Newborn Screening for Severe Combined Immunodeficiency-A History of the TREC Assay

Bausch-Jurken, Mary T.; Verbsky, James; Routes, John M.

doi:10.3390/ijns3020014

Cited by 10 publications

(8 citation statements)

References 36 publications

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“…A similar approach has been described to identify patients with PNP deficiency [ 34 ]. A two-tiered testing approach using TREC analysis combined with IL-7 measurement has also been proposed as a means to increase the specificity of SCID screening [ 35 ]; however, this has not yet been optimized for application in large-scale screening programs [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

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

2017

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The primary objective of population-based newborn screening is the early identification of asymptomatic infants with a range of severe diseases, for which effective treatment is available and where early diagnosis and intervention prevent serious sequelae. Primary immunodeficiency diseases (PID) are a heterogeneous group of inborn errors of immunity. Severe combined immunodeficiency (SCID) is one form of PID which is uniformly fatal without early, definitive therapy, and outcomes are significantly improved if infants are diagnosed and treated within the first few months of life. Screening for SCID using T cell receptor excision circle (TREC) analysis has been introduced in many countries worldwide. The utility of additional screening with kappa recombining excision circles (KREC) has also been described, enabling identification of infants with severe forms of PID manifested by T and B cell lymphopenia. Here, we review the early origins of newborn screening and the evolution of screening methodologies. We discuss current strategies employed in newborn screening programs for PID, including TREC and TREC/KREC-based screening, and consider the potential future role of protein-based assays, targeted sequencing, and next generation sequencing (NGS) technologies, including whole genome sequencing (WGS).

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Section: Introductionmentioning

confidence: 99%

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

2017

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“…Recently, the implementation of newborn screening programs using T-cell receptor excision circles (TREC) has become a significant advancement in identifying patients with SCID or profound T-cell lymphopenia [ 45 ]. Compared to patients diagnosed based on clinical features, those identified through newborn screening or positive familial history can receive an early and accurate diagnosis within the first month of life [ 45 ]. As a result, they can undergo HSCT or gene therapy by three months of age before severe complications arise [ 45 ].…”

Section: Reviewmentioning

confidence: 99%

“…Compared to patients diagnosed based on clinical features, those identified through newborn screening or positive familial history can receive an early and accurate diagnosis within the first month of life [ 45 ]. As a result, they can undergo HSCT or gene therapy by three months of age before severe complications arise [ 45 ]. This approach has led to significantly improved outcomes for these patients.…”

Section: Reviewmentioning

confidence: 99%

Guardians of Immunity: Advances in Primary Immunodeficiency Disorders and Management

Peddi,

Vuppalapati,

Sreenivasulu

et al. 2023

Cureus

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Primary immunodeficiency disorders (PIDs) are a heterogeneous group of genetic conditions profoundly impacting immune function. The investigation spans various PID categories, offering insights into their distinct pathogenic mechanisms and clinical manifestations. Within the adaptive immune system, B-cell, T-cell, and combined immunodeficiencies are dissected, emphasizing their critical roles in orchestrating effective immune responses. In the realm of the innate immune system, focus is directed toward phagocytes and complement deficiencies, underscoring the pivotal roles of these components in initial defense against infections. Furthermore, the review delves into disorders of immune dysregulation, encompassing hemophagocytic lymphohistiocytosis (HLH), autoimmune lymphoproliferative syndrome (ALPS), immune dysregulation, polyendocrinopathy, enteropathy, and X-linked(IPEX), and autoimmunity polyendocrinopathy candidiasis-ectodermal dystrophy(APECED), elucidating the intricate interplay between immune tolerance and autoimmunity prevention. Diagnostic strategies for PIDs are explored, highlighting advancements in genetic and molecular techniques that enable precise identification of underlying genetic mutations and alterations in immune function. We have also outlined treatment modalities for PIDs, which often entail a multidisciplinary approach involving immunoglobulin replacement, antimicrobial prophylaxis, and, in select cases, hematopoietic stem cell transplantation. Emerging therapies, including gene therapy, hold promise for targeted interventions. In essence, this review encapsulates the complexity of PIDs, emphasizing the critical importance of early diagnosis and tailored therapeutic interventions. As research advances, a clearer understanding of these disorders emerges, fostering optimism for enhanced patient care and management in the future.

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“…TRECs are not replicated during mitosis and so are diluted in the cell population with each round of cell division (11). TREC measurement is used to quantify thymic output and cell division history, and is implemented in newborn screening programs for Severe Combined Immunodeficiency (12). Different subpopulations of T cells have different concentrations of TRECs depending on the number of cell divisions they have undergone since thymic production.…”

Section: Introductionmentioning

confidence: 99%

Absolute quantification of rare gene targets in limited samples using crude lysate and ddPCR

Kaur,

Adams,

Kibirige

et al. 2024

Preprint

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Background Accurate quantification of rare genes from limited clinical samples is crucial for research purposes but is technically challenging. In particular, nucleic acid extraction for quantification of gene targets may lead to target loss. Here, we report the development and validation of a novel crude lysate ddPCR assay for the absolute quantification of rare genes, TRECs in our case, from infrequent cells, that removes the need for DNA extraction, hence minimizing the target loss. Methods The analytical validation was performed on PBMCs extracted from the blood of healthy donors. Standard ddPCR was first optimized to detect TREC copies/cell and then applied to a crude lysate ddPCR assay. The assay was optimized by varying several steps. The optimised assay was directly compared to standard ddPCR and the performance of the assay quantified. Results The newly developed assay showed good agreement with the standard ddPCR assay in the range from 0.0003 to 0.01 TRECs/cell. The assay had a limit of quantification of <0.0003 TRECs/cell and a limit of detection of <0.0001 TRECs/cell; this performance is favourable compared to standard ddPCR. The intra-assay variation was low. This method can also be applied to fixed and permeabilized cells. Conclusions The newly developed crude lysate ddPCR assay for quantifying rare targets from limited samples has high accuracy, specificity, and reproducibility; additionally, it eliminates the need for DNA extraction for absolute quantification. The assay has the potential to be used for quantification of other trace targets from small samples.

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Newborn Screening for Severe Combined Immunodeficiency-A History of the TREC Assay

Cited by 10 publications

References 36 publications

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

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

Guardians of Immunity: Advances in Primary Immunodeficiency Disorders and Management

Absolute quantification of rare gene targets in limited samples using crude lysate and ddPCR

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