First patient in the Iranian Registry with novel DOCK2 gene mutation, presenting with skeletal tuberculosis, and review of literature

Background Dedicator of cytokinesis 2 (DOCK2) deficiency is an inborn error of immunity characterized by cellular and humoral immunological abnormalities leading to early-onset infections. Case presentation We reported a novel case of a 27 months old girl presenting with recurrent pneumonia and a history of skeletal tuberculosis at the age of 19-month-old. Her immunological workup revealed persistent lymphopenia and low CD4 + T cell count along with elevated levels of CD19 +, CD20 +, CD16 +, and CD56 + cells. Furthermore, she had a high level of immunoglobulin (Ig) E and a slightly reduced IgM level with a non-protective antibody titer against diphtheria. The whole-exome sequencing (WES) analysis identified a homozygous frameshift deletion mutation (c.1512delG, p.I505Sfs*28) in exon 16 of the DOCK2 gene. We also conducted electronic searches in PubMed, Web of Science, and Scopus databases and reviewed the articles reporting patients with DOCK2 deficiency. The literature search yielded 14 DOCK2-deficient patients suffering from both cellular and humoral immune defects leading to early-onset infections, particularly human herpesvirus (HHV) infection. Conclusion DOCK2 deficiency should be considered in the context of severe or unusual early-onset infections, especially HHV infections, in a patient with a probable clinical diagnosis of combined immunodeficiency. We also recommended that DOCK2-deficient patients might benefit from T-cell receptor excision circle (TREC) assay as part of the routine newborn screening program.

Future Perspectives of Newborn Screening for Inborn Errors of Immunity

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.

Newborn Screening for Severe Combined Immunodeficiency Using the Multiple of the Median Values of T-Cell Receptor Excision Circles

All newborn screening programs screen for severe combined immunodeficiency by measurement of T-cell receptor excision circles (TRECs). Herein, we report our experience of reporting TREC assay results as multiple of the median (MoM) rather than using conventional copy numbers. This modification simplifies the assay by eliminating the need for standards with known TREC copy numbers. Furthermore, since MoM is a measure of how far an individual test result deviates from the median, it allows normalization of TREC assay data from different laboratories, so that individual test results can be compared regardless of the particular method, assay, or reagents used.

PP574 Cost-Effectiveness Of Newborn Screening Of Primary Immunodeficiency Diseases: A Systematic Review And Economic Evaluation

IntroductionPrimary immunodeficiency diseases (PIDs) are a heterogeneous group of over 200 disorders with defects in the function and/or development of the immune system. Although early screening is imperative for improving therapeutic efficiency and preventing disease-associated morbidity, its widespread use has been limited, owing to the low incidence of PIDs. It is particularly important to evaluate the cost-effectiveness of PIDs screening for newborns. The aim of this study was to provide an overview of the existing cost-effectiveness evidence on newborn screening of PIDs and to provide reference for decision-makers in China and other developing countries.MethodsWe conducted a systematic review using three electronic databases (PubMed, CNKI, and CSPD) of cost and cost-effectiveness studies of PIDs screening published during 2000–2019. Two reviewers independently searched databases and screened titles, abstracts and full texts; a third reviewer resolved disputes when necessary. The initial search returned 124 references, of which 10 full articles were included in the review. Five of the studies conducted analyses using model-based techniques.ResultsSevere combined immunodeficiency (SCID) was the predominantly studied condition (80%). Most studies (70%) examined the T-cell receptor excision circle (TREC) assay. A healthcare system's perspective was commonly used (50%) for cost calculations, and most studies (50%) were US-based. The majority (67%) of the studies found the TREC assay an effective screening tool for SCID, but the incremental cost-effectiveness ratio (ICER) varied across screening test specificity and disease incidence.ConclusionsEvidence from the published literature demonstrated that newborn screening for PIDs generally appeared to be cost-effective, and most importantly, it is lifesaving and allows children with PIDs an opportunity to live a healthier life. However, the type of PIDs included in this study were limited and most studies were done in developed countries whose health systems are different from low-/middle-income countries (LMIC). Further research is required to identify the cost-effectiveness of PIDs screening both in developed and developing countries.

Population-Based Screening for Severe Combined Immunodeficiency in Manitoba, Canada

The incidence of Severe Combined Immunodeficiency (SCID) in Manitoba, (1/15,000), is at least three to four times higher than the national average and that reported from other jurisdictions. It is overrepresented in two population groups: Mennonites (ZAP70 founder mutation) and First Nations of Northern Cree ancestry (IKBKB founder mutation). We have previously demonstrated that in these two populations the most widely utilized T-cell receptor excision circle (TREC) assay is an ineffective newborn screening test to detect SCID as these patients have normal numbers of mature T-cells. We have developed a semi-automated, closed tube, high resolution DNA melting procedure to simultaneously genotype both of these mutations from the same newborn blood spot DNA extract used for the TREC assay. Parallel analysis of all newborn screening specimens utilizing both TREC analysis and the high resolution DNA procedure should provide as complete ascertainment as possible of SCID in the Manitoba population.