Newborn screening (NBS) in the US began in the State of Maine in the early 1960’s when Dr. Robert Guthrie developed a bacterial inhibition test to detect elevated levels of phenylalanine in dried blood spots, and showed that the test could be used to screen for the presence of phenylketonuria (PKU). With that beginning, other States began to screen newborns, each State deciding for itself which disorders to screen and how to perform the screening tests. Thus as late as 1997, many states only screened for around 5 disorders and only two disorders were screened for by all 50 states, PKU and congenital hypothyroidism.
In the mid-1990’s an LC/MS/MS method combining acylcarnitine and amino acid analysis was developed which detected up to 50 inborn error of metabolism from a single punch of a dried blood spot. This development revolutionized NBS. In 2002, the American College of Medical Genetics was tapped to develop a unified national NBS program and they convened an expert working group for that purpose (1). The expert group recommended a panel of 29 “core disorders” be screened for by all States, with a group of 22 “secondary targets” also being picked up, as part of the differential diagnosis of the 29 disorders in the core group. The expert group also refined the criteria for inclusion of a disorder in NBS from a long list of criteria to three basic ones: 1) that the disorder is detectable at a time (24-48 hours after birth) at which it does not present clinically, 2) that the test for the disorder is adequately sensitive and specific, and 3) that the condition is treatable, such that the treatment is effective and cost effective compared to not treating the disorder. By 2007, all 50 States were screening for this core group of disorders.
In 2010, the Secretary of the Health & Human Services recommended that Severe Combined Immunodeficiency (SCID) be added to the 29 Core conditions and be screened by all States.
SCID is a group of about 14 distinct genetic defects that all result in primary immunodeficiency. It is clinically well-defined, it results in death inside of a year if not treated and it has increasingly available, effective treatment options. Until recently however, it was not included in NBS programs because there was no single test available that could be used to effectively screen for the condition. That changed when a test was developed that takes advantage of one of the defining characteristics of all types of SCID, the absence or near absence of functional T cells.
In the course of T-cell maturation in the thymus, T cell DNA undergoes V(D)J gene rearrangement in order to achieve functional and variable T cell receptors on the cell surface. During V(D)J gene rearrangement, small exogenous circles of DNA are created by the process of excising unwanted DNA segments. These small DNA circles are called TREC, T cell excision circles. Douek, et al developed a quantitative competitive PCR assay (QC-PCR) to measure the amount of TREC in isolated T cells as an indicator of thymic function (2). Puck and Chan then adapted Douek’s assay into a quantitative real time PCR (qRT-PCR) assay which uses dried blood spots and showed that it could be used to screen for SCID (3). They and others reasoned that without functional T cells, it was likely that there would also be no or very low concentrations of TREC. The assay has been modified and improved since first being reported, and is now being used by 11 States to add SCID to their NBS programs, with 7 additional States working to add SCID testing. An immunoassay test has also been developed for this purpose which quantifies the number of CD3 positive cells, using CD45 positive cells as in internal control (4). CD3 is a part of the T-cell receptor complex on mature T-cells and CD45 is a common cell surface marker found on all differentiated leukocytes.
The over-riding purpose of NBS programs is to detect inborn errors of metabolism at a time shortly after birth, before they cause physiological damage and become clinically evident, and to treat those disorders appropriately to prevent or mitigate the morbidity and/or mortality associated with them. With the advent of new testing, SCID has become a disorder that now meets all the criteria for inclusion into the NBS programs, and all States should move toward its inclusion.
- American College of Medical Genetics (ACMG) Newborn Screening Expert Group – “Newborn Screening: Toward a Uniform Screening Panel and System” http://www.acmg.net/resources/policies/NBS/NBS-sections.htm Accessed March 7, 2013.
- Douek DC, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 1998. 396:690-695.
- Chan K, Puck JM. Development of population-based newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol 2005; 115:391-8
- Janik DK, et al. A multiplex immunoassay using Guthrie specimen to detect t-cell deficiencies including severe combined immunodeficiency disease. Clin Chem 2010; 56(9):1460 – 1465.