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Newborn Screening for Severe Combined Immune Deficiency—Selected Papers from the ISNS-SCID Meeting

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

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 35296

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Prof. Dr. Jim R. Bonham

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Guest Editor

Department of Clinical Chemistry, Sheffield Children's NHS Foundation Trust, Sheffield S10 2TH, UK
Interests: quality assurance; inherited metabolic disorders; genomics; IT supporting patients; system governance
Special Issues, Collections and Topics in MDPI journals

Dr. Peter C. J. I. Schielen

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Office of the International Society for Neonatal Screening, Reigerskamp 273, 3607 HP Maarssen, The Netherlands
Interests: (neonatal screening in) Europe; (neonatal screening and) the Wilson and Jungner criteria; lysosomal storage diseases; application of next generation sequencing in neonatal screening; inherited errors of metabolism; tandem mass spectrometry; genomics; artificial intelligence in neonatal screening; cystic fibrosis; screening policies and governance; quality assurance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since the US state of Wisconsin first began newborn screening for severe combined immune deficiency (SCID) in 2008, many countries around the world have begun to screen for this important disorder, and it is now more than ten years since it was added to the Recommended Uniform Screening Panel in the USA.

During that time, we have learned much about this condition. The success of bone marrow transplant has improved, and enzyme replacement and gene modification have become part of the treatments that can be offered.

The technology used to screen for this condition has also changed with the growth of real-time PCR, offering the possibility to multiplex other disorders alongside SCID. A wealth of knowledge has been gained during this time concerning the practical operation of screening programs, the use and organization of confirmatory testing, and the range of related disorders identified by the measurement of T-cell receptor excision circles (TRECs) in newborn screening blood spot samples. Analysis of external quality assurance data from 75 participants in 22 countries around the world offers us the possibility to describe assay performance over a number of years.

Early in 2021, a two-day conference drew speakers from around the world including Europe, the USA, and New Zealand to explore and share their combined knowledge. We were able to hear first-hand from clinicians, laboratory scientists working in screening and immunology, and those who have been planning and scrutinizing the implementation of SCID programs in different countries.

In all, 15 international experts drawn from 10 countries were generous enough to share their collective experience to describe the state of the art in newborn screening for SCID, and many of these have agreed to contribute to a Special Issue: Newborn Screening for Severe Combined Immune Deficiency—Selected Papers from the ISNS-SCID Meeting. While we already have submissions for this Special Issue we explicitly invite you to submit your contribution to this important issue-thus, we hope to have an even more complete coverage of neonatal screening for SCID.

Prof. Dr. Jim Bonham
Dr. Peter C.J.I. Schielen
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 submissions that pass pre-check are 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) for publication in this open access journal is 1600 CHF (Swiss Francs). 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 (12 papers)

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Research

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6 pages, 364 KiB

Open AccessArticle

Introducing Newborn Screening for Severe Combined Immunodeficiency—The New Zealand Experience

by Natasha Heather, Mark de Hora, Shannon Brothers, Pippa Grainger, Detlef Knoll and Dianne Webster

Int. J. Neonatal Screen. 2022, 8(2), 33; https://doi.org/10.3390/ijns8020033 - 10 May 2022

Cited by 3 | Viewed by 3566

Abstract

Screening for severe combined immunodeficiency (SCID) was added to the New Zealand national newborn screening programme in December 2017. Documentation pertaining to the application to add SCID to the panel and screening results over the first three years were reviewed. Screening evaluation metrics were shown to differ according to site of collection (babies in a neonatal intensive care unit vs. the community), definition of a positive test (out-of-range result vs. result leading to a further action on baby), and screening target/case definition (primary SCID vs. non-SCID T-cell lymphopenia). Our experience demonstrates both the value of close clinical involvement during the implementation phase of SCID screening and that the use of standard definitions will facilitate international comparison. Full article

(This article belongs to the Special Issue Newborn Screening for Severe Combined Immune Deficiency—Selected Papers from the ISNS-SCID Meeting)

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15 pages, 1322 KiB

Open AccessArticle

First Year of TREC-Based National SCID Screening in Sweden

by Christina Göngrich, Olov Ekwall, Mikael Sundin, Nicholas Brodszki, Anders Fasth, Per Marits, Sam Dysting, Susanne Jonsson, Michela Barbaro, Anna Wedell, Ulrika von Döbeln and Rolf H. Zetterström

Int. J. Neonatal Screen. 2021, 7(3), 59; https://doi.org/10.3390/ijns7030059 - 25 Aug 2021

Cited by 11 | Viewed by 3621

Abstract

Screening for severe combined immunodeficiency (SCID) was introduced into the Swedish newborn screening program in August 2019 and here we report the results of the first year. T cell receptor excision circles (TRECs), kappa-deleting element excision circles (KRECs), and actin beta (ACTB) levels were quantitated by multiplex qPCR from dried blood spots (DBS) of 115,786 newborns and children up to two years of age, as an approximation of the number of recently formed T and B cells and sample quality, respectively. Based on low TREC levels, 73 children were referred for clinical assessment which led to the diagnosis of T cell lymphopenia in 21 children. Of these, three were diagnosed with SCID. The screening performance for SCID as the outcome was sensitivity 100%, specificity 99.94%, positive predictive value (PPV) 4.11%, and negative predictive value (NPV) 100%. For the outcome T cell lymphopenia, PPV was 28.77%, and specificity was 99.95%. Based on the first year of screening, the incidence of SCID in the Swedish population was estimated to be 1:38,500 newborns. Full article

(This article belongs to the Special Issue Newborn Screening for Severe Combined Immune Deficiency—Selected Papers from the ISNS-SCID Meeting)

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5 pages, 537 KiB

Open AccessArticle

Implementation of SCID Screening in Denmark

by Marie Bækvad-Hansen, Dea Adamsen, Jonas Bybjerg-Grauholm and David Michael Hougaard

Int. J. Neonatal Screen. 2021, 7(3), 54; https://doi.org/10.3390/ijns7030054 - 12 Aug 2021

Cited by 6 | Viewed by 2234

Abstract

Screening for SCID was added to the Danish Neonatal Screening Program in February 2020. The screening uses a RealtimePCR kit and we here present the results and experiences with the validation of the kit and the first 10 months of screening. Full article

(This article belongs to the Special Issue Newborn Screening for Severe Combined Immune Deficiency—Selected Papers from the ISNS-SCID Meeting)

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9 pages, 1225 KiB

Open AccessArticle

Newborn Screening for SCID: Experience in Spain (Catalonia)

by Ana Argudo-Ramírez, Andrea Martín-Nalda, Jose Manuel González de Aledo-Castillo, Rosa López-Galera, Jose Luis Marín-Soria, Sonia Pajares-García, Mónica Martínez-Gallo, Marina García-Prat, Roger Colobran, Jacques G. Riviere, Yania Quintero, Tatiana Collado, Antonia Ribes, Judit García-Villoria and Pere Soler-Palacín

Int. J. Neonatal Screen. 2021, 7(3), 46; https://doi.org/10.3390/ijns7030046 - 20 Jul 2021

Cited by 6 | Viewed by 3550

Abstract

Newborn screening (NBS) for severe combined immunodeficiency (SCID) started in Catalonia in January-2017, being the first Spanish and European region to universally include this testing. In Spain, a pilot study with 5000 samples was carried out in Seville in 2014; also, a research project with about 35,000 newborns will be carried out in 2021–2022 in the NBS laboratory of Eastern Andalusia. At present, the inclusion of SCID is being evaluated in Spain. The results obtained in the first three and a half years of experience in Catalonia are presented here. All babies born between January-2017 and June-2020 were screened through TREC-quantification in DBS with the Enlite Neonatal TREC-kit from PerkinElmer. A total of 222,857 newborns were screened, of which 48 tested positive. During the study period, three patients were diagnosed with SCID: an incidence of 1 in 74,187 newborns; 17 patients had clinically significant T-cell lymphopenia (non-SCID) with an incidence of 1 in 13,109 newborns who also benefited from the NBS program. The results obtained provide further evidence of the benefits of early diagnosis and curative treatment to justify the inclusion of this disease in NBS programs. A national NBS program is needed, also to define the exact SCID incidence in Spain. Full article

(This article belongs to the Special Issue Newborn Screening for Severe Combined Immune Deficiency—Selected Papers from the ISNS-SCID Meeting)

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7 pages, 592 KiB

Open AccessArticle

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

by Michael F. Cogley, Amy E. Wiberley-Bradford, Sean T. Mochal, Sandra J. Dawe, Zachary D. Piro and Mei W. Baker

Int. J. Neonatal Screen. 2021, 7(3), 43; https://doi.org/10.3390/ijns7030043 - 12 Jul 2021

Cited by 2 | Viewed by 2662

Abstract

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. Full article

(This article belongs to the Special Issue Newborn Screening for Severe Combined Immune Deficiency—Selected Papers from the ISNS-SCID Meeting)

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7 pages, 1240 KiB

Open AccessArticle

Newborn Screening for Severe Combined Immunodeficiency: Do Preterm Infants Require Special Consideration?

by Anne E. Atkins, Michael F. Cogley and Mei W. Baker

Int. J. Neonatal Screen. 2021, 7(3), 40; https://doi.org/10.3390/ijns7030040 - 08 Jul 2021

Cited by 5 | Viewed by 2412

Abstract

The Wisconsin Newborn Screening (NBS) Program began screening for severe combined immunodeficiency (SCID) in 2008, using real-time PCR to quantitate T-cell receptor excision circles (TRECs) in DNA isolated from dried blood NBS specimens. Prompted by the observation that there were disproportionately more screening-positive cases in premature infants, we performed a study to assess whether there is a difference in TRECs between full-term and preterm newborns. Based on de-identified SCID data from 1 January to 30 June 2008, we evaluated the TRECs from 2510 preterm newborns (gestational age, 23–36 weeks) whose specimens were collected ≤72 h after birth. The TRECs from 5020 full-term newborns were included as controls. The relationship between TRECs and gestational age in weeks was estimated using linear regression analysis. The estimated increase in TRECs for every additional week of gestation is 9.60%. The 95% confidence interval is 8.95% to 10.25% (p ≤ 0.0001). Our data suggest that TRECs increase at a steady rate as gestational age increases. These results provide rationale for Wisconsin’s existing premature infant screening procedure of recommending repeat NBS following an SCID screening positive in a premature infant instead of the flow cytometry confirmatory testing for SCID screening positives in full-term infants. Full article

(This article belongs to the Special Issue Newborn Screening for Severe Combined Immune Deficiency—Selected Papers from the ISNS-SCID Meeting)

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Review

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10 pages, 6040 KiB

Open AccessReview

Establishing Newborn Screening for SCID in the USA: Experience in California

by Jennifer M. Puck and Andrew R. Gennery

Int. J. Neonatal Screen. 2021, 7(4), 72; https://doi.org/10.3390/ijns7040072 - 31 Oct 2021

Cited by 7 | Viewed by 3335

Abstract

Newborn screening for severe combined immunodeficiency (SCID) has developed from the realization that infants affected with SCID require prompt diagnosis and treatment to avoid fatal infectious complications. Screening DNA from infant dried blood spots for T-cell receptor excision circles (TRECs), byproducts of normal antigen-receptor gene rearrangement, has proven to be a reliable method to identify infants with SCID and other serious T lymphocyte defects before the onset of serious infections. The experience of the SCID newborn screening program in California after screening over 3 million infants demonstrates the effectiveness of this measure. Full article

(This article belongs to the Special Issue Newborn Screening for Severe Combined Immune Deficiency—Selected Papers from the ISNS-SCID Meeting)

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9 pages, 803 KiB

Open AccessReview

Neonatal Screening for SCID: The French Experience

by Marie Audrain and Caroline Thomas

Int. J. Neonatal Screen. 2021, 7(3), 42; https://doi.org/10.3390/ijns7030042 - 12 Jul 2021

Cited by 4 | Viewed by 2730

Abstract

After it was demonstrated in 2005 that T cell receptor excision circle (TREC) quantification for dried blood spot (DBS) samples on Guthrie cards is an effective means of SCID screening and following several pilot studies, the practice was formally recommended in the US in 2010. More and more countries have adopted it since then. In France, before the health authorities could recommend adding SCID to the list of five diseases that were routinely screened for, feasibility and cost-effectiveness studies had to be conducted with a sufficiently large cohort of neonates. We carried out three such studies: The first sought to verify the effectiveness of the assay. The second, DEPISTREC, evaluated the feasibility of universal SCID screening in France and assessed the clinical benefit and economic advantage it would provide. Through the third study, NeoSKID, still under way and to continue until recommendations are issued, we have been offering SCID screening in the Pays de la Loire region of France. This review briefly describes routine newborn screening (NBS) and management of primary immunodeficiency diseases (PIDs) in France, and then considers the lessons from our studies and the status of SCID screening implementation within the country. Full article

(This article belongs to the Special Issue Newborn Screening for Severe Combined Immune Deficiency—Selected Papers from the ISNS-SCID Meeting)

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8 pages, 1782 KiB

Open AccessProject Report

Study Design for an Evaluation of Newborn Screening for SCID in the UK

by David Elliman

Int. J. Neonatal Screen. 2022, 8(1), 4; https://doi.org/10.3390/ijns8010004 - 10 Jan 2022

Cited by 1 | Viewed by 2563

Abstract

Severe combined immunodeficiency is a rare inherited disorder, which, if untreated, invariably proves fatal in late infancy or early childhood. With treatment, the prognosis is much improved. Early treatment of the siblings of cases, before they become symptomatic, has shown considerable improvements in outcomes. Based on this and the development of a test that can be used on the whole population of neonates (measurement of T-cell receptor excision circles—TRECs), many countries have added it to their routine newborn bloodspot screening programmes. The UK National Screening Committee (UKNSC) has considered whether SCID should be added to the UK screening programme and concluded that it was likely to be cost effective, but that there were a number of uncertainties that should be resolved before a national roll-out could be recommended. These include some aspects of the test, such as: cost; the use of different assays and cut-off levels to reduce false positive rates, while maintaining sensitivity; the overall benefits of screening for disease outcome in patients with SCID and other identified disorders; the need for a separate pathway for premature babies; the acceptability of the screening programme to parents of babies who have normal and abnormal (both true and false positive) screening results. To achieve this, screening of two thirds of babies born in England over a two-year period has been planned, beginning in September 2021. The outcomes and costs of care of babies identified by the screening will be compared with those of babies identified with SCID in the rest of the UK. The effect of the screening programme on parents will form part of a separate research project. Full article

(This article belongs to the Special Issue Newborn Screening for Severe Combined Immune Deficiency—Selected Papers from the ISNS-SCID Meeting)

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6 pages, 1459 KiB

Open AccessCommentary

Flow Cytometry Confirmation Post Newborn Screening for SCID in England

by Kimberly C. Gilmour

Int. J. Neonatal Screen. 2022, 8(1), 1; https://doi.org/10.3390/ijns8010001 - 23 Dec 2021

Viewed by 2468

Abstract

An evaluation program for newborn screening for Severe Combined Immunodeficiency began in England in September 2021 based on TREC analysis. Flow cytometry is being used as the follow up diagnostic test for patients with low/absent TRECS. The immunology laboratories have established a protocol and values for diagnosing SCID, other T lymphopenias and identifying healthy babies. This commentary describes the flow cytometry approach used in England to define SCID, T lymphopenia and normal infants after a low TREC result. It provides background to the flow cytometry assays being used and discusses the need to monitor and potentially change these values over time. Full article

(This article belongs to the Special Issue Newborn Screening for Severe Combined Immune Deficiency—Selected Papers from the ISNS-SCID Meeting)

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5 pages, 241 KiB

Open AccessCase Report

Early Diagnosis and Treatment of Purine Nucleoside Phosphorylase (PNP) Deficiency through TREC-Based Newborn Screening

by Andrea Martín-Nalda, Jacques G. Rivière, Mireia Català-Besa, Marina García-Prat, Alba Parra-Martínez, Mónica Martínez-Gallo, Roger Colobran, Ana Argudo-Ramírez, Jose Luis Marín-Soria, Judit García-Villoria, Laura Alonso, Jose Antonio Arranz-Amo, Giancarlo la Marca and Pere Soler-Palacín

Int. J. Neonatal Screen. 2021, 7(4), 62; https://doi.org/10.3390/ijns7040062 - 29 Sep 2021

Cited by 2 | Viewed by 3128

Abstract

Purine nucleoside phosphorylase (PNP) deficiency is a rare inherited disorder, resulting in severe combined immunodeficiency. To date, PNP deficiency has been detected in newborn screening only through the use of liquid chromatography tandem mass spectrometry. We report the first case in which PNP [...] Read more.

(This article belongs to the Special Issue Newborn Screening for Severe Combined Immune Deficiency—Selected Papers from the ISNS-SCID Meeting)

3 pages, 188 KiB

Open AccessCommentary

Need for Uniform Definitions in Newborn Screening for SCID: The Next Challenge for Screeners and Immunologists

by Mirjam van der Burg

Int. J. Neonatal Screen. 2021, 7(3), 52; https://doi.org/10.3390/ijns7030052 - 06 Aug 2021

Cited by 6 | Viewed by 1858

Abstract

During the ISNS meeting “Newborn Screening for SCID ‘State of the Art’” on 26 and 27 January 2021, the topic of case definitions and related issues were discussed. There is currently a lack of uniform definitions and therefore a lack of uniform registration of screen-positive cases. This severely hampers the comparison of outcomes of different screening programs and the exchange of experiences gained by the different countries performing SCID screening, which is essential to improve screening programs. In this letter, I outline the current situation and indicate the need for uniform definitions and classification, which in my view needs to be a joined effort of screeners and immunologists. Full article

(This article belongs to the Special Issue Newborn Screening for Severe Combined Immune Deficiency—Selected Papers from the ISNS-SCID Meeting)

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Newborn Screening for Severe Combined Immune Deficiency—Selected Papers from the ISNS-SCID Meeting

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