SCID newborn screening: What we've learned

Abstract

Newborn screening for severe combined immunodeficiency, the most profound form of primary immune system defects, has long been recognized as a measure that would decrease morbidity and improve outcomes by helping patients avoid devastating infections and receive prompt immune-restoring therapy. The T-cell receptor excision circle test, developed in 2005, proved to be successful in pilot studies starting in the period 2008 to 2010, and by 2019 all states in the United States had adopted versions of it in their public health programs. Introduction of newborn screening for severe combined immunodeficiency, the first immune disorder accepted for population-based screening, has drastically changed the presentation of this disorder while providing important lessons for public health programs, immunologists, and transplanters.

Keywords: Primary immunodeficiency; T-cell receptor excision circle (TREC); dried blood spot; lymphopenia; newborn screening; severe combined immunodeficiency (SCID).

Figure 1.. Generation of the δRec-ψJα TREC.

The germ line configuration of the TCRA locus, with TCRD embedded, is shown at the top of the Figure, which also shows the signal and joining sequences (gray circles) at which the DNA is cut to excise the TCRD locus. The DNA segment excised is shown in its linear form, lower left, and following ligation at the fragment ends, lower right, to form a T cell receptor excision circle (TREC). PCR primers (black arrows) can amplify a short DNA segment containing the joined ends of the circle.

Figure 2.. Causes of T cell lymphopenia in 212 infants.

Included were 50 with typical or leaky SCID (including Omenn syndrome); 72 with a final diagnosis of a syndrome or single gene disorder associated with T cell impairment (of whom 22 were undiagnosed for several months or more); 25 with congenital conditions associated with secondary TCL; 33 with preterm birth alone; and 33 for whom no underlying defect was identified. ^a Includes 3 cases of diabetic embryopathy, and one each of CLOVES syndrome (congenital lipomatous, overgrowth, vascular malformations, epidermal nevi and skeletal anomalies), EXTL3 deficiency (immunoskeletal dysplasia with neurodevelopmental abnormalities), Fryns syndrome (multiple anomalies with diaphragmatic defects), Nijmegen breakage syndrome (DNA repair defect in NBN causing immune defects, microcephaly, short stature and malignancy), Noonan syndrome (congenital heart disease, characteristic facial and physical features, short stature), and RAC2 deficiency (a non-SCID primary immunodeficiency affecting neutrophils and lymphocytes). ^b Includes 2 cases of maternal immunosuppressive medication (azathioprine, fingolimod) and one case of neonatal teratoma of the thymus. ^c Infants with TCL associated with preterm birth alone, grouped by birth weight.