Alkaptonuria (AKU). https://akusociety.org/information-and-support/history-of-aku/. Accessed 8/29/22.
2. Folling A. Über Ausscheidung von Phenylbrenztraubensäure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillität. Hoppe-Seyler's Zeitschrift für physiologische Chemie 1934;227:169-181.
3. Folling A. Excretion of phenylpyruvic acid in urine as a metabolic anomaly in connection with imbecility. Nord. Med. Tidskr. 1934:1054–1059.
4. The Guthrie Test. How Did It All Begin? https://www.museumofdisability.org/exhibits/past/birth-of-newborn-screening/the-guthrie-test/. Accessed 8/22/22.
5. El-Hattab AW, Almannai M, Sutton VR. Newborn Screening: History, Current Status, and Future Directions. Pediatr Clin North Am 2018;65:389-405.
6. Bickel H, Gerrard J, Hickmans EM. Influence of phenylalanine intake on phenylketonuria. Lancet 1953;265:812-3.
7. Guthrie R, Susi A. A Simple Phenylalanine Method for Detecting Phenylketonuria in Large Populations of Newborn Infants. Pediatrics 1963;32:338-43.
8. Tarini BA. The current revolution in newborn screening: new technology, old controversies. Arch Pediatr Adolesc Med 2007;161:767-72.
9. Klein AH, Agustin AV, Foley TP, Jr. Successful laboratory screening for congenital hypothyroidism. Lancet 1974;2:77-9.
10. Chace DH, Kalas TA, Naylor EW. Use of tandem mass spectrometry for multianalyte screening of dried blood specimens from newborns. Clin Chem 2003;49:1797-817.
11. Newborn screening: toward a uniform screening panel and system. Genet Med 2006;8 Suppl 1:1S-252S.
12. https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp. Accessed 8/30/22.
13. Dondorp WJ, de Wert GM, Niermeijer MF. Genomic sequencing in newborn screening programs. Jama 2012;307:2146; author reply 2147.
14. Bick D, Ahmed A, Deen D, Ferlini A, Garnier N, Kasperaviciute D, et al. Newborn Screening by Genomic Sequencing: Opportunities and Challenges. Int J Neonatal Screen 2022;8.