Newborn Screening for Primary Immune Deficiencies with a TREC/KREC/ACTB Triplex Assay—A Three-Year Pilot Study in Sweden

Abstract

Background: Screening newborns for severe combined immunodeficiency (SCID) has become essential, since efficient methods to identify infants with these disorders exist and early stem cell transplantation is life-saving. Method: We performed a three-year screening trial in Stockholm comprised of 89,462 newborn infants. The number of T-cell receptor excision circle (TREC)/kappa-deleting recombination excision circle (KREC)/β-actin (ACTB) copies were quantified simultaneously by real time polymerase chain reaction (PCR) in 3.2 mm punches from dried blood samples taken in the regular neonatal screening program. Results: Five patients with immune deficiencies were identified: two with SCID caused by mutations in the Artemis-and adenosine deaminase gene, respectively, one with ataxia telangiectasia and two with reversible agammagloblinemia, which so far, is of unknown cause. This points to an incidence of SCID at the same level as in other studies (around 1:50,000). In 19 recalled infants, low KREC levels and in one case, also low TREC levels, were caused by immunosuppressive treatment of the mother during pregnancy. The levels normalized within a month in all these infants. The total recall rate was 0.10%, and 40% of the recalled infants were born prematurely (<37 weeks gestation). Among 69 patients with inborn errors of metabolism screened retrospectively, only two, who were severely ill with organic acidemias when the sample was taken, and two with mitochondrial disorders, screened positive.

Newborn Screening for Primary Immunodeficiency Diseases: History, Current and Future Practice

“…In addition, infants with forms of PID other than SCID may have low TREC, for example in ataxia telangiectasia and combined immunodeficiency diseases (CID). Thus far in prospective pilot studies, many cases of CID without an identifiable molecular cause have been detected using the TREC assay [ 27 , 28 , 30 ] and these patients require clinical characterization and long-term follow-up.…”

Benefits, challenges and prospects of newborn screening for primary immunodeficiency

“…Screening programs are widely supported by government and patient organizations, such as Jeffrey Modell Foundation (JMF), and Immunodeficiency Foundation (IDF) 17 . According to published data, in Europe the screening programs have been implemented in several provinces of Spain (Catalonia, Seville) 18 , in Stockholm region (Sweden) 19 , France 20 , in several provinces of the Netherlands 3 and in Switzerland 21 . Pilot projects of newborn screening for SCID have been or are currently underway in a number of countries, in particular in Italy, Germany, Japan, Norway, Turkey, Slovenia, Iceland, Denmark, Poland, the Czech Republic and Brazil 9,22 .…”

“…In most countries, the populational SCID screening program uses the TREC analysis 3,16,18,19,[25][26][27][28] . TREC/ KREC assay was used in Sweden 19 , and since 2019 it has been used in Switzerland 21 . TREC/ KREC assay has also been used in a number of pilot studies in Spain (Seville) 29 , Iran 30 , and in the Polish-German transborder area 24 .…”

Parents’ Perspectives and Societal Acceptance of Implementation of Newborn Screening for SCID in the Netherlands

“…Similar to other countries [19][20][21][22][23], the Netherlands started a prospective implementation pilot study (SONNET-study) in April 2018, focusing on parental perspective, cost-effectiveness, and practical implications for screening, diagnostics, and clinical follow-up. As parents are important stakeholders in NBS, their support is paramount.…”