First Year of Israeli Newborn Screening for Severe Combined Immunodeficiency—Clinical Achievements and Insights

Abstract

Severe combined immunodeficiency (SCID), the most severe form of T cell immunodeficiency, is detectable through quantification of T cell receptor excision circles (TRECs) in dried blood spots obtained at birth. Herein, we describe the results of the first year of the Israeli SCID newborn screening (NBS) program. This important, life-saving screening test is available at no cost for every newborn in Israel. Eight SCID patients were diagnosed through the NBS program in its first year, revealing an incidence of 1:22,500 births in the Israeli population. Consanguine marriages and Muslim ethnic origin were found to be a risk factor in affected newborns, and a founder effect was detected for both IL7Rα and DCLRE1C deficiency SCID. Lymphocyte subset analysis and TREC quantification in the peripheral blood appear to be sufficient for confirmation of typical and leaky SCID and ruling out false positive (FP) results. Detection of secondary targets (infants with non-SCID lymphopenia) did not significantly affect the management or outcomes of these infants in our cohort. In the general, non-immunodeficient population, TREC rises along with gestational age and birth weight, and is significantly higher in females and the firstborn of twin pairs. Low TREC correlates with both gestational age and birth weight in extremely premature newborns. Additionally, the rate of TREC increase per week consistently accelerates with gestational age. Together, these findings mandate a lower cutoff or a more lenient screening algorithm for extremely premature infants, in order to reduce the high rate of FPs within this group. A significant surge in TREC values was observed between 28 and 30 weeks of gestation, where median TREC copy numbers rise by 50% over 2 weeks. These findings suggest a maturational step in T cell development around week 29 gestation, and imply moderate to late preterms should be screened with the same cutoff as term infants. The SCID NBS program is still in its infancy, but is already bearing fruit in the early detection and improved outcomes of children with SCID in Israel and other countries.

Determining Reference Ranges for Trec and Krec Assays in Immune Deficiency Screening of Newborns in Russian Federation

“…Полученные нами медианные значения TREC (195 копий на мкл цельной крови) наиболее близки к таковым, полученным с использованием моноплексных "in-house" тест-систем [13,14,26,29,31,41,44,47]. Между тем значения TREC в исследованиях проведенных с использованием коммерческого набора Enlite™ Neonatal TREC kit (PerkinElmer, Turku, Finland), отличаются несколько меньшими значениями (96-112 копий на мкл) [6,7,8,10,42,43].…”

Development of a Population-Based Newborn Screening Method for Severe Combined Immunodeficiency in Manitoba, Canada

“…However, their approach is different from ours as T-NGS is a second tier mutation screening tool on DBS from Saudi newborns ascertained by low TREC assays. Both Biggs et al [17] and Rechavi et al [4] discuss the challenge of a TRECS-based assay alone for neonatal SCID detection, its fundamental inability to detect immunodeficiencies that result from T-cell dysfunction without T-cell lymphopenia and the need to be aware of these T-cell positive SCID variants that will be missed by TRECS-methodology alone. With our combined methods we believe we will significantly reduce the number of false negatives in our Manitoba population than if we used TRECS alone.…”

“…In March 2015, the Federal US Committee on Newborn Screening recommended the addition of Severe Combined Immunodeficiency (SCID) to the routine newborn screening panel and now is offered in over 40 States in the United States [2,3]. Since then several countries including Israel [4], Taiwan [5] and one Canadian province of Ontario [6] have introduced newborn screening for SCID. Many others are conducting pilot projects or have proposals being considered [7][8][9][10].…”

Introducing Newborn Screening for Severe Combined Immunodeficiency (SCID) in the Dutch Neonatal Screening Program

“…As the Dutch Health Council has already deemed SCID a suitable candidate for the Dutch newborn screening program, that meets the Wilson and Jungner criteria [23], this pilot study does not focus on whether the TREC assay is a suitable method for the detection of SCID. The effectiveness of newborn screening for SCID has already been proven in other screening programs abroad [6,7], and previous research has provided us with a clear overview of the SCID disease in the Netherlands [24]. The implementation pilot will answer four main research questions: How can the TREC-screening method be implemented in the current neonatal screening program?…”

“…The screening organisations (5) will be informed about the registration of the newborn at city hall (4), after which screeners will visit the parents at home or in the hospital (6). They will perform the heel prick and send the heel prick card by post to one of the five screening laboratories (7). The heel prick cards are then analysed and the results are registered in the laboratory information system (LIMS) and the national monitoring database Praeventis (8).…”