Quantification of κ-deleting recombination excision circles in Guthrie cards for the identification of early B-cell maturation defects

Nakagawa, Noriko; Imai, Kohsuke; Kanegane, Hirokazu; Sato, Hiroki; Yamada, Masafumi; Kondoh, Kensuke; Okada, Satoshi; Kobayashi, Masao; Agematsu, Kazunaga; Takada, Hidetoshi; Mitsuiki, Noriko; Oshima, Koichi; Ohara, Osamu; Suri, Deepti; Rawat, Amit; Singh, Surjit; Pan‐Hammarström, Qiang; Hammarström, Lennart; Reichenbach, Janine; Seger, Reinhard; Ariga, Tadashi; Hara, Tetsuo; Miyawaki, Toshio; Nonoyama, Shigeaki

doi:10.1016/j.jaci.2011.01.052

Cited by 91 publications

(71 citation statements)

References 10 publications

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“…With this methodology, patients with defects in the production of T-cells can be identified, but isolated B-cell defects escape detection. The development of a triplex assay for the simultaneous quantitation of TREC/KREC and ACTB has been shown to identify patients who also have isolated B-cell defects like X-linked agammaglobulinemia and Nijmegen breakage syndrome [11,12]. We now report the results of an NBS trial in the County of Stockholm during the years 2013-2016 with the TREC/KREC/ACTB triple assay.…”

Section: Discussionmentioning

confidence: 99%

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

Zetterström

Barbaro

Ohlsson

et al. 2017

IJNS

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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.

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Section: Discussionmentioning

confidence: 99%

“…A similar method for the analysis of kappa-deleting recombination excision circles (KRECs) has been developed for the quantification of novel B-lymphocytes [11]. Patients with severe B-cell deficiency such as X-linked agammaglobulinemia (XLA) can be identified with the KREC assay.…”

Section: Introductionmentioning

confidence: 99%

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

Zetterström

Barbaro

Ohlsson

et al. 2017

IJNS

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“…Measurement of TREC and KREC levels TREC, sjKREC and cjKREC levels were measured by real-time PCR as described previously [15][16][17][18][19] at 1, 3 and 6 months, and yearly after HCT. RNase P was used as an internal control.…”

Section: Introductionmentioning

confidence: 99%

Cord blood transplantation is associated with rapid B-cell neogenesis compared with BM transplantation

Nakatani

Imai

Shigeno

et al. 2014

Bone Marrow Transplant

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Hematopoietic cell transplantation (HCT) is used for treatment of hematopoietic diseases. Assessment of T-and B-cell reconstitution after HCT is crucial because poor immune recovery has a major effect on the clinical course. In this study, we retrospectively analyzed T-cell receptor excision circles (TRECs) as well as signal and coding joint kappa-deleting recombination excision circles (sjKRECs and cjKRECs, respectively) as markers of newly produced lymphocytes in 133 patients (56 primary immunodeficient and 77 malignant cases, median (range): 12 (0-62) years old). We analyzed the kinetics of TREC and KREC recovery and determined the factors that contributed to better immune recovery. KRECs became positive earlier than TRECs and increased thereafter. Younger recipient age had a favorable effect on recovery of sjKRECs and cjKRECs. Compared with BM and peripheral blood, our data suggested that cord blood (CB) provided rapid B-cell recovery. CB also provided better B-cell neogenesis in adult HCT recipients. Chronic GVHD was associated with low TRECs, but not increased sjKRECs/cjKRECs. Finally, positive sjKRECs 1 month after HCT were associated with fewer infectious episodes. Monitoring of TRECs and KRECs may serve as a useful tool for assessment of immune reconstitution post HCT.

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“…Several countries in Europe, Australasia and the Middle East have also commenced SCID screening programs, or are evaluating these in prospective studies (Table 1). In addition to the detection of TREC levels as surrogate markers for thymic T cell output, it is also possible to evaluate B cell production by quantifying kappa-recombining excision circles (KREC), which are produced by similar mechanisms during rearrangement of the variable, diversity and joining domains (V(D)J recombination) of the B cell immunoglobulin kappa gene [15]. A multiplexed assay measuring TREC and KREC, along with beta-actin levels as a control for DNA quantity provides a strategy for simultaneous screening for T and B cell lymphopenia [16].…”

Section: The Present: Screening For T and B Cell Lymphopeniamentioning

confidence: 99%

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

King

Ludvigsson

Hammarström

2017

IJNS

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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.

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Quantification of κ-deleting recombination excision circles in Guthrie cards for the identification of early B-cell maturation defects

Cited by 91 publications

References 10 publications

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

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

Cord blood transplantation is associated with rapid B-cell neogenesis compared with BM transplantation

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

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