Published Online: July 2013
T cell receptor excision circles (TRECs), a biomarker for naïve T cell production, have been harnessed to perform DNA-based newborn screening for severe combined immunodeficiency (SCID). Following early pilot application in Wisconsin and Massachusetts, SCID newborn screening has been increasingly adopted so that nearly half of all infants born in the US are now screened with TRECs, and expansion to more states and countries worldwide is underway.
In a recent issue of The Journal of Allergy and Clinical Immunology (JACI), Kwan et al present the results of the first two years of universal newborn TREC screening in California. Nearly a million ethnically diverse infants were screened, and their diagnoses and outcomes were tracked.
TREC measurement on universally collected newborn dried blood spots, with positive infants receiving flow cytometric enumeration of lymphocyte subsets, has changed the presentation of SCID. Instead of the “classical” and too-often fatal cumulative and opportunistic infections with failure to thrive, we now diagnose SCID in very young, pre-symptomatic infants by immunologic and molecular phenotyping, allowing us to safeguard their health with prophylactic measures and provide definitive immune restoring therapies, including hematopoietic cell or thymus transplantation, enzyme replacement and gene therapy. Subjects in California with typical SCID, leaky SCID, and Omenn syndrome included four infants with defects in the X-linked IL-2 receptor "Y" chain, four infants with RAG1 (recombinase activating gene 1) defects, three infants with IL-7 receptor "a" chain defects, one infant with JAK3 (Janus kinase 3) mutation, one with cartilage hair hypoplasia due to mutation of the RMRP gene, and one with no known molecular cause. These subjects, plus one with complete DiGeorge syndrome, received immune restoring treatments with over a 96% survival rate. Moreover, additional infants with congenital syndromes and secondary T-cell lymphopenia were identified. Overall, one in 19,900 infants had fewer than 1,500 T cells/uL, with diagnoses shown in the Figure [below].
California’s highly specific TREC test plus integration of confirmatory flow cytometry into the newborn screening program assured prompt, economical, and uniform diagnosis and referral of patients to treatment centers. Newborn screening has for the first time permitted an unbiased determination of incidence and ethnic distribution of SCID and other conditions associated with low T cells. Infants found to have low T cells but no identified gene defects may have previously unstudied immunodeficiencies, offering the potential to reveal insights into T lymphocyte biology on the molecular as well as the population level.
The Journal of Allergy and Clinical Immunology (JACI) is the official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.