Newborn Screening for Primary Immunodeficiency Diseases: The Past, the Present and the Future

Abstract

Primary immunodeficiency diseases (PID) are a heterogeneous group of disorders caused by inborn errors of immunity, with affected children presenting with severe, recurrent or unusual infections. Over 300 distinct genetic molecular abnormalities resulting in PID have been identified, and this number continues to rise. Newborn screening for PID has been established in many countries, with the majority of centers using a PCR-based T cell receptor excision circle (TREC) assay to screen for severe combined immunodeficiency (SCID) and other forms of T cell lymphopenia. Multiplexed screening including quantitation of kappa-recombining exclusion circles (KREC) has also been described, offering advantages over TREC screening alone. Screening technologies are also expanding to include protein-based assays to identify complement deficiencies and granulocyte disorders. Given the rapid advances in genomic medicine, a potential future direction is the application of next-generation sequencing (NGS) technologies to screen infants for a panel of genetic mutations, which would enable identification of a wide range of diseases. However, several ethical and economic issues must be considered before moving towards this screening strategy.

Epigenetic immune cell counting in human blood samples for immunodiagnostics

“…However, TREC/KREC analysis fails to detect other specific lymphocyte subsets defective in other severe PIDs, such as natural killer (NK) cells, regulatory T (T reg ) cells, or neutrophils. Despite this limitation, TREC newborn screening is effective and shows improved disease outcome due to early diagnosis (10).…”

Newborn Screening for Primary Immunodeficiencies: The Gaps, Challenges, and Outlook for Developing Countries

“…TRECs are small circular DNA by-products produced during T cell receptor recombination in naïve T cells (12). They were found to be specific to naïve T cells and their levels decline with age in healthy individuals and HIV patients.…”

“…TREC copy numbers are measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) (13). They are reduced or absent in severe combined immunodeficiency (SCID) and other T cell lymphopenias (12). The assay is highly sensitive for detection of SCID with severe T cell lymphopenia, albeit not for SCID variants.…”

“…Whether prematurity per se is a risk factor of having low TRECs or not is debatable (23). Multiple congenital anomalies and congenital heart disease are associated with low TREC levels (12). Maternal drug history is important since maternal intake of azathioprine was associated with low KREC level in offspring (24,25).…”

“…Currently, few countries of the MENA region have taken to newborn screening. These are Qatar in 2012 (12), Israel in 2015 (42), and Lebanon in 2018. UAE, Iran, and Turkey have taken some steps in this regard.…”