Future Perspectives of Newborn Screening for Inborn Errors of Immunity

Abstract

Newborn screening (NBS) programs continue to expand due to innovations in both test methods and treatment options. Since the introduction of the T-cell receptor excision circle (TREC) assay 15 years ago, many countries have adopted screening for severe combined immunodeficiency (SCID) in their NBS program. SCID became the first inborn error of immunity (IEI) in population-based screening and at the same time the TREC assay became the first high-throughput DNA-based test in NBS laboratories. In addition to SCID, there are many other IEI that could benefit from early diagnosis and intervention by preventing severe infections, immune dysregulation, and autoimmunity, if a suitable NBS test was available. Advances in technologies such as KREC analysis, epigenetic immune cell counting, protein profiling, and genomic techniques such as next-generation sequencing (NGS) and whole-genome sequencing (WGS) could allow early detection of various IEI shortly after birth. In the next years, the role of these technical advances as well as ethical, social, and legal implications, logistics and cost will have to be carefully examined before different IEI can be considered as suitable candidates for inclusion in NBS programs.

Keywords: KREC; TREC; epigenetic immune cell counting; inborn errors of immunity; newborn screening; next-generation sequencing; severe combined immunodeficiency.

Figure 1

Epigenetic immune cell counting. Unique cell type-specific DNA methylation markers were identified. After bisulfite conversion of the genomic DNA, unmethylated CpG dinucleotides are converted and amplified to TpGs, whereas methylated CpGs remain unaltered. Bisulfite conversion translates epigenetic markers into sequence information, allowing immune cell quantification with qPCR [37]. Figure from Epimune GmbH, Berlin, Germany.

Figure 2

Different types of immune cells that can be identified with epigenetic immune cell counting and examples of corresponding quantitative defects or IEI. Th17—T-helper 17, def—deficiency, IL6ST—IL6 signal transducer, ZNF341—zinc finger protein 341, FOXP3—forkhead box P3, Treg—regulatory T-cell, ZAP-70—zeta-chain-associated protein kinase 70, MHC—major histocompatibility complex, SCID—severe combined immunodeficiency, CID—combined immunodeficiency, XLA—X-linked agammaglobulinemia, ARA—autosomal recessive agammaglobulinemia, NK-cell—natural killer cell, MCM4—minichromosome maintenance complex component 4, IRF8—interferon regulatory factor 8, RTEL1—regulator of telomere elongation helicase 1, SCN—severe congenital neutropenia, IEI—inborn error of immunity.