International Journal of Neonatal Screening

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Open AccessArticle

Co-Designing a Provincial Newborn Screening Implementation Framework in Pakistan Using a Sequential Blended Workshop Model

by Aysha H. Khan, Lena Jafri, Dianne Webster, Farkhanda Ghafoor, Tariq Zafar, Afzal Saeed, Jaida Manzoor, Fouzia Ishaq, Tayyaba K. Butt, Saima Zaki, Azeema Jamil and Hafsa Majid

Int. J. Neonatal Screen. 2026, 12(3), 74; https://doi.org/10.3390/ijns12030074 - 11 Sep 2026

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Abstract

Newborn screening (NBS) in Pakistan remains limited by fragmented service delivery, uneven provincial capacity, and the absence of an implementation pathway that links policy intent to operational planning. This study aimed to co-design a provincial NBS implementation framework for Punjab. To do so, [...] Read more.

Newborn screening (NBS) in Pakistan remains limited by fragmented service delivery, uneven provincial capacity, and the absence of an implementation pathway that links policy intent to operational planning. This study aimed to co-design a provincial NBS implementation framework for Punjab. To do so, we used a sequential blended workshop model supported by visual planning methods. We conducted a qualitative, three-phase co-design process with 19 participants from laboratory medicine, pediatrics, obstetrics, public health, academia, and policy. Phase I consisted of pre-work and an online workshop to establish a shared knowledge base and identify implementation barriers and enablers. Phase II used an in-person, visually facilitated planning workshop to translate these findings into a provincial NBS implementation framework. Phase III involved a asynchronous email-based review to refine the framework and reach consensus. Content analysis from Phase I identified five implementation domains: physical and technical infrastructure, operational systems, clinical integration, workforce and engagement, and governance and policy. In Phase II, these domains were translated into a visual implementation framework that specified priorities, stakeholders, risks, enablers, and action areas for phased rollout. Congenital hypothyroidism was identified as the most feasible entry-point condition. The final framework positioned NBS not as a stand-alone pilot, but as a coordinated provincial system requiring governance, financing, referral pathways, quality assurance, and workforce development. This study contributes an implementation-oriented model for moving from fragmented NBS initiatives to a provincial implementation framework in a low- and middle-income setting. It also offers a practical foundation for broader national scale-up. Full article

(This article belongs to the Special Issue Newborn Screening Developing Programs in Asia)

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13 pages, 4884 KB

Open AccessCase Report

Classical Homocystinuria Incidentally Diagnosed Following a Normal Newborn Screening Result

by José Manuel González de Aledo-Castillo, Mercedes Casado-Río, Sonia Pajares, Silvia Meavilla Olivas, Laura Gort, Laura Martí Sánchez, Abraham J. Paredes-Fuentes, Leticia Pias-Peleteiro, Marta Gomez-Chiari, Montserrat Quintana Vidaurri, Rosa María López-Galera, Ana Argudo-Ramírez, Jaime Sainz de Medrano, Rafael Artuch Iriberri, Judit García-Villoria and Aída Ormazábal Herrero

Int. J. Neonatal Screen. 2026, 12(3), 73; https://doi.org/10.3390/ijns12030073 - 4 Sep 2026

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Abstract

Classical homocystinuria (HCY) due to cystathionine beta-synthase (CBS) deficiency is included in many newborn screening programs, which traditionally use dried blood spot (DBS) methionine as the primary biomarker. However, some patients have normal or only mildly elevated methionine in the neonatal period, leading [...] Read more.

Classical homocystinuria (HCY) due to cystathionine beta-synthase (CBS) deficiency is included in many newborn screening programs, which traditionally use dried blood spot (DBS) methionine as the primary biomarker. However, some patients have normal or only mildly elevated methionine in the neonatal period, leading to false-negative results. We report a four-month-old male infant referred for sagittal craniosynostosis, whose metabolic evaluation revealed markedly elevated plasma methionine and total homocysteine concentrations. Genetic analysis identified a homozygous, pathogenic variant (c.1007G>A) in the CBS gene, confirming HCY. On retrospective review, the DBS sample had been collected at 48 h of life, and methionine was within the reference range. Consequently, the screening algorithm had not triggered second-tier total homocysteine testing. Sanger sequencing of the original DBS sample confirmed the same homozygous CBS variant, ruling out sample swap and establishing the case as a true false-negative result. Treatment with pyridoxine and folic acid rapidly normalized biochemical parameters, consistent with a pyridoxine-responsive phenotype. This case illustrates that normal neonatal methionine does not exclude CBS deficiency and that genomic newborn screening approaches could detect this disease more reliably. Full article

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23 pages, 4124 KB

Open AccessReview

Progress and Prospects of Newborn Screening in China

by Xiaoqiang Hao, Xinwen Huang, Rulai Yang, Xin Yang, Xiaolei Huang and Zhengyan Zhao

Int. J. Neonatal Screen. 2026, 12(3), 72; https://doi.org/10.3390/ijns12030072 - 2 Sep 2026

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Abstract

Newborn screening (NBS) is a critical component of the three-tiered prevention strategy for birth defects, reducing congenital disorder burden and improving long-term child health outcomes. Over the past 45 years, NBS in China has evolved into a nationwide quality-controlled network driven by policy [...] Read more.

Newborn screening (NBS) is a critical component of the three-tiered prevention strategy for birth defects, reducing congenital disorder burden and improving long-term child health outcomes. Over the past 45 years, NBS in China has evolved into a nationwide quality-controlled network driven by policy support and technological advances. Currently, phenylketonuria and congenital hypothyroidism are included in universal NBS across the country, and several provinces have expanded to encompass congenital adrenal hyperplasia, glucose-6-phosphate dehydrogenase deficiency, and additional inherited metabolic disorders identified through tandem mass spectrometry. The application of next-generation sequencing and other technologies has further enhanced detection capacity and expanded detectable disease spectra. Meanwhile, the National Quality Management System for NBS (QMS-NBS) has realized the visualization and standardization of screening quality and performance. Despite these advances, challenges remain, including regional disparities, inadequate follow-up, and long-term management. This review summarizes the historical evolution and policy framework of NBS in China, outlines the development of screening institutions, the spectrum and incidence of screened disorders, advances in detection technologies, and the establishment of QMS-NBS. It also highlights future priorities: expanding screened conditions, strengthening follow-up and long-term care, promoting regional equity, and advancing novel technologies to improve child health and foster precision public health. Full article

(This article belongs to the Special Issue Newborn Screening Developing Programs in Asia)

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8 pages, 519 KB

Open AccessArticle

Analytical Study Showing a False-Negative Limitation of Deletion-Based Newborn Screening for Spinal Muscular Atrophy Using a Compound Heterozygous SMN1 Control

by Yuichi Abe, Sato Suzuki-Muromoto, Motomichi Kosuga, Tetsuya Isayama, Go Tajima, Yasuhito Aoki, Nobuyuki Ishige and Yushi Ito

Int. J. Neonatal Screen. 2026, 12(3), 71; https://doi.org/10.3390/ijns12030071 - 31 Aug 2026

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Abstract

Newborn screening (NBS) facilitates the presymptomatic diagnosis and early treatment of spinal muscular atrophy (SMA). An analytical study was conducted to evaluate the performance and limitations of a real-time polymerase chain reaction-based SMA-NBS assay. Dried blood spot specimens collected from 21 newborns and [...] Read more.

Newborn screening (NBS) facilitates the presymptomatic diagnosis and early treatment of spinal muscular atrophy (SMA). An analytical study was conducted to evaluate the performance and limitations of a real-time polymerase chain reaction-based SMA-NBS assay. Dried blood spot specimens collected from 21 newborns and three patients with genetically confirmed SMA were analyzed. The SMA controls included two patients with homozygous SMN1 deletion and one with compound heterozygous SMN1 variants. SMN1 exon 7 copy numbers were quantified and interpreted. All newborn participants had SMN1 copy numbers above the screening cutoff value of 668 copies/µL and were classified as screening-negative. The two SMA controls with homozygous SMN1 deletion showed no detectable SMN1 amplification, which is consistent with positive screening results. In contrast, the compound heterozygous SMA control exhibited a mean SMN1 value of 7330 copies/µL, which was more than tenfold above the screening cutoff and would therefore have been classified as screening-negative; this value also fell within the range observed in the newborn cohort. This patient had a negative NBS result at birth despite subsequently developing genetically confirmed SMA. The SMA-NBS assay accurately detected patients with homozygous SMN1 deletion. However, it did not identify patients with compound heterozygous SMN1 variants. In conclusion, deletion-based SMA-NBS has an inherent false-negative limitation, and a negative screening result does not completely exclude an SMA diagnosis. Full article

(This article belongs to the Collection Newborn Screening in Japan)

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15 pages, 8369 KB

Open AccessArticle

Application of CLIR-Based Post-Analytical Tools to Dutch NBS Data Demonstrates Its Potential Impact on the Performance of CPT1, GA-1, IVA and MSUD Screening in a Disorder-Specific Way

by Nils W. F. Meijer, Rose E. Maase, Patricia L. Hall, Wouter F. Visser, Klaas Koop, Annet M. Bosch, M. Rebecca Heiner-Fokkema and Monique G. M. de Sain-van der Velden

Int. J. Neonatal Screen. 2026, 12(3), 70; https://doi.org/10.3390/ijns12030070 - 24 Aug 2026

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Abstract

Newborn screening (NBS) for inborn errors of metabolism is challenged by high false-positive rates, which may lead to parental anxiety and increased healthcare costs associated with diagnostic follow-up. False-positive results often arise from changes in metabolite concentrations that mimic metabolic disorders as a [...] Read more.

Newborn screening (NBS) for inborn errors of metabolism is challenged by high false-positive rates, which may lead to parental anxiety and increased healthcare costs associated with diagnostic follow-up. False-positive results often arise from changes in metabolite concentrations that mimic metabolic disorders as a consequence of differences in perinatal factors or nutritional status. To address this, Collaborative Laboratory Integrative Reports (CLIR) and the associated post-analytical tools (PATs) using multivariate interpretation and covariate-adjusted reference intervals may be used to improve specificity of NBS algorithms. In the current study, we examined whether CLIR can be applied to optimize the Dutch NBS program by reducing the false-positive rates. We developed and validated a CLIR-based PAT for CPT1 deficiency, GA-I, IVA and MSUD within the Dutch NBS program. Single-condition tools (SCTs) and multivariate approaches, including marker ratios and covariate adjustments, were evaluated for their ability to discriminate true- and false-positive referrals. For CPT1 deficiency, age-adjusted SCT combined with birthweight, location correction, and the C18:1/methionine ratio substantially reduced false positives. For GA-I, C3DC-based ratios improved specificity while preserving true-positive detection, potentially reflecting postnatal renal immaturity in some cases. For IVA, the dual scatter plot fully separated true- and false-positive referrals, highlighting the limitations of single-marker screening. For MSUD, differences between false-positive and true-positive cases were more pronounced, yet a similar number of false positives were still referred; valine-related markers contributed to false positives, while leucine and the Xle/Phe ratio better identified true positives. CLIR-based post-analytical tools enhanced NBS specificity through covariate-aware, multivariate interpretation. This provides important input for decision makers in both the Dutch NBS, as well as the NBS community worldwide. Full article

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11 pages, 3724 KB

Open AccessArticle

Refining MMA Screening in the Dutch Newborn Screening Program: Lessons from Vitamin B12 Deficiency and Genetic Cases

by Nils W. F. Meijer, Klaas Koop, Rose E. Maase, Patricia L. Hall, Wouter F. Visser, Esmeralda Oussoren, Annet M. Bosch, M. Rebecca Heiner-Fokkema and Monique G. M. de Sain-van der Velden

Int. J. Neonatal Screen. 2026, 12(3), 69; https://doi.org/10.3390/ijns12030069 - 21 Aug 2026

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Abstract

Since October 2019, screening for methylmalonic acidemia (MMA) has been implemented in the Dutch Newborn Screening (NBS) program. Since implementation, most referrals for MMA have been the result of (maternal) vitamin B12 deficiency. Although vitamin B12 deficiency is an important condition and early [...] Read more.

Since October 2019, screening for methylmalonic acidemia (MMA) has been implemented in the Dutch Newborn Screening (NBS) program. Since implementation, most referrals for MMA have been the result of (maternal) vitamin B12 deficiency. Although vitamin B12 deficiency is an important condition and early detection can confer health benefits, its identification was not the original objective of the screening. We therefore examined whether genetic forms of MMA can be distinguished from acquired forms. Early distinction between these forms is essential for guiding clinical management, informing prognosis, and enabling appropriate genetic counseling. Specifically, we tested whether the use of Collaborative Laboratory Integrated Reports (CLIR) to complement NBS results improved specificity of the test for genetic MMAs. We found that with the use of CLIR, genetic conditions including methylmalonyl-CoA mutase (mut) deficiency and cobalamin (cbl) A, B, C and D deficiency can be partially differentiated from acquired causes. This results in a significant reduction in the number of second-tier tests required. However, this approach may also exclude certain other genetic causes. Based on all findings, we provide considerations and implications for MMA screening that may inform decision-makers in (other) NBS programs. Full article

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16 pages, 1586 KB

Open AccessArticle

Optimizing Kappa-Deleting Recombination Excision Circles (KREC) Cut-Off Values in Russian Newborn Screening Program: Balancing Sensitivity and False-Positive Rates

by Andrey Marakhonov, Anna Mukhina, Irina Efimova, Natalya Balinova, Yulia Rodina, Rena Zinchenko, Sergey Voronin, Anna Shcherbina and Sergey Kutsev

Int. J. Neonatal Screen. 2026, 12(3), 68; https://doi.org/10.3390/ijns12030068 - 19 Aug 2026

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Abstract

Newborn screening (NBS) for primary immunodeficiencies (PIDs) increasingly incorporates kappa-deleting recombination excision circles (KREC) to enable early detection of B-cell lymphopenia, particularly agammaglobulinemia (AGG). However, optimal KREC cut-off values remain poorly defined, limiting sensitivity and contributing to high false-positive rates. We evaluated KREC-based [...] Read more.

Newborn screening (NBS) for primary immunodeficiencies (PIDs) increasingly incorporates kappa-deleting recombination excision circles (KREC) to enable early detection of B-cell lymphopenia, particularly agammaglobulinemia (AGG). However, optimal KREC cut-off values remain poorly defined, limiting sensitivity and contributing to high false-positive rates. We evaluated KREC-based NBS using data from a nationwide Russian program that screened more than 3.4 million newborns. KREC measurements from 66 patients with genetically confirmed AGG and 534 newborns with initially abnormal screening results but normal immunophenotyping were analyzed using statistical and ROC-based approaches. By using a KREC cut-off of 100 copies per 10⁵ cells in the first NBS sample and a KREC cut-off of 250 copies per 10⁵ cells after a polymerase chain reaction (PCR) test on a second dried blood spot (DBS) collected approximately 19 days later, the detection of classical and atypical X-linked AGG, other forms of AGG, and additional PIDs associated with B-cell lymphopenia was significantly improved. Retrospective analysis of a pilot cohort (n = 202,908) indicated that, if a KREC cut-off of 250 copies per 10⁵ cells was applied with the second PCR test, this adjustment would increase the proportion of screen-positive newborns to 2.75‰. To reduce the resulting referral burden, we assessed third KREC testing of a third DBS sample approximately 2 months after birth and showed that persistent KREC reduction distinguishes AGG from transient B-cell lymphopenia. We propose a revised three-step NBS algorithm incorporating a third PCR test with a cut-off of 850 copies per 10⁵ cells. This strategy reduces unnecessary referrals while maintaining diagnostic sensitivity and clinical safety, supporting implementation of adaptive, multistep NBS approaches. Full article

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32 pages, 2908 KB

Open AccessArticle

The Spanish Uniform Newborn Screening Panel (SUSP): A National Consensus Framework for Harmonized Newborn Screening

by Judit García-Villoria, Rosa María López-Galera, Carmen Delgado-Pecellín, Dolores Rausell Félix, Cristóbal Colón, Hugo Rocha, Belén Pérez, Antonia Ribes, María Luz Couce and Domingo González-Lamuño

Int. J. Neonatal Screen. 2026, 12(3), 67; https://doi.org/10.3390/ijns12030067 - 13 Aug 2026

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Abstract

Newborn screening (NBS) is a cornerstone of preventive medicine, enabling early diagnosis and treatment of severe congenital disorders. In Spain, despite the existence of a Basic Common Portfolio, the absence of a harmonized national panel has led to significant inter-regional variability, affecting equity [...] Read more.

Newborn screening (NBS) is a cornerstone of preventive medicine, enabling early diagnosis and treatment of severe congenital disorders. In Spain, despite the existence of a Basic Common Portfolio, the absence of a harmonized national panel has led to significant inter-regional variability, affecting equity in access to early diagnosis. The Spanish Uniform Screening Panel (SUSP) was developed through a structured nationwide consensus process involving all NBS centers in Spain, with additional input from Portugal. The process included a comprehensive survey of current practices, expert workshops, multiple consensus rounds, and predefined inclusion criteria. Disease nomenclature was standardized using OMIM and ORPHAcode identifiers. Conditions were classified as primary screening targets or secondary findings, and consensus was reached on confirmatory biochemical and genetic testing pathways. The operational dataset comprised 48 biomarker-based screening entries. Because some conditions can be detected through multiple primary markers, duplicate analytical routes were retained but counted once, resulting in a total 189 unique clinical conditions, including 87 primary and 102 secondary conditions. The SUSP represents the first nationwide harmonized framework for newborn screening in Spain and constitutes a major step toward equitable and standardized implementation. It provides a scalable model that may inform other countries facing similar disparities. Full article

(This article belongs to the Special Issue Equity Issues in Newborn Screening)

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19 pages, 2454 KB

Open AccessReview

Mucopolysaccharidosis Type II Screening, Diagnosis, and Management: A Literature Review and Practical Recommendations for Newborn Screening Programs and Health Care Providers to Support Families and Improve Outcomes

by Amy Gaviglio, Natasha Bonhomme, Barbara Burton, Norman Matthew Ellinwood, Joseph Muenzer, Kim Stephens, Ravi Pathak and Carolyn Schaeffer-Koziol

Int. J. Neonatal Screen. 2026, 12(3), 66; https://doi.org/10.3390/ijns12030066 - 12 Aug 2026

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Abstract

Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome), is a rare X-linked lysosomal disease that leads to progressive tissue and organ damage. Early treatment is essential as most symptoms of MPS II are not reversible. Consequently, MPS II has been added [...] Read more.

Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome), is a rare X-linked lysosomal disease that leads to progressive tissue and organ damage. Early treatment is essential as most symptoms of MPS II are not reversible. Consequently, MPS II has been added to many newborn screening (NBS) programs. This narrative literature review provides practical recommendations from a multidisciplinary expert panel on the US-based NBS for MPS II and its diagnosis and clinical management. Recommendations for NBS programs include aiming for universal access to NBS within their jurisdiction, implementing tiered testing to support diagnostic accuracy, and providing infrastructure for confirmatory testing and post-screening support for families. Recommendations for health care providers (HCPs) include communicating test results empathetically and alongside verbal and written information, allowing families to express their feelings, and consulting an MPS II specialist to support treatment recommendations. The NBS programs and HCPs should work together to ensure positive screening results are communicated effectively and to provide equitable access to treatment and long-term care. Such a coordinated and appropriately resourced effort involving NBS programs, HCPs, and patient advocates will ensure better support for families and the best possible outcomes for individuals with MPS II. Full article

(This article belongs to the Special Issue Advances in Newborn Screening for Lysosomal Disorders: From Laboratory Screening to Diagnosis)

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15 pages, 2272 KB

Open AccessArticle

Optimizing Informed Consent for Australian Newborn Bloodspot Screening and Research: Consensus Workshop Insights and Recommendations

by Carolyn Mazariego, Mahitha Ramanathan, Deborah A. Johnston, Zhicheng Li, Brittany C. McGill, Marina Okamura, Lauren Kelada, Ilona Juraskova, Claire E. Wakefield and Natalie Taylor

Int. J. Neonatal Screen. 2026, 12(3), 65; https://doi.org/10.3390/ijns12030065 - 10 Aug 2026

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Abstract

Informed consent is fundamental to Australian newborn bloodspot screening (NBS), but emerging genomic screening technologies pose new challenges to clinical care and research. Optimizing consent processes is necessary to support ethical practice and maintain public trust as NBS evolves. This study aimed to [...] Read more.

Informed consent is fundamental to Australian newborn bloodspot screening (NBS), but emerging genomic screening technologies pose new challenges to clinical care and research. Optimizing consent processes is necessary to support ethical practice and maintain public trust as NBS evolves. This study aimed to identify gaps and opportunities to improve NBS consent processes in Queensland, Australia, while also exploring preliminary insights into the evolving complexity of consent in the context of genomic NBS (gNBS) and NBS-related research. A qualitative study design was used, with two facilitated interest-holder workshops (a total of 12 h) involving 86 participants (healthcare professionals, policy-makers, researchers, genomics experts, and consumer representatives). Workshop 1 (n = 25) was held virtually, and Workshop 2 (n = 61) was held in person. Thematic analysis was used to identify practical recommendations and ethical considerations. Participants identified three priority domains for improving consent in Queensland’s NBS program: (1) revision of the Guthrie Card and consent statement, (2) development of consistent, antenatal information resources across healthcare providers, and (3) standardized consent delivery training for healthcare staff. Discussions also highlighted tensions around information requirements for informed consent, revealing growing complexities regarding layered consent models. While recommendations on research consent were not fully developed at the workshop, insights highlighted the growing complexity and divergence of views on layered consent models. Findings suggest that improving NBS consent requires both operational reform and reassessment of ethical standards, alongside broader interest-holder engagement and feasible, scalable models also suited to genomic technologies. A nationally consistent framework is needed. Full article

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17 pages, 1529 KB

Open AccessArticle

Features and Legal Practice of Dried Blood Spot Card Biobanking in Europe: Balancing Research Potential with Parental and Children’s Rights

by Sophie ter Braak, Mette Nyegaard, Christian Munch Hagen, Marie Bækvad-Hansen, Madara Auzenbaha, François Boemer, James R. Bonham, Patricia Borde, Ian Brincat, David Cheillan, Vera Frankova, Leifur Franzson, Ksenija Fumić, Urh Groselj, Tom L. G. M. van den Kerkhof, Riikka Kurkijärvi, Giancarlo la Marca, Tatjana Milenković, Olve Moldestad, Vyacheslav Mitkin, Florentina Moldovanu, Marios Vogazianos, Jürgen G. Okun, Lene Sörensen, Gulnara Svyatova, Ildikó Szatmári, Maja Raičević, Karit Reinson, Trine Tangeraas, Alma Toromanović, Laura Vilarinho, Svetlana Vorslova, Raquel Yahyaoui, Maximillian Zeyda, Dianne Webster and Peter C. J. I. Schielen Show full author list Hide full author list

Int. J. Neonatal Screen. 2026, 12(3), 64; https://doi.org/10.3390/ijns12030064 - 5 Aug 2026

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Abstract

Neonatal screening using Dried Blood Spot (DBS) cards is an important and successful public health facility in Europe, enabling early detection of congenital disorders for early treatment and prevention of overt disease. Biobanks of stored DBS cards offer significant potential for biomedical research. [...] Read more.

Neonatal screening using Dried Blood Spot (DBS) cards is an important and successful public health facility in Europe, enabling early detection of congenital disorders for early treatment and prevention of overt disease. Biobanks of stored DBS cards offer significant potential for biomedical research. Biobanking and secondary use of DBS cards also raise ethical and legal issues, particularly concerning the rights of parents and children. This study provides a comprehensive overview of legislation and legal practices governing DBS biobanking across 29 European countries, based on a survey conducted in collaboration with the International Society for Neonatal Screening. Findings reveal a highly heterogeneous landscape: 15 countries have national legislation, five have regional guidelines, and nine lack formal regulations. Only four countries require explicit parental consent for DBS storage, with considerable variation in approval processes for research use. A harmonization of practices, with the European General Data Protection Regulation (GDPR) as a basis for future regulation, supplemented by clearer guidance on ‘public interest’ and robust safeguards for individual rights may lead to more transparent and consistent governance, which is essential to balance scientific progress with the protection of parental and children’s rights in DBS-based research across Europe. Full article

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16 pages, 696 KB

Open AccessArticle

Attitudes Toward Sex-Specific Versus Universal Newborn Screening for X-Linked Adrenoleukodystrophy in Hong Kong

by Chloe Miu Mak, Hoi Ying Wu, Ariel Ying Wong, Felicite Enyu Song, Toby Chun Hei Chan, Cheuk Wing Fung, Suet Na Wong, Edgar Wai Lok Hau and Matthew Chun Wing Yeung

Int. J. Neonatal Screen. 2026, 12(3), 63; https://doi.org/10.3390/ijns12030063 - 31 Jul 2026

Viewed by 659

Abstract

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder and is associated with serious clinical consequences. While newborn screening (NBS) could facilitate early identification and timely intervention, its implementation for X-ALD remains controversial due to ethical concerns arising from its X-linked recessive inheritance [...] Read more.

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder and is associated with serious clinical consequences. While newborn screening (NBS) could facilitate early identification and timely intervention, its implementation for X-ALD remains controversial due to ethical concerns arising from its X-linked recessive inheritance pattern, particularly regarding female newborns. This study aims to explore the perspectives of healthcare professionals and the general public on NBS for X-ALD in Hong Kong. An online survey with 20 quantitative questions on ethical considerations was conducted from May to August 2024. Among a total of 259 responses, most respondents (99.2%) supported NBS for their male newborns, primarily because it facilitates early diagnosis and effective management. The majority of the respondents were in favor of offering NBS to female newborns, citing potential benefits for the management of adult-onset disease, enhanced family planning and support, and opportunities for extended family screening. However, some respondents expressed concerns regarding (1) psychological stress and anxiety from uncertain disease onset and frequent monitoring; (2) potential genetic discrimination and adverse impact on insurance premiums/coverage; (3) affordability and accessibility of expensive treatments, such as gene therapy; and (4) ethical issues regarding children’s “right to an open future”, particularly for late-onset female X-ALD. To address these concerns while respecting family autonomy, we propose an opt-in system with clear, balanced information for parents, combined with a three-tier screening algorithm. In summary, while inclusion of X-ALD in Hong Kong’s NBS program receives strong community support, targeted measures are needed to mitigate the identified ethical and practical barriers. Full article

(This article belongs to the Special Issue Equity Issues in Newborn Screening)

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13 pages, 1795 KB

Open AccessArticle

Experience with Implementation of Pulse Oximetry Screening for Critical Congenital Heart Disease in a Low–Middle-Income Country

by Abena Adaboh, Daem Celestin, Alex Agyekum, Nana Serwaa Osei, Araba Mensah, Sadath Sayeed and Nana-Akyaa Yao

Int. J. Neonatal Screen. 2026, 12(3), 62; https://doi.org/10.3390/ijns12030062 - 30 Jul 2026

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Abstract

The adoption of pulse oximetry screening (POS) in low- and middle-income countries remains limited. We describe the development, implementation, and evaluation of a POS program at two of the leading tertiary centers in Accra, Ghana, based on a modified American Academy of Pediatrics [...] Read more.

The adoption of pulse oximetry screening (POS) in low- and middle-income countries remains limited. We describe the development, implementation, and evaluation of a POS program at two of the leading tertiary centers in Accra, Ghana, based on a modified American Academy of Pediatrics protocol. Screening was conducted by trained research assistants. Operational experiences of research assistants were evaluated using a mixed-methods approach, including post-implementation surveys (n = 14) and focus group discussions (n = 10). Although participants felt comfortable with the level of instruction, they recommended incorporating simulation exercises to strengthen management of failed screens. Key challenges included difficulty locating newborns due to fragmented wards and paper-based records, equipment durability issues, and complex coordination for echocardiography following failed screens. Early discharge practices and high neonatal intensive care unit admissions reduced screening coverage among high-risk infants. Despite limited referral systems and surgical capacity, the POS pilot increased provider awareness, improved diagnostic clarity and demonstrated feasibility. Sustainable expansion will require more efficient referral networks as well as investment in pediatric cardiology training and cardiac surgical infrastructure. Full article

(This article belongs to the Special Issue Global Updates on the Advancements in CCHD Screening)

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20 pages, 31773 KB

Open AccessReview

A Comprehensive Meta-Analytical Investigation into the Incidence of Neonatal Amino Acid Metabolic Disorders Across China

by Qiongfang Yao, Shuting Huang, Fei Kong, Min Wu, Xiaolong Qiu, Peiran Zhao, Yinglin Zeng, Jinying Luo, Jinfu Zhou and Liangpu Xu

Int. J. Neonatal Screen. 2026, 12(3), 61; https://doi.org/10.3390/ijns12030061 - 30 Jul 2026

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Abstract

Amino acid metabolic disorders (AAMs) are a group of inherited metabolic diseases caused by defects in enzymes or transporters involved in amino acid metabolism. This systematic review and meta-analysis aimed to evaluate the incidence, disease spectrum, and regional distribution of AAMs in China. [...] Read more.

Amino acid metabolic disorders (AAMs) are a group of inherited metabolic diseases caused by defects in enzymes or transporters involved in amino acid metabolism. This systematic review and meta-analysis aimed to evaluate the incidence, disease spectrum, and regional distribution of AAMs in China. A comprehensive search of PubMed, Embase, Web of Science, and major Chinese databases identified studies published between January 2002 and December 2025. After rigorous screening and quality assessment, 65 studies were included, encompassing 16,757,850 newborns and 2928 confirmed AAM cases. The most prevalent subtypes included hyperphenylalaninemia (HPA), hypermethioninemia (MET), citrin deficiency (CD), citrullinemia type 1 (CTLN1), maple syrup urine disease (MSUD), ornithine transcarbamylase deficiency (OTCD), and tyrosinemia (HT). The pooled incidence of AAMs was estimated at 184.0 (95% confidence interval 155.0–218.0) per million newborns. Significant regional differences were observed in the overall incidence of AAMs, with a higher incidence in northern China than southern China (287.0 vs. 126.0 per million, p < 0.0001). This difference was largely attributable to the substantially higher prevalence of HPA in northern China, whereas other major AAM subtypes showed no significant north–south differences. In contrast, no significant north–south differences were identified for other major subtypes. Additionally, the proportion of tetrahydrobiopterin deficiency (BH4D) among HPA cases was significantly higher in southern China (p < 0.001). These findings provide comprehensive epidemiological evidence on AAMs in China and highlight the importance of region-specific newborn screening strategies. Full article

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3 pages, 146 KB

Open AccessEditorial

Cystic Fibrosis Newborn Screening: Progress and Perspectives

by Marci K. Sontag and Susanna A. McColley

Int. J. Neonatal Screen. 2026, 12(3), 60; https://doi.org/10.3390/ijns12030060 - 29 Jul 2026

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Abstract

Newborn screening (NBS) for cystic fibrosis (CF) was first implemented almost 50 years ago, and many improvements have been made to the initial algorithms, educational approaches, and available therapies [...] Full article

(This article belongs to the Special Issue Advances in Cystic Fibrosis Newborn Screening: From Laboratory Testing to Diagnosis)

10 pages, 8240 KB

Open AccessCase Report

Homozygosity for a Clinically Significant GALC Haplotype Associated with Late-Infantile Krabbe Disease Detected on Newborn Screening: Implications for Clinical Management and Genetic Counseling

by Daniel R. Schecter, Colleen Donnelly, Amy White, Hillary Raynes, Gordon Heller, Deepa Rajan, Carlos A. Saavedra-Matiz, Joseph Orsini, Jaap-Jan Boelens, Dietrich Matern and Jaya Ganesh

Int. J. Neonatal Screen. 2026, 12(3), 59; https://doi.org/10.3390/ijns12030059 - 29 Jul 2026

Viewed by 799

Abstract

Krabbe disease is an autosomal recessive leukodystrophy caused by a deficiency of the lysosomal enzyme galactosylceramidase (GALC), responsible for the degradation of galactolipids, resulting in toxic psychosine accumulation and progressive demyelination of the central and peripheral nervous systems. Newborn screening (NBS) has increased [...] Read more.

Krabbe disease is an autosomal recessive leukodystrophy caused by a deficiency of the lysosomal enzyme galactosylceramidase (GALC), responsible for the degradation of galactolipids, resulting in toxic psychosine accumulation and progressive demyelination of the central and peripheral nervous systems. Newborn screening (NBS) has increased recognition of later-onset Krabbe disease, although interpretation of complex GALC genotypes remains challenging, particularly in the presence of “pseudodeficiency” and modifier alleles. In this case report, we describe a child with late-infantile Krabbe disease identified through NBS with markedly reduced GALC activity and a homozygous GALC haplotype containing c.956A>G (p.Tyr319Cys; Y319C) and c.1685T>C (p.Ile562Thr; I562T), in addition to other benign variants. Retrospective analysis of the newborn screening specimen demonstrated mild psychosine elevation. Despite preserved neurodevelopment, longitudinal surveillance demonstrated progressive cerebral white matter abnormalities by 3 years and 9 months of age and psychosine elevation in erythrocytes (14 pmol/g Hb; controls < 5), prompting umbilical cord blood transplantation (UCBT). Following transplantation, GALC enzyme activity normalized, psychosine levels decreased, and serial neuroimaging demonstrated radiographic stability without neurologic regression at last follow-up (9 years old). This case expands the phenotypic spectrum associated with homozygosity for the p.Tyr319Cys variant and highlights the role of p.Ile562Thr in amplifying the pathogenic potential when in cis with p.Tyr319Cys. This GALC haplotype illustrates how “pseudodeficiency” and modifier alleles may collectively influence biochemical, radiologic, and clinical disease expression. These findings emphasize the importance of integrating genotype, psychosine, enzyme activity, and longitudinal neuroimaging when evaluating infants with NBS results positive for Krabbe disease. Full article

(This article belongs to the Special Issue Advances in Newborn Screening for Lysosomal Disorders: From Laboratory Screening to Diagnosis)

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14 pages, 1306 KB

Open AccessArticle

Newborn Screening for Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency and Analysis of SLC25A13 Gene Mutations in Hefei, China

by Qingqing Ma, Junxing Chen, Yong Huang, Yan Wang, Wangsheng Song, Hongyu Xu, Yuhui Wan and Haili Hu

Int. J. Neonatal Screen. 2026, 12(3), 58; https://doi.org/10.3390/ijns12030058 - 28 Jul 2026

Viewed by 522

Abstract

Citrin deficiency (CD) is an autosomal recessive disorder and represents one of the urea cycle disorders. This study aims to analyze the detection rate, clinical features, and genetic mutation characteristics of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in the Hefei region [...] Read more.

Citrin deficiency (CD) is an autosomal recessive disorder and represents one of the urea cycle disorders. This study aims to analyze the detection rate, clinical features, and genetic mutation characteristics of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in the Hefei region of China. We conducted NICCD screening using tandem mass spectrometry (MS/MS) for infants born in Hefei City between January 2016 and December 2025. Screen-positive cases were subjected to genetic testing via next-generation sequencing (NGS), with subsequent validation by Sanger sequencing. Clinical manifestations, biochemical parameters, and genetic mutation profiles of confirmed cases were systematically analyzed. A total of 924,676 newborns underwent screening, identifying 17 cases of NICCD, yielding a detection rate of 1/54,393, with two false-negative cases identified. The most prevalent mutation site is c.852_855del (p.M285Pfs*2). Following diagnosis, health education, dietary guidance, and symptomatic treatment were administered, resulting in favorable outcomes in the majority of cases. However, one infant exhibited significant growth retardation despite early therapeutic intervention that normalized biochemical parameters. Furthermore, an infant was found to have gallstones at birth and subsequently diagnosed with a liver hemangioma at one year of age. Some patients may experience missed screenings due to delayed elevations in citrulline levels. Therefore, even for newborns with negative screening results, timely assessments of liver function, MS/MS, and genetic testing are recommended for infants experiencing prolonged jaundice. This approach enables early identification and intervention. The combination of MS/MS with genetic screening may serve as a reliable strategy to reduce false-negative results in NICCD screening. Full article

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15 pages, 242 KB

Open AccessArticle

Communicating a Congenital Cytomegalovirus Diagnosis: Parent Experiences and a Clinical Framework

by Megan Honor Pesch, Laura C. Taylor, Sean P. McKenzie and Gail Demmler-Harrison

Int. J. Neonatal Screen. 2026, 12(3), 57; https://doi.org/10.3390/ijns12030057 - 24 Jul 2026

Viewed by 433

Abstract

Congenital cytomegalovirus (cCMV) is characterized by highly variable outcomes; how diagnostic information is communicated to families is critical, yet parent experiences of communication following a cCMV diagnosis are not well described. The objective was to examine parent experiences of communication following a cCMV [...] Read more.

Congenital cytomegalovirus (cCMV) is characterized by highly variable outcomes; how diagnostic information is communicated to families is critical, yet parent experiences of communication following a cCMV diagnosis are not well described. The objective was to examine parent experiences of communication following a cCMV diagnosis and identify opportunities to improve communication in the setting of clinical uncertainty. The method used was semi-structured interviews with 41 mothers of children with cCMV explored communication of diagnostic results, interactions with healthcare providers, and perceptions of information clarity, timing, and adequacy. Transcripts were analyzed using thematic analysis. Participants described variability in diagnostic communication, including differences in timing, modality, and content. Some received in-person counseling, whereas others learned of the diagnosis through phone calls, written communication, or electronic health portals prior to provider contact. Many reported limited explanation, insufficient anticipatory guidance, and inconsistent or incomplete information across providers. These communication gaps contributed to confusion, increased reliance on external information sources, and diminished trust in the healthcare system. Participants emphasized the importance of clear, compassionate communication that acknowledges uncertainty while providing actionable guidance. Communication surrounding cCMV diagnosis is inconsistent and often does not meet family needs. Diagnostic disclosure should function as a clinical intervention requiring clear, patient-centered, longitudinal communication to support families navigating uncertainty. Full article

16 pages, 879 KB

Open AccessArticle

Improving Severe Combined Immunodeficiency and Cystic Fibrosis Newborn Screening by Replacing Current Tests with First-Tier Targeted Gene Sequencing

by Bennett O. V. Shum, Carel Pretorius, Ilya Henner, Emre Basar, Urs Wilgen, Glenn Bennett and Jacobus P. J. Ungerer

Int. J. Neonatal Screen. 2026, 12(3), 56; https://doi.org/10.3390/ijns12030056 - 23 Jul 2026

Viewed by 992

Abstract

Newborn screening benefits children with rare diseases by enabling early detection and intervention, which improves health outcomes. False-positive results are one harm of screening, with infants subject to further testing to resolve a positive screen and parents susceptible to psychosocial distress while awaiting [...] Read more.

Newborn screening benefits children with rare diseases by enabling early detection and intervention, which improves health outcomes. False-positive results are one harm of screening, with infants subject to further testing to resolve a positive screen and parents susceptible to psychosocial distress while awaiting the results. Newborn bloodspot screening (NBS) for severe combined immunodeficiency (SCID) using quantitative polymerase chain reaction (qPCR) and cystic fibrosis (CF) screening using immunoreactive trypsinogen (IRT) have high false-positive rates, with more than five infants screening positive and unaffected, for each child diagnosed. We used first-tier targeted gene sequencing (TGS) to prospectively screen 3025 newborns for CF, SCID and spinal muscular atrophy (SMA) and compared the results to current screening protocols using multiplex qPCR and IRT. TGS identified one infant with CF, missed by the IRT assay, and detected an infant with SMA, who screened positive with multiplex qPCR. TGS had zero false-positive results for SCID, CF and SMA. By contrast, multiplex qPCR and IRT screening protocols had approximately nine false positives for each child diagnosed with CF (positive predictive value, PPV 10.00%) and SCID (PPV 10.13%). Replacing current SCID and CF screening protocols with TGS would reduce NBS false positives and may result in a higher sensitivity for CF. TGS sensitivity and specificity would be comparable to qPCR for SMA. A larger trial is required to determine TGS sensitivity and cost-effectiveness. Full article

(This article belongs to the Special Issue Genetic and Genomic Technologies in Newborn Screening: Current Applications and Future Directions)

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10 pages, 517 KB

Open AccessReview

The Dual Role of Neonatal Pulse Oximetry Screening and Fetal Echocardiography in Congenital Heart Disease Detection Around the World

by Anita Krishnan, Carolyn Sommer, Chinenyenwa Mpamaugo, Sonia Voleti Chivukula, Lisa A. Hom, Gerard R. Martin and Mary T. Donofrio

Int. J. Neonatal Screen. 2026, 12(3), 55; https://doi.org/10.3390/ijns12030055 - 21 Jul 2026

Viewed by 444

Abstract

Congenital heart disease is the most common birth defect worldwide. Perinatal detection, either in utero or prior to hospital discharge is important for planning delivery, ordering adjunct testing, and planning for surgical or medical care. In countries with access to ultrasound screening, prenatal [...] Read more.

Congenital heart disease is the most common birth defect worldwide. Perinatal detection, either in utero or prior to hospital discharge is important for planning delivery, ordering adjunct testing, and planning for surgical or medical care. In countries with access to ultrasound screening, prenatal detection is highly accurate though with variable sensitivity and specificity around the world. Pulse oximetry screening, in some cases coupled with murmur auscultation in the nursery can also reach very high degrees of sensitivity for critical congenital heart disease. Use of the modalities per guidelines and recommendations is an important aspect of decreasing infant mortality and morbidity worldwide. Full article

(This article belongs to the Special Issue Global Updates on the Advancements in CCHD Screening)

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14 pages, 1097 KB

Open AccessArticle

Reference Values of Peripheral Perfusion Index in Healthy Neonates and Preliminary Observations of Congenital Heart Disease in Tibet: A Cohort Study

by Miaomiao Wei, Yaoyao Dong, Ciren Zhuoma, Lin Peng, Youping Tian, Qing Gu, Sheng Wei, Bianba Zhuoma, Xiaojing Hu and Guoying Huang

Int. J. Neonatal Screen. 2026, 12(3), 54; https://doi.org/10.3390/ijns12030054 - 20 Jul 2026

Viewed by 487

Abstract

The peripheral perfusion index (PPI) is a non-invasive indicator of peripheral tissue perfusion in neonates. However, reference values for the PPI at different postnatal time points in healthy neonates residing at high altitudes, as well as early perfusion characteristics in infants with congenital [...] Read more.

The peripheral perfusion index (PPI) is a non-invasive indicator of peripheral tissue perfusion in neonates. However, reference values for the PPI at different postnatal time points in healthy neonates residing at high altitudes, as well as early perfusion characteristics in infants with congenital heart disease (CHD) in these settings, remain inadequately defined. The primary aim was to determine the dynamic changes in and percentile-based reference values of the PPI in healthy neonates during the first 6–72 h after birth in the high-altitude region of Tibet. A secondary, exploratory aim was to observe PPI patterns in neonates with CHD born during the same period and to compare the two groups, given the limited number of CHD cases enrolled. A longitudinal cohort study was conducted among consecutively born neonates in a high-altitude region of Tibet. The PPI was measured in the right hand (pre-ductal) and either foot (post-ductal) at 6, ~12, ~24, ~48, and ~72 h after birth. Generalized Additive Models for Location, Scale and Shape (GAMLSS) were used to construct percentile reference curves for healthy neonates. Generalized Estimating Equations (GEE) were applied to evaluate differences in the PPI across time points, measurement sites, and between groups (healthy vs. CHD). A total of 1043 neonates were enrolled, including 1034 in the healthy group and only 9 CHD cases. In healthy neonates, the PPI increased progressively within the first 72 h, with a rapid rise from 6 to 24 h, a slower increase from 24 to 48 h, and stabilization between 48 and 72 h. At all time points, the lower-limb PPI was significantly higher than the upper-limb PPI (p < 0.001). The 50th percentile (P₅₀) values for the upper-limb PPI at 6, 12, 24, 48, and 72 h were 2.32, 2.46, 2.62, 2.63, and 2.77, respectively; corresponding values for the lower-limb PPI were 2.53, 2.64, 2.76, 2.77, and 2.90. Compared to the healthy group, neonates with CHD at high altitudes had similar PPI at 6 h. However, their PPI was significantly lower between 12 and 48 h. At 72 h, no statistically significant difference was found between the groups, likely due to the small sample size of CHD infants. Conclusions: This study provides a reference for routine perfusion assessment in stable neonates born at high altitudes. Due to the limited sample size (only 9 CHD cases), our findings on PPI changes in neonates with CHD remain preliminary. The normative PPI percentile curves established in this study offer objective baseline perfusion data for stable neonates living in high-altitude areas. Future large-scale cohort studies are still needed to validate the clinical value of the PPI as a perfusion monitoring tool in infants with CHD. Full article

(This article belongs to the Special Issue Newborn Screening for Physical/Structural Birth Defects)

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13 pages, 1816 KB

Open AccessReview

Pulse Oximetry Screening in the Newborn: Can Modifications to the Screening Algorithm Improve Detection?

by Andrew K. Ewer

Int. J. Neonatal Screen. 2026, 12(3), 53; https://doi.org/10.3390/ijns12030053 - 20 Jul 2026

Viewed by 649

Abstract

Pulse oximetry screening (POS) is a simple non-invasive tool which enables the early detection of critical congenital heart defects (CCHDs). POS has moderate sensitivity and high specificity; it is cost-effective, readily accepted by parents and healthcare professionals, and its introduction significantly reduces mortality [...] Read more.

Pulse oximetry screening (POS) is a simple non-invasive tool which enables the early detection of critical congenital heart defects (CCHDs). POS has moderate sensitivity and high specificity; it is cost-effective, readily accepted by parents and healthcare professionals, and its introduction significantly reduces mortality from CCHDs. As a result, most high-income countries and many middle-income countries have introduced, or are considering introducing, POS. Despite the international uptake of POS, there is still no consensus regarding the most appropriate screening algorithm, although several have been described. In addition, this review will consider the variations—and their relative advantages and disadvantages—between POS algorithms and also explore how modifications to existing algorithms—such as the addition of a perfusion index or the incorporation of machine learning—may have the potential to improve future detection of CCHDs. Full article

(This article belongs to the Special Issue Global Updates on the Advancements in CCHD Screening)

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15 pages, 4099 KB

Open AccessArticle

Hearing Screening-Driven Investigation of Newborns for Congenital Cytomegalovirus Infection at a German University Hospital

by Niko Kohmer, Lena Mistry, Thorsten Mosler, Sabine Kramer, Annette Weiß, Alfred Lennart Bissinger, Nora Doberschuetz, Ulrich Rochwalsky, Holger F. Rabenau and Horst Buxmann

Int. J. Neonatal Screen. 2026, 12(3), 52; https://doi.org/10.3390/ijns12030052 - 8 Jul 2026

Viewed by 674

Abstract

Congenital Cytomegalovirus (cCMV) infection is the leading non-genetic cause of sensorineural hearing loss in newborns. Systematic nationwide screening programmes are lacking. Antiviral valganciclovir therapy could improve auditory outcomes if initiated within the first 30 days of life, making timely diagnosis crucial. To address [...] Read more.

Congenital Cytomegalovirus (cCMV) infection is the leading non-genetic cause of sensorineural hearing loss in newborns. Systematic nationwide screening programmes are lacking. Antiviral valganciclovir therapy could improve auditory outcomes if initiated within the first 30 days of life, making timely diagnosis crucial. To address this, we investigated whether a hearing screening-based protocol is suitable. Between 2015 and 2019, newborns, aged ≤21 days, with repeated abnormal newborn hearing screening (NHS) were prospectively enrolled at University Hospital Frankfurt. Oral mucosal swabs were tested for CMV DNA by real-time PCR, with confirmatory urine and blood diagnostics in positive cases. Of 2741 infants presenting for repeat NHS, 2059 (75.1%) showed normal bilateral findings. Of the 682 (24.9%) with abnormal results, 575 (84.3%) were aged >21 days and thus ineligible. A total of 107 infants (3.9%) met both criteria—abnormal NHS and aged ≤21 days—of whom 100 entered per-protocol analysis. Two (2%) were confirmed as cCMV-positive and received valganciclovir. Among the 48 infants who additionally underwent DBS testing, diagnostic sensitivity and specificity were 100%. The presented NHS-driven cCMV protocol reliably identified cCMV-infected newborns to offer timely antiviral therapy. In the absence of universal cCMV screening, this targeted approach offers a challenging but WHO screening-criteria-compliant strategy to enable timely antiviral intervention. Full article

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16 pages, 4049 KB

Open AccessArticle

Implementation of TREC/KREC Newborn Screening in a High-Birth-Rate Population: A Pilot Study of 5000 Neonates in South Kazakhstan

by Gulzada Abdushukurova, Alken Auyelova, Banu Kadyrbayeva, Ardak Ayazbekov, Dina Mussayeva, Ainash Oshibayeva, Kumissay Babayeva, Liliya Khairullina, Karlygash Sadykova and Gulnaz Nuskabaeva

Int. J. Neonatal Screen. 2026, 12(3), 51; https://doi.org/10.3390/ijns12030051 - 7 Jul 2026

Viewed by 1111

Abstract

The early detection of Severe Combined Immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) prevents fatal outcomes. This study presents the first pilot TREC/KREC newborn screening (NBS) program in southern Kazakhstan, a high-birth-rate region, to establish local reference ranges and assess operational viability. A multiplex [...] Read more.

The early detection of Severe Combined Immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) prevents fatal outcomes. This study presents the first pilot TREC/KREC newborn screening (NBS) program in southern Kazakhstan, a high-birth-rate region, to establish local reference ranges and assess operational viability. A multiplex real-time PCR assay was used to quantify T-cell (TREC) and kappa-deleting recombination excision circles (KRECs) from dried blood spots of 5000 unselected neonates. Biomarkers were normalized to copies per

10^{6}

cells using albumin as a diploid reference gene. Regional 0.5th percentile cut-offs were established (TREC < 3165 copies/

10^{6} c e l l s

and KREC < 2554 copies/

10^{6}

cells), and gender and gestational age did not significantly impact biomarker levels. While a low birth weight (≤2500 g) significantly reduced KREC levels, the extreme lower distribution tails remained unaffected, validating the use of universal, unstratified thresholds. Applying these cut-offs yielded an optimal 1.0% initial recall rate. Consistent with global incidence rates, no true positive cases were identified. The established assay and universal percentile cut-offs demonstrate high levels of analytical reliability and demographic stability. This pilot confirms the regional pediatric healthcare infrastructure’s readiness for a routine, population-based NBS program without the need for complex algorithms. Full article

(This article belongs to the Special Issue Newborn Screening Developing Programs in Asia)

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20 pages, 1972 KB

Open AccessArticle

Expanding 5q-SMA Newborn Screening in Latin America: A Brazilian Model for National and Regional Implementation

by Diogo Nani, Rodrigo Holanda Mendonça, Felipe Franco da Graça, Vitoria Regia Pereira Pinheiro, Mirella Carneireiro, Bruna Glaucia Farah, Marcondes Cavalcante França, Jr., Carmen Silvia Gabetta, Graziela Polido, Cristina Iwabe, Frederico Monfardini, Alulin Tácio Quadros Santos Monteiro Fonseca, Paulo Breinis, Carmela Maggiuzzo Grindler, Carlos Eugenio Fernandez de Andrade, Athene Maria de Marco França Mauro, Edmar Zanoteli, Wilson Marques, Jr., Léa Maria Zanini Maciel, Acary Souza Bulle Oliveira, Maria da Penha Ananias Morita, Edward Yang and Vanessa Luiza Romanelli Tavares Show full author list Hide full author list

Int. J. Neonatal Screen. 2026, 12(3), 50; https://doi.org/10.3390/ijns12030050 - 7 Jul 2026

Viewed by 1007

Abstract

5q spinal muscular atrophy (5q-SMA) is a leading genetic cause of infant mortality. Presymptomatic intervention with disease-modifying therapies significantly improves motor outcomes, but effectiveness depends on early detection through newborn screening (NBS). Despite global 5q-SMA NBS expansion and recent Brazilian federal legislation, regional [...] Read more.

5q spinal muscular atrophy (5q-SMA) is a leading genetic cause of infant mortality. Presymptomatic intervention with disease-modifying therapies significantly improves motor outcomes, but effectiveness depends on early detection through newborn screening (NBS). Despite global 5q-SMA NBS expansion and recent Brazilian federal legislation, regional disparities and a lack of systematic monitoring hinder access to timely diagnosis and care. This study addresses these gaps by evaluating a statewide pilot program in São Paulo. We used multiplex real-time PCR to detect SMN1 exon 7 deletions in dried blood spots, confirming SMN1/2 copy numbers via MLPA in positive cases. Under real-world conditions, timeliness key performance indicators were evaluated to assess operational efficiency. 194,714 newborns were screened with 14 positive cases, yielding a prevalence of 1:13,908. First-tier results and treatment initiation occurred at a median of 10.8 and 28 days of life, respectively. Notably, 78.6% of patients had two SMN2 copies, of which approximately half were symptomatic by the first evaluation, highlighting the critical need for rapid screening to prevent irreversible motor decline. Screening achieved 100% specificity. This pilot demonstrates the feasibility of 5q-SMA NBS within the Brazilian public health system, providing essential evidence to overcome logistical and socioeconomic barriers and support nationwide expansion. Full article

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20 pages, 2583 KB

Open AccessArticle

Preliminary Data of the First Year of Newborn Screening for Metachromatic Leukodystrophy (MLD) in Lombardy

by Alessandra Vasco, Andrea Meta, Clarissa Berardo, Davide Camerlengo, Francesca Fumagalli, Davide Tonduti, Iris Fiamingo, Cristina Montrasio, Diana Postorivo, Manuela Rizzetto, Sabrina Fede, MLD-NBS Study Group, Roberto Bozic, Francisco Ferron, Valeria Calbi, Gianvincenzo Zuccotti, Alessandro Aiuti, Giancarlo la Marca, Stephana Carelli and Cristina Cereda

Int. J. Neonatal Screen. 2026, 12(3), 49; https://doi.org/10.3390/ijns12030049 - 30 Jun 2026

Viewed by 1333

Abstract

Metachromatic leukodystrophy (MLD) is a rare, autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA, MIM #250100), which leads to progressive demyelination in the central and peripheral nervous systems, resulting in severe neurodegeneration and premature death. With [...] Read more.

Metachromatic leukodystrophy (MLD) is a rare, autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA, MIM #250100), which leads to progressive demyelination in the central and peripheral nervous systems, resulting in severe neurodegeneration and premature death. With the recent approval of the first ex vivo gene therapy for MLD, newborn screening (NBS) programs have begun to implement pilot studies for early detection, as identifying affected individuals during the pre-symptomatic therapeutic window is crucial. We present the analytical workflow and the NBS algorithm developed during the first year of MLD screening in Lombardy. The screening strategy comprised a first-tier test (1TT) using mass spectrometry to quantify sulfatide concentrations, a second-tier test (2TT) measuring ARSA enzymatic activity, and a third-tier test (3TT) based on whole-exome sequencing. A total of 16,130 newborns were screened for MLD. Of these, 6.41% required retesting (1TT), 1.53% underwent duplicate 2TT, and 0.36% proceeded to 3TT. No neonates were recalled, and no cases of MLD were identified through the screening program. The first-year implementation of MLD NBS in Lombardy demonstrates that a mass spectrometry-based sulfatide assay combined with a multi-tiered screening algorithm is feasible and reliable. Incorporating genetic analysis alongside expanded validation of additional sulfatide species may enhance specificity, reduce false positives, and facilitate timely identification of infants affected by MLD. Full article

(This article belongs to the Special Issue Advances in Newborn Screening for Lysosomal Disorders: From Laboratory Screening to Diagnosis)

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14 pages, 668 KB

Open AccessArticle

Universal Dried Blood Spot Screening for Congenital Cytomegalovirus: A Slovenian National Implementation Pilot

by Nika Eržen, Jernej Kovač, Barbka Repič Lampret, Urh Grošelj, Aneta Soltirovska Šalamon and Gregor Nosan

Int. J. Neonatal Screen. 2026, 12(3), 48; https://doi.org/10.3390/ijns12030048 - 29 Jun 2026

Viewed by 847

Abstract

Congenital cytomegalovirus infection (cCMV) is the most common congenital infection and an important cause of sensorineural hearing loss and neurodevelopmental impairment, yet many affected infants remain undetected under selective screening approaches. We conducted a prospective national pilot study to evaluate the feasibility and [...] Read more.

Congenital cytomegalovirus infection (cCMV) is the most common congenital infection and an important cause of sensorineural hearing loss and neurodevelopmental impairment, yet many affected infants remain undetected under selective screening approaches. We conducted a prospective national pilot study to evaluate the feasibility and diagnostic yield of universal dried blood spot (DBS)-based screening for cCMV within the Slovenian newborn screening program. DBS samples collected within 72 h of life were tested by polymerase chain reaction (PCR), and screen-positive newborns underwent confirmatory urine PCR within 21 days together with standardized clinical evaluation. Among 5556 screened newborns, 13 (0.23%) screened positive and cCMV was confirmed in 10, corresponding to a lower-bound birth prevalence of 1.80 per 1000 live births (95% confidence interval, 0.98–3.31), because confirmatory testing was limited to DBS-positive newborns. None of the confirmed cases were clinically suspected at birth, and all passed newborn hearing screening. Six infants met protocol-defined criteria for symptomatic cCMV and received valganciclovir. Historical registry-based clinical case ascertainment in Slovenia corresponded to 0.09 detected cases per 1000 live births. These findings demonstrate the feasibility of universal DBS-based cCMV screening within an established newborn screening infrastructure and suggest substantial under-ascertainment under selective clinical detection pathways. Full article

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11 pages, 500 KB

Open AccessArticle

Combined Intracerebroventricular Enzyme Replacement and Cord Blood Transplantation in Patients with Mucopolysaccharidosis Type II Diagnosed Through Newborn Screening

by Yuki Ueda, Shinsuke Hirabayashi, Masayuki Miura, Satoshi Yamada, Sachiko Nakakubo, Midori Nakajima, Takeru Goto, Jutaro Abe, Yukayo Terashita, Atsushi Manabe, Torayuki Okuyama and Kiyoshi Egawa

Int. J. Neonatal Screen. 2026, 12(3), 47; https://doi.org/10.3390/ijns12030047 - 26 Jun 2026

Viewed by 1000

Abstract

Enzyme replacement therapy (ERT) for central nervous system symptoms and newborn screening (NBS) is available in Japan for patients with mucopolysaccharidosis type II (MPS II). Of 12 suspected cases identified through the NBS program, 3 patients were diagnosed with neuronopathic MPS II (2 [...] Read more.

Enzyme replacement therapy (ERT) for central nervous system symptoms and newborn screening (NBS) is available in Japan for patients with mucopolysaccharidosis type II (MPS II). Of 12 suspected cases identified through the NBS program, 3 patients were diagnosed with neuronopathic MPS II (2 directly from the screened cohort and 1 affected sibling). We reviewed the clinical courses of these patients, who were treated with intracerebroventricular (ICV) ERT using idursulfase beta (Hunterase^®) followed by umbilical cord blood transplantation (CBT). Heparan sulfate (HS) in the cerebrospinal fluid (CSF) was longitudinally measured as a therapeutic biomarker, and developmental age was evaluated. All patients achieved successful engraftment with no severe complications, except for one patient with sinusoidal obstruction syndrome. The CSF HS concentration showed a temporary increase during the ERT discontinuation period, which can be attributed to CBT, and a subsequent reduction after the resumption of ICV-ERT. The patients exhibited age-appropriate development. The pattern of change in HS indicates the importance of continuing ICV-ERT even after hematopoietic stem cell transplantation. The study results demonstrate that the combination of ICV-ERT and CBT may yield promising outcomes in patients with neuronopathic MPS II, underscoring the importance of early intervention through NBS. Full article

(This article belongs to the Special Issue Advances in Newborn Screening for Lysosomal Disorders: From Laboratory Screening to Diagnosis)

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16 pages, 917 KB

Open AccessReview

Ethical, Legal, and Social Implications of Newborn Screening in Africa: A Scoping Review

by Victory Oghenetega Samuel, Abdullahi Adeyinka Adejare and Ushotanefe Useh

Int. J. Neonatal Screen. 2026, 12(3), 46; https://doi.org/10.3390/ijns12030046 - 25 Jun 2026

Viewed by 773

Abstract

Newborn screening initiatives have the potential to mitigate childhood morbidity in Africa, but they also have special ethical, legal, and social implications (ELSI) that are influenced by issues with the health system, cultural diversity, and limited resources. This scoping review explores the ELSI [...] Read more.

Newborn screening initiatives have the potential to mitigate childhood morbidity in Africa, but they also have special ethical, legal, and social implications (ELSI) that are influenced by issues with the health system, cultural diversity, and limited resources. This scoping review explores the ELSI of newborn screening across Africa to identify key challenges, gaps, and future research needs. A systematic search identified 27 peer-reviewed studies published between 2008 and 2025, covering 12 African countries. Data were extracted on study characteristics, disease types, and ELSI dimensions from African Journals Online (AJOL), Scopus, PubMed, Web of Science, and BMJ Journals. Thematic analysis mapped recurring ethical, legal, and social concerns. Most studies examined ethical and social dimensions, while legal frameworks were rarely addressed. South Africa, Tanzania, and Ghana contributed the largest number of publications. Sickle cell disease (52%) and hearing screening (30%) were the dominant foci. Common ethical issues included informed consent, privacy, and justice; legal gaps centered on the absence of data protection and frameworks; and social concerns involved stigma, awareness, and cultural perceptions of hereditary disease. Ethical and social issues dominate NBS discourse in Africa, whereas legal oversight remains limited. To guarantee fair, reliable, and long-lasting newborn screening programs, national policy guidelines, community involvement, and context-specific ethical frameworks must be strengthened. Full article

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15 pages, 3432 KB

Open AccessReview

Development of Clinical Pathways for Early Diagnosis and Management of SCID, SMA, and XLA Through Newborn Screening in Malaysia

by Alia Zainudin, Thin Thin Aye, Chloe Chen Sze Yun, Gaayathri Kumarasamy and Adli Ali

Int. J. Neonatal Screen. 2026, 12(3), 45; https://doi.org/10.3390/ijns12030045 - 23 Jun 2026

Viewed by 1040

Abstract

Severe Combined Immunodeficiency (SCID), Spinal Muscular Atrophy (SMA), and X-Linked Agammaglobulinemia (XLA) are rare but life-threatening genetic disorders in infants that can lead to severe infections, progressive neuromuscular degeneration, or severe immune dysfunction associated with significant morbidity and mortality if not diagnosed early. [...] Read more.

Severe Combined Immunodeficiency (SCID), Spinal Muscular Atrophy (SMA), and X-Linked Agammaglobulinemia (XLA) are rare but life-threatening genetic disorders in infants that can lead to severe infections, progressive neuromuscular degeneration, or severe immune dysfunction associated with significant morbidity and mortality if not diagnosed early. Advances in newborn screening (NBS) technologies have enabled pre-symptomatic detection of these conditions, allowing early initiation of life-saving interventions such as hematopoietic stem cell transplantation, gene therapy, and immunoglobulin replacement therapy. However, the absence of a standardized national clinical pathway linking screening, confirmatory testing, and specialist referral in Malaysia continues to contribute to delayed diagnosis and suboptimal patient outcomes. This review examines and synthesizes current evidence on the clinical pathways for early diagnosis and management of SCID, SMA, and XLA, with particular emphasis on diagnostic workflows, screening technologies, and healthcare system challenges within the Malaysian context. The review examines disease epidemiology, consequences of delayed diagnosis, and the role of expanded NBS under the Screening for Health, Intervention, Nurturing of Every Child (SHINE) program in improving early diagnosis and management. In addition, the paper outlines the current NBS landscape, the use of multiplex real-time polymerase chain reaction (PCR) assays for simultaneous detection of T-cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and survival motor neuron 1 (SMN1) gene deletion of exon 7 from dried blood spot (DBS) samples. A structured diagnostic framework incorporating screening interpretation, confirmatory testing, and urgency-based referral pathways is also proposed. By addressing current operational barriers and coordinating laboratory referral systems, expanding NBS programs could significantly improve early diagnosis and long-term outcomes for infants affected by SCID, SMA, and XLA in Malaysia. Full article

(This article belongs to the Special Issue Newborn Screening Developing Programs in Asia)

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Int. J. Neonatal Screen., Volume 12, Issue 3 (September 2026) – 30 articles

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