Abstract:
Newborn metabolic screening had its origin in the 1960s with the introduction of the Guthrie Bacterial Inhibition Assay (BIA) for PKU. For nearly 20 years, the BIA was used to screen for PKU plus a number of additional disorders including maple syrup urine disease, tyrosinemia, and homocystinuria. In the mid-1970s the BIA assays were replaced by fluorometric assays; and newborn screening for congenital hypothyroidism, congenital adrenal hyperplasia, and cystic fibrosis was introduced using radioimmunoassays or enzyme immunoassays. Second-tier confirmatory DNA testing for common mutations in cystic fibrosis, galactosemia, biotinidase deficiency and MCAD deficiency was introduced using PCR and light cycler technology. Tandem mass spectrometry was introduced in 1992 for amino acid and acylcarnitine profiling. This amino acid scan replaced the BIA and fluorometric assays for PKU and the other amino acid disorders, while the acylcarnitine scan permitted the detection of disorders in organic acid metabolism (propionic, methylmalonic, isovaleric, glutaric acid and 3-Me-Crotonyl Glycinuria, as well as HMG CoA Lyase, β-Ketothiolase, and Multiple CoA Carboxylase Deficiencies) and fatty acids oxidation metabolism (MCAD, LCHAD, VLCAD, SCAD, CPTII and MADD). Duchenne muscular dystrophy and spinal muscular atropy are being incorporated into some newborn screening programs. In recent years, many newborn screening programs have added screening for various lysosomal storage disorders including globoid cell leukodystrophy (Krabbe), Gaucher, Fabry, Mucopolysaccharidosis I (Hurler) and II (Hunter), acid sphingomyelinase deficiency, and Pompe disease. Initially these disorders were screened for using individual enzyme assays, but more recently these assays have been replaced by tandem mass spectrometry, high performance liquid chromatography, and digital microfluidics.
The current cost of comprehensive newborn screening programs is rapidly approaching the point where primary targeted whole exome (WES) or whole genome sequencing (WGS) will become cost-effective. Already there are large scale pilot molecular newborn screening programs underway in many parts of the world. The Generation study in the UK led by Genomics England in partnership with the NHS focuses on >200 treatable conditions and plans to sequence 100,000 newborns. Other large scale newborn molecular screening studies include the BeginNGS in California, ScreenPlus in New York, and FirstSteps in Greece. Most European countries have pilot studies. There are also studies in Australia, China, and other Asian countries. It is important to note that, as we move toward primary molecular newborn screening, we will need to maintain second-tier biochemical methods to determine if the variants that are detected are pathological or benign polymorphisms. The future of newborn screening as it incorporates WES or WGS over the next decades will be filled with the addition of hundreds of treatable disorders and we will be faced with many exciting challenges. Newborns in the future will, however, be the beneficiaries of this exciting expansion of a very successful public health program.
