The case for newborn screening for severe combined immunodeficiency and related disorders

Abstract

Early detection of primary immunodeficiency is recognized as important for avoiding infectious complications that compromise outcomes. In particular, severe combined immunodeficiency (SCID) is fatal in infancy unless affected infants can be diagnosed before the onset of devastating infections and provided with an immune system through allogenic hematopoietic cell transplantation, enzyme replacement, or gene therapy. A biomarker of normal T cell development, T cell receptor excision circles (TRECs), can be measured in DNA isolated from the dried blood spots routinely obtained for newborn screening; infants identified as lacking TRECs can thus receive confirmatory testing and prompt intervention. Early results of TREC testing of newborns in five states indicate that this addition to the newborn screening panel can be successfully integrated into state public health programs. A variety of cases with typical SCID genotypes and other T lymphocytopenic conditions have been detected in a timely manner and referred for appropriate early treatment.

Figure 1

Copy number detected in actual nursery dried blood samples, recovered from state screening laboratories and tested by quantitative PCR of TRECs (o) and a control genomic DNA segment from the β-actin gene (×). Copy number is normalized to the amount of DNA isolated from a 3 mm punch from a dried blood filter, which is equivalent to about 3 μL of blood (J. Puck, unpublished data).

Figure 2

California algorithm for newborn screening and follow-up for SCID and related conditions. TREC and β-actin gene PCR adapted by PerkinElmer for the California Genetic Disease Screening Program. Values expressed as copies per 1 μL of blood (J. Puck, J. Church, and F. Lorey, unpublished data).