Genomics in newborn screening.

ewborn screening has substantially changed the geneticmetabolic world and greatly expanded the concept of preventive medicine. This expansion has been marked by two major milestones in the 50-year history of newborn screening: the first, pre-tandem mass spectrometry, included the early detection of phenylketonuria (PKU), galactosemia, homocystinuria, maple syrup urine disease, congenital hypothyroidism, congenital adrenal hyperplasia, sickle cell disease, and biotinidase deficiency; the second, tandem mass spectrometry-based, has seen an explosive increase in information, often instrumental for diagnosis, prevention, and appropriate management of many additional metabolic disorders including the organic acidemias and fatty acidoxidation defects not previously covered. The latter era, however, has also had its share of shortcomings and pitfalls, much of which related to inconclusive diagnosis and incomplete knowledge of natural history. Determining the precise disorder in the identified infant is critical to his/her proper clinical care and treatment as well as to providing accurate information and genetic counseling to the family. There are several possibilities for making a definitive diagnosis. In some diseases, such as tyrosinemia type I, there is a specific analyte, succinylacetone, which defines the disorder. In other disorders, represented most frequently by PKU, the metabolite profile is so abnormal and so characteristic that there is virtually no doubt as to the diagnosis. Many other disorders now included in newborn screening, however, require a determination of clearly reduced activity of the relevant enzyme or finding two pathogenic mutations in the gene that encodes the enzyme to unequivocally establish the diagnosis. Proving reduced enzyme activity can be considered the gold standard but enzyme assays may require tissue not readily accessible or assays not widely available or that sometimes yield equivocal results. Determining the mutations (genotyping) is more widely available and easier to perform but its role has not been clearly formulated. The limited genotyping for 1 or only a very few mutations known to be frequent in a disorder has been implemented in the newborn