History and current status of newborn screening for severe combined immunodeficiency

Abstract

The development of a T-cell receptor excision circle (TREC) assay utilizing dried blood spots in universal newborn screening has allowed the early detection of T-cell lymphopenia in newborns. Diagnosis of severe combined immunodeficiency (SCID) in affected infants in the neonatal period, while asymptomatic, permits early treatment and restoration of a functional immune system. SCID was the first immunodeficiency disease to be added to the Recommended Uniform Screening Panel of Core Conditions in the United States in 2010, and it is now implemented in 26 states in the U.S. This review covers the development of newborn screening for SCID, the biology of the TREC test, its current implementation in the U.S., new findings for SCID in the newborn screening era, and future directions.

Keywords: DiGeorge syndrome; T-cell lymphopenia; T-cell receptor excision circle (TREC); hematopoietic cell transplantation; primary immunodeficiency; severe combined immunodeficiency.

Figure 1

Generation of the δRec-ψJα TREC, showing primers, black arrows, used to amplify and quantitate TREC junction fragment. Excision of the TCRD locus from the TCRA locus results in the excised fragment which circularizes to form the δRec-ψJα TREC, found in >70% of αβ T cell receptor expressing T cells. Reprinted from Journal of Allergy and Clinical Immunology, Vol. 129, J.M. Puck, Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: The winner is T-cell receptor excision circles, pp. 607–616. Copyright 2012, with permission from Elsevier.

Figure 2

Distribution of SCID genotypes in the presence of newborn screening. (A) In California, approximately 2,250,000 infants were screened in 4.5 years; SCID incidence was 1 per 59,000 births. (B) A study of 11 SCID NBS programs in the U.S. with 3,030,083 infants screened found an incidence of 1 per 58,000 births; genotype distribution was similar, and included detection of single incidences of additional SCID genotypes CD3D, TTC7A and chromosome 12p duplication.

Figure 3

Map of the U.S. showing states that have implemented SCID NBS (with year in which this commenced, solid gray), and states that have plans to start NBS for SCID (hatched gray). In Louisiana (LA) and Puerto Rico (PR), SCID NBS was started in 2010 but was discontinued due to lack of funding for the screening programs. There are no known plans for SCID NBS implementation in the unshaded states. Information courtesy of Dr. Amy Brower (Newborn Screening Translational Research Network) and Emily Hovermale (Immune Deficiency Foundation).