Special Issue "Newborn Screening for primary immunodeficiency diseases – Past, Present and Future"

A special issue of International Journal of Neonatal Screening (ISSN 2409-515X).

Deadline for manuscript submissions: closed (15 April 2017)

Special Issue Editors

Guest Editor
Prof. Dr. Lennart Hammarström

Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska University Hospital Huddinge, Stockholm, Sweden
Website | E-Mail
Interests: primary immunodeficiency, genetics, newborn screening
Guest Editor
Dr. Stephan Borte

Department of Laboratory Medicine (LABMED), H5, Division of Clinical Immunology, Karolinska Universitetssjukhuset, Huddinge F79 14186 Stockholm, Sweden
Website | E-Mail
Interests: primary immunodeficiency, pediatrics, genetics, newborn screening

Special Issue Information

Dear Colleagues,

Newborn screening for primary immunodeficiency is coming of age! Following the seminal paper by Jenifer Puck and her group in 2005, describing the T Cell Receptor Excision Circle assay (TREC), screening of newborns using this assay started in Wisconsin a few years later. During 2017, it is expected that all states in the US will be screening for T cell lymphopenia (as a sign of SCID). National screening using the TREC assay has also been implemented in Taiwan and Israel and pilot trials are ongoing in many additional countries.

The KREC assay, using a similar technology but analyzing B cells (Kappa Receptor Excision Circle assay) was published in 2011 and has been used to identify children with B cell lymphopenia. Subsequently, a combined assay (TREC/KREC/beta actin) was developed for the simultaneous detection of both T and B cell lymphopenia.

Further development of assays for detection of newborn children with various forms of primary immunodeficiency were developed in the following years and discussions on the appropriare use of next generation sequencing methods are currently underway.

This Special Issue (by invitation only) of the International Journal of Neonatal Screening, devoted to “Newborn Screening for primary immunodeficiency diseases – Past, Present and Future”, will thus consider where we have been, where we are, and where we might be going.

Best regards

Lennart Hammarström and Stephan Borte

Prof. Dr. Lennart Hammarström
Dr. Stephan Borte
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Neonatal Screening is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) is waived for well-prepared manuscripts submitted to this issue. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (7 papers)

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Research

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Open AccessArticle Newborn Screening for Primary T- and B-Cell Immune Deficiencies—A Prospective Study in Andalucía
Int. J. Neonatal Screen. 2017, 3(4), 27; doi:10.3390/ijns3040027
Received: 7 July 2017 / Revised: 21 August 2017 / Accepted: 22 September 2017 / Published: 7 October 2017
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Abstract
Background: Quantification of T-cell-receptor-excision circles (TRECs) and kappa-deleting-recombination-excision circles (KRECs) from dried blood spots (DBS) allows detection of neonates with severe T-cell and/or B-cell lymphopenia that are potentially affected by severe combined immunodeficiency (SCID), as well as X-linked agammaglobulinemia (XLA). Methods: Determination of
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Background: Quantification of T-cell-receptor-excision circles (TRECs) and kappa-deleting-recombination-excision circles (KRECs) from dried blood spots (DBS) allows detection of neonates with severe T-cell and/or B-cell lymphopenia that are potentially affected by severe combined immunodeficiency (SCID), as well as X-linked agammaglobulinemia (XLA). Methods: Determination of TRECs and KRECs using a triplex RT-PCR (TRECS-KRECS-β-actin) assay from prospectively collected DBS between February 2014 and December 2016 in three hospitals in Seville, Spain. Cut-off levels were TRECs < 6/punch, KRECs < 4/punch and b-actin > 700/punch. Internal (SCID, XLA, ataxia telangiectasia) and external controls (CDC) were included. Results: A total of 8943 DBS samples obtained from 8814 neonates were analysed. Re-punching was necessary in 124 samples (1.4%) due to insufficient β-actin values (<700 copies/punch). Preterm neonates (GA < 37 weeks) and neonates with a BW < 2500 g showed significantly lower TRECs and KRECs levels (p < 0.001). Due to repeated pathological results, ten neonates were re-sampled (0.11%), of which five neonates (0.055%) confirmed the pathological results: one case was a fatal chromosomopathy (TRECs 1/KRECs 4); two were extreme premature newborns (TRECs 0/KRECs 0 and TRECs 1/KRECs 20 copies/punch); and 2 neonates were born to mothers receiving azathioprine during pregnancy (TRECs 92/KRECs 1 and TRECs 154/KRECs 3 copies/punch). All controls were correctly identified. Conclusions: Severe T- and B-cell lymphopenias were correctly identified by the TRECS-KRECS-β-actin assay. Prematurity and low BW are associated with lower TREC and KREC levels. Extreme prematurity and maternal immune suppressive therapy can cause false positive results of TRECs and KRECs values. Full article
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Open AccessFeature PaperArticle Newborn Screening for Severe Combined Immunodeficiency in Taiwan
Int. J. Neonatal Screen. 2017, 3(3), 16; doi:10.3390/ijns3030016
Received: 30 March 2017 / Revised: 2 June 2017 / Accepted: 19 June 2017 / Published: 23 June 2017
Cited by 2 | PDF Full-text (455 KB) | HTML Full-text | XML Full-text
Abstract
A study of newborn screening for severe combined immunodeficiency (SCID) by detecting the T-cell receptor excision circle (TRECs) copy number in dried blood spots (DBSs) collected from newborns 3 days of age began in 2010 in Taiwan, and SCID screening was subsequently implemented
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A study of newborn screening for severe combined immunodeficiency (SCID) by detecting the T-cell receptor excision circle (TRECs) copy number in dried blood spots (DBSs) collected from newborns 3 days of age began in 2010 in Taiwan, and SCID screening was subsequently implemented country-wide in 2012. A total of 920,398 newborns were screened during a period of 78 months. Of these, 175 newborns (0.02%) were requested to undergo an immune function survey, and 136 cases (1 in 6768 newborns) were ultimately diagnosed as having T cell lymphopenia. The screening detected seven cases of typical SCID, with an incidence of 1 in 131,485 newborns (95% confidence interval, 1/63,693~1/271,434). Hematopoietic stem cell transplantation was performed in six patients before overt infection occurred, and the survival rate was 100%. The screening also detected eight cases of SCID variants and 20 cases of 22q11.2 deletion syndrome. Other etiologies of T lymphopenia were identified, and those newborns were evaluated and managed according to their immunological status. Owing to the introduction of newborn screening by measuring the TREC copy number, early administration of treatments became possible for newborns with conditions that put them at risk of primary or secondary immunodeficiency. Full article
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Open AccessArticle Newborn Screening for Primary Immune Deficiencies with a TREC/KREC/ACTB Triplex Assay—A Three-Year Pilot Study in Sweden
Int. J. Neonatal Screen. 2017, 3(2), 11; doi:10.3390/ijns3020011
Received: 7 April 2017 / Revised: 9 May 2017 / Accepted: 10 May 2017 / Published: 19 May 2017
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Abstract
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
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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. Full article
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Review

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Open AccessReview A Practical Guide to Implementing Population Newborn Screening (NBS) for Severe Combined Immunodeficiency (SCID)
Int. J. Neonatal Screen. 2017, 3(4), 29; doi:10.3390/ijns3040029
Received: 11 September 2017 / Revised: 8 November 2017 / Accepted: 8 November 2017 / Published: 10 November 2017
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Abstract
This review should be seen as a practical tool, one which we hope illustrates potential routes to follow when seeking to implement or lobby for severe combined immunodeficiency newborn screening (SCID NBS) at a national or regional level. Experience has shown that there
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This review should be seen as a practical tool, one which we hope illustrates potential routes to follow when seeking to implement or lobby for severe combined immunodeficiency newborn screening (SCID NBS) at a national or regional level. Experience has shown that there are country- and region-wide variations in terms of awareness of the need for SCID NBS and the processes required to demonstrate and prove the importance of SCID NBS. This guide therefore aims to share experiences and equip readers with evidence while also directing them to key further reading and resources that provide support, data, and existing frameworks that are relevant to making the case for mandatory NBS for SCID. Full article
Open AccessReview Newborn Screening for Severe Combined Immunodeficiency in the US: Current Status and Approach to Management
Int. J. Neonatal Screen. 2017, 3(2), 15; doi:10.3390/ijns3020015
Received: 17 April 2017 / Revised: 30 May 2017 / Accepted: 30 May 2017 / Published: 21 June 2017
Cited by 2 | PDF Full-text (1529 KB) | HTML Full-text | XML Full-text
Abstract
In the US, the assay of T cell receptor excision circles (TRECs) in newborn dried blood spot specimens to detect severe combined immunodeficiency (SCID) was first piloted in 2008 in the state of Wisconsin. It has been rapidly adopted with 49 states and
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In the US, the assay of T cell receptor excision circles (TRECs) in newborn dried blood spot specimens to detect severe combined immunodeficiency (SCID) was first piloted in 2008 in the state of Wisconsin. It has been rapidly adopted with 49 states and Puerto Rico now either routinely screening all newborns or planning to do so in 2017. Advances in SCID NBS over the last 9 years have revolutionized the ability to detect SCID and has led to profound improvement in outcomes of affected children. Full article
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Open AccessReview Newborn Screening for Severe Combined Immunodeficiency-A History of the TREC Assay
Int. J. Neonatal Screen. 2017, 3(2), 14; doi:10.3390/ijns3020014
Received: 11 May 2017 / Accepted: 14 June 2017 / Published: 18 June 2017
Cited by 1 | PDF Full-text (1148 KB) | HTML Full-text | XML Full-text
Abstract
Infants born with T cell lymphopenias, especially severe combined immunodeficiency (SCID) are at risk for serious, often fatal infections without intervention within the first year or two of life. The majority of these disorders can be detected through the use of the T
[...] Read more.
Infants born with T cell lymphopenias, especially severe combined immunodeficiency (SCID) are at risk for serious, often fatal infections without intervention within the first year or two of life. The majority of these disorders can be detected through the use of the T cell recombination excision circle assay (TREC assay.) The TREC assay detects the presence of non-replicating, episomal DNA that is formed during T cell development. This assay initially developed to measure thymic output during aging and HIV infection, has undergone modifications for the purpose of newborn screening (NBS) for SCID. To meet the requirements for inclusion on NBS panels, the assay needed to utilize blood from dried blood spots on NBS cards, and be both sensitive and specific, avoiding the costs of false positives. Currently, the assay relies upon real time, quantitative PCR (RT-qPCR) to detect TRECs in punches taken from dried blood spots. This review seeks to highlight some of the early work leading up to the initial implementation of the TREC assay for SCID detection, and the subsequent revisions made to optimize the assay. Full article
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Open AccessReview Newborn Screening for Severe Combined Immunodeficiency in Israel
Int. J. Neonatal Screen. 2017, 3(2), 13; doi:10.3390/ijns3020013
Received: 23 April 2017 / Revised: 24 May 2017 / Accepted: 12 June 2017 / Published: 17 June 2017
Cited by 3 | PDF Full-text (213 KB) | HTML Full-text | XML Full-text
Abstract
Newborn screening (NBS) programs for severe combined immunodeficiency (SCID), the most severe type of primary immunodeficiency, are being implemented in more and more countries with every passing year. Since October 2015, SCID screening via T cell receptor excision circle (TREC) quantification in dried
[...] Read more.
Newborn screening (NBS) programs for severe combined immunodeficiency (SCID), the most severe type of primary immunodeficiency, are being implemented in more and more countries with every passing year. Since October 2015, SCID screening via T cell receptor excision circle (TREC) quantification in dried blood spots (DBS) has been part of the Israeli NBS program. As an NBS program in its infancy, SCID screening is still evolving, making gathering input from the various programs crucial for compiling an ideal screening algorithm. The relatively high rate of consanguineous marriages in Israel, especially among non-Jews, correlates with an increased incidence of SCID. The Israeli algorithm uses a commercial kit and consists of a two-Guthrie card confirmation system prior to referral to a national immunology center. Preliminary data from the first year and a half of SCID screening in Israel has identified a surprisingly high prevalence of DNA cross-link repair protein 1c (DCLRE1C; ARTEMIS) mutations as the cause of SCID in Israel. The clinically unbiased nature of SCID screening helps unearth mild/leaky SCID phenotypes, resulting in a better understanding of true SCID prevalence and etiology. Full article

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: SCID screening - How it all began
Author: Jack Routes (USA)

Title: SCID screening in the US
Author: Jennifer Puck

Title: SCID screening in Taiwan
Authors: YH Chien, WI Lee

Title: SCID screening in Israel
Author: Amos Etzioni

Title: SCID screening in Spain (Andalucia)
Author: Olaf Neth

Title: TREC/KREC pilot screening in Sweden
Author: Ulrika von Döbeln

Title: TREC/KREC pilot screening in the Netherlands
Authors: Peter Schielen, Mirjam van der Burg

Title: A roadmap for SCID screening
Author: Bobby Gaspar

Title: Beyond SCID - targeted screening for selected diseases including complement and granulocyte deficiencies
Author: Stephan Borte

Title: Future outlook - targeted gene panels, WES and WGS
Author: Lennart Hammarström

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