International Journal of Neonatal Screening

10 pages, 274 KB

Open AccessArticle

Conjugated Hyperbilirubinemia in Early Infancy: Rethinking Diagnostic Cut-Offs—A Retrospective Analysis

by Daniel Pfurtscheller, Carola Ganzer, Ena Suppan, Melina Winkler, Bernhard Schwaberger, Lisa Sallmon, Gerhard Pichler and Benno Kohlmaier

Int. J. Neonatal Screen. 2026, 12(2), 33; https://doi.org/10.3390/ijns12020033 - 11 May 2026

Abstract

Background: Conjugated hyperbilirubinemia in early infancy is a critical indicator of hepatobiliary dysfunction. Prompt and accurate identification is essential to diagnose cholestatic liver disease (CLD), particularly biliary atresia. Current guidelines define conjugated bilirubin (CB) ≥ 1 mg/dL as abnormal, irrespective of total bilirubin [...] Read more.

Background: Conjugated hyperbilirubinemia in early infancy is a critical indicator of hepatobiliary dysfunction. Prompt and accurate identification is essential to diagnose cholestatic liver disease (CLD), particularly biliary atresia. Current guidelines define conjugated bilirubin (CB) ≥ 1 mg/dL as abnormal, irrespective of total bilirubin (TB). This study aimed to evaluate whether combining absolute and relative CB thresholds improves diagnostic performance for CLD. Methods: We retrospectively analyzed all infants aged ≤ 6 months of chronological age with CB ≥ 1 mg/dL admitted to the Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Austria, between January 2004 and February 2025. During that period, 116,104 infants were born at our hospital catchment area; 3119 of these underwent bilirubin fractionation, and 257 infants (0.2% of total births) had a CB ≥ 1 mg/dL and were included in the analysis. Clinical and biochemical data were extracted. Diagnostic performance of the absolute (CB ≥ 1 mg/dL) and in combination with the relative (CB ≥ 20% of TB) thresholds was assessed using receiver operating characteristic (ROC) analysis for the detection of CLD. Results: Among 257 infants, 47 (18%) were diagnosed with CLD. The median age at the time of blood sampling was 18 days (IQR 9–31). The combined criterion (CB ≥ 1 mg/dL and ≥20% of TB) achieved 100% sensitivity and 61.2% specificity (AUC = 0.82, 95% CI 0.79–0.92; p < 0.001). Implementation of the combined cut-off reduced the number needed to screen from 5.5 to 2.7, representing nearly a twofold improvement in diagnostic efficiency. Conclusions: Applying both absolute (≥1 mg/dL) and relative (≥20% of total bilirubin) CB thresholds substantially improves detection of neonatal CLD in early infancy. This combined approach maintains full sensitivity while reducing false positives and unnecessary investigations, thereby enhancing diagnostic efficiency in early infancy. Full article

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

20 pages, 311 KB

Open AccessArticle

by Yuko Matsumoto, Yuko Kushihashi, Akiko Suwa and Go Tajima

Int. J. Neonatal Screen. 2026, 12(2), 32; https://doi.org/10.3390/ijns12020032 - 6 May 2026

Abstract

Newborn mass screening improves outcomes for inborn errors of metabolism (IEM); nonetheless, home-based dietary therapy imposes a substantial parental burden. In this study, we explored differences in parents’ health coping behaviors, assessed using the Coping Health Inventory for Parents (CHIP), based on the [...] Read more.

Newborn mass screening improves outcomes for inborn errors of metabolism (IEM); nonetheless, home-based dietary therapy imposes a substantial parental burden. In this study, we explored differences in parents’ health coping behaviors, assessed using the Coping Health Inventory for Parents (CHIP), based on the presence of dietary therapy, child age group, and diagnostic category. A 21-item, CHIP-based questionnaire was distributed via the JaSMIn registry to parents of children with IEM up to school age. Overall, 201 valid responses (56.1% response rate) were analyzed regarding the implementation and perceived usefulness of coping behaviors, stratified by child age, enrollment, diagnosis, and dietary therapy. Parents in the dietary-therapy group reported more coping behaviors than did those in the non-dietary-therapy group. Notably, parents of children aged 1–3 years (not yet in preschool) and those of children with organic acid metabolism disorders rated “daily home practice of treatments” as a highly useful coping behavior. Health-related coping behaviors among parents of children with IEM vary substantially according to child age and disease characteristics. Therefore, family support strategies should be tailored to specific developmental stages and treatment requirements. Full article

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

6 pages, 478 KB

Open AccessEditorial

Newborn Critical Congenital Heart Disease Screening Using Pulse Oximetry in a Global Context: Progress, Disparities, and the Importance of Early Detection

by Lisa A. Hom and Gerard R. Martin

Int. J. Neonatal Screen. 2026, 12(2), 31; https://doi.org/10.3390/ijns12020031 - 5 May 2026

Abstract

Congenital heart disease (CHD) remains the number one cause of mortality due to congenital defects in children under the age of one [...] Full article

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

16 pages, 1298 KB

Open AccessArticle

Pilot Newborn Screening for Vitamin B12 Deficiency in the Czech Republic: Results and Detailed Studies on Identified Babies and Their Mothers

by Samuel Stanovský, Josef Bártl, Petr Chrastina, Viktor Kožich, Jakub Krijt, Kristýna Nelicová, Jitka Sokolová, Truong An Nguyen, Richard Plavka, Květa Pelinková, Drahomíra Springer, Klára Berková, Zbyněk Straňák, Jan Janota, Katarína Tichá, Jiří Zach and Tomáš Honzík

Int. J. Neonatal Screen. 2026, 12(2), 30; https://doi.org/10.3390/ijns12020030 - 5 May 2026

Abstract

Neonatal vitamin B12 (B12) deficiency can cause neurodevelopmental harm, and newborn screening (NBS) may enable early detection and treatment. We conducted a multicenter pilot project in four Prague university hospitals between 1 June 2022 and 30 June 2025. Algorithms included the determination of [...] Read more.

Neonatal vitamin B12 (B12) deficiency can cause neurodevelopmental harm, and newborn screening (NBS) may enable early detection and treatment. We conducted a multicenter pilot project in four Prague university hospitals between 1 June 2022 and 30 June 2025. Algorithms included the determination of propionylcarnitine-derived primary markers using flow-injection tandem mass spectrometry and second-tier methylmalonic acid (MMA), with total homocysteine measured only when MMA was increased. Of 34,302 screened newborns with consent, 1365 (3.98%) triggered second-tier testing; 9 had MMA >2.5 µmol/L, of which 8 met the case definition after confirmatory testing, giving a birth frequency of 1:4228 (95% CI 1:2176–1:9931). Positive predictive value was 0.59% (95% CI 0.25–1.15%) and 88.89% (95% CI 51.75–99.72%) for the primary test and second-tier MMA, respectively, with a false positive rate of 0.00292% (95% CI 0.000074–0.01625%). All affected infants were treated orally with cyanocobalamin. Maternal work-up identified confirmed B12 deficiency in four of eight mothers and premalignant gastric changes in two of four positive women. These data support the feasibility, low cost, and clinical utility of incorporating B12 deficiency into Czech NBS, with benefits extending beyond newborn health. Full article

13 pages, 2874 KB

Open AccessArticle

Neonatal Screening for CAH in Sweden—Results of Implementing Second-Tier Testing

by Karin Engström, Rolf H. Zetterström, Anna Wedell and Anna Nordenström

Int. J. Neonatal Screen. 2026, 12(2), 29; https://doi.org/10.3390/ijns12020029 - 1 May 2026

Abstract

Newborn screening for congenital adrenal hyperplasia (CAH) is effective in identifying patients with severe forms before a potentially lethal crisis, but has a relatively high false-positive rate. The aim of this study was to improve the national neonatal screening program in Sweden and [...] Read more.

Newborn screening for congenital adrenal hyperplasia (CAH) is effective in identifying patients with severe forms before a potentially lethal crisis, but has a relatively high false-positive rate. The aim of this study was to improve the national neonatal screening program in Sweden and the positive predictive value by implementing LC-MS/MS second-tier testing. A combination of two independent parameters, the steroid hormone ratio (androstenedione+17-hydroxyprogesterone)/cortisol and the concentration of 21-deoxycortisol and adjustment of cut-off levels resulted in an increase in the positive predictive value (PPV) from 14% to 84% for full-term infants. In total, the false-positive screening cases decreased by 88%. CYP21A2 genotyping was used to determine the severity of CAH in identified cases. We report on the stepwise approach that was used to optimize the cut-off levels for full-term and preterm infants in order not to miss any true cases in the process. Full article

(This article belongs to the Special Issue The Impact of Second-Tier Tests on Newborn Screening Performance: Benefits and Challenges)

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10 pages, 1345 KB

Open AccessArticle

The Variation in IRT in Different Ethnic Groups in England—Implications for a Newborn Screening Programme for CF in Diverse Multiethnic Populations

by Toby Greenfield, Lesley Tetlow, James R. Bonham, Catherine Collingwood, Laura Wainwright, Liz Robinson, Dave Wright, Beverly Hird, Tejswurree Ramgoolam, Caroline Griffith, Lynette Shakespeare, Mehdi Mirzazadeh, Rachelle Garstone, Deborah Finnerty, Nick Flynn, Nazia Taj and Maya Desai

Int. J. Neonatal Screen. 2026, 12(2), 28; https://doi.org/10.3390/ijns12020028 - 28 Apr 2026

Abstract

Increasing ethnic diversity raises potential inequalities within screening programmes. In the UK, newborns are screened for CF by initially measuring IRT. Dried blood spot IRT levels above a set cut-off require follow-up testing to establish a screening result. Variation exists in IRT levels [...] Read more.

Increasing ethnic diversity raises potential inequalities within screening programmes. In the UK, newborns are screened for CF by initially measuring IRT. Dried blood spot IRT levels above a set cut-off require follow-up testing to establish a screening result. Variation exists in IRT levels between different ethnicities and therefore impacts the number of potentially false positive results obtained from ethnic groups. Over a 4-year period, IRT data was collected, and the 99.5th centile was calculated for different ethnic groups. Significant differences were noticed between ethnic groups, and the CF outcome data over a 10-year period were then analysed to establish the effect this had on positive predictive values. The largest difference in IRT 99.5th centile values was seen between the White British and Black African groups. Positive predictive values for Black African and Indian ethnic groups were much lower than the other groups. Rather than try to incorporate ethnicity into the UK CF screening algorithm, we suggest making CF clinicians aware of the differences between different ethnic groups to inform counselling families who receive screen-positive results. Full article

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11 pages, 489 KB

Open AccessArticle

21-Deoxycortisone: A Novel Sensitive and Specific Newborn Screening Marker for Congenital Adrenal Hyperplasia

by Mark de Hora, Natasha Heather, Dianne Webster, Benjamin B. Albert and Paul Hofman

Int. J. Neonatal Screen. 2026, 12(2), 27; https://doi.org/10.3390/ijns12020027 - 27 Apr 2026

Abstract

21-deoxycortisol is a sensitive and specific blood marker for congenital adrenal hyperplasia (CAH). We postulated that 21-deoxycortisone, the 11β-hydroxysteroid dehydrogenase metabolite of 21-deoxycortisol, may also be an accurate bloodspot marker of CAH. Measurement of 21-deoxycortisone was performed on 42 residual NBS specimens with [...] Read more.

21-deoxycortisol is a sensitive and specific blood marker for congenital adrenal hyperplasia (CAH). We postulated that 21-deoxycortisone, the 11β-hydroxysteroid dehydrogenase metabolite of 21-deoxycortisol, may also be an accurate bloodspot marker of CAH. Measurement of 21-deoxycortisone was performed on 42 residual NBS specimens with a true positive result for CAH, 11 with a false negative result, and 439 specimens with a false positive result. For this study, the test was considered positive if 21-deoxycortisone was detected. The sensitivity and specificity of 21-deoxycortisone as a marker for classical CAH was calculated and compared to 21-deoxycortisol data from a previous New Zealand study. The method for 21-deoxycortisone measurement was linear to 1000 nmol/L and precision was 7.3–10.3%. The lower limit of quantification was 2 nmol/L, and recovery was 99%. 21-deoxycortisone was ≥2 nmol/L in all 42 true positive samples and in 10 false negative samples, and was not detected in the false positive group of specimens. The sensitivity of 21-deoxycortisone was 98.1%, and specificity was 100%. In a previous study, the sensitivity of 21-deoxycortisol was 88.7% and specificity was 99.8% in 1910 newborn screening tests carried out between 2018 and 2021. Incorporating 21-deoxycortisone into a second-tier test and adjustment of primary screening protocols could improve the accuracy of newborn screening for CAH. Longer term prospective studies on the performance of 21-deoxycortisone are warranted. Full article

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18 pages, 282 KB

Open AccessArticle

Parental Views on the Psychosocial Impact of False-Positive Results Following Newborn Screening for Severe Combined Immunodeficiency in England

by Pru Holder, Chloe Musa, Anju Keetharuth, Fiona Ulph, Jim B. Chilcott, Louise Moody, Ellinor K. Olander and Jane Chudleigh

Int. J. Neonatal Screen. 2026, 12(2), 26; https://doi.org/10.3390/ijns12020026 - 21 Apr 2026

Abstract

The project aimed to explore the psychosocial impact on parents of receiving a false-positive outcome following a positive newborn bloodspot screening (NBS) result for SCID for their child. A mixed-methods design was employed using semi-structured interviews and standardised health-related questionnaires (EQ-5D-5L, ITQOL-47, and [...] Read more.

The project aimed to explore the psychosocial impact on parents of receiving a false-positive outcome following a positive newborn bloodspot screening (NBS) result for SCID for their child. A mixed-methods design was employed using semi-structured interviews and standardised health-related questionnaires (EQ-5D-5L, ITQOL-47, and GAD-7). The participants were recruited from six National Health Service hospital trusts in England involved in the NHS England In-Service Evaluation of Screening for SCID. A total of 22 interviews were conducted with 28 parents. Health-related questionnaire data were collected from 26 of these parents. The interviews were analysed using a reflexive deductive approach to thematic analysis. For the health-related questionnaire data, a comparison of group means against population norms was undertaken using t-tests with unequal variances. The findings from the interviews showed that receiving a false-positive outcome following a positive NBS SCID result could cause parents to have an enhanced view of their child’s vulnerability in the short term. However, negative sequelae were largely mitigated as parents viewed their child’s exposure to ‘normal’ infections as evidence of a functional immune system. The health-related questionnaire data showed that the parents had significantly worse health than the population norm (as indicated by EQ-VAS: p = 0.0296); however, all the other measures were non-significant. More research is needed to explore the potential longer-term psychosocial impact of a false-positive screening result for SCID on parents beyond their child’s first year of life. Full article

10 pages, 1048 KB

Open AccessArticle

COASY-Associated Disorders as a Differential Diagnosis in Cases with Newborn Screening Results Suggestive of CPT-I

by Zinandré Stander, Amy L. White, Matthew Lynch, David Coman, Justin Rosati, Diana Bailey, Jessica Johnson, Bo Hoon Lee, ChinTo Fong, Joseph Orsini, Matthew J. Schultz, Devin Oglesbee, Dimitar Gavrilov, Dietrich Matern, Patricia L. Hall and Silvia Tortorelli

Int. J. Neonatal Screen. 2026, 12(2), 25; https://doi.org/10.3390/ijns12020025 - 17 Apr 2026

Abstract

COASY-related disorders (CRDs) are a spectrum of autosomal recessive conditions caused by the dysfunction of CoA synthase, an enzyme responsible for the final steps of CoA synthesis. Clinical manifestations of CRDs are highly variable, ranging from perinatal lethal pontocerebellar hypoplasia to childhood-onset [...] Read more.

COASY-related disorders (CRDs) are a spectrum of autosomal recessive conditions caused by the dysfunction of CoA synthase, an enzyme responsible for the final steps of CoA synthesis. Clinical manifestations of CRDs are highly variable, ranging from perinatal lethal pontocerebellar hypoplasia to childhood-onset neurodegenerative brain iron accumulation, which is often recognized after clinical regression. Recent reports have described a few individuals with CRD who screened positive for carnitine palmitoyltransferase-I deficiency by newborn screening (NBS). However, heterogeneous clinical presentations, conflicting biochemical/molecular sequencing of CPT1A, and a lack of metabolic characterization have led to lengthy, costly diagnostic journeys. To address some of these aspects, this investigation retrospectively evaluated NBS acylcarnitine patterns in five CRD cases using Collaborative Laboratory Integrated Reports (CLIR). A total of 25 metabolites/ratios were identified to deviate significantly from reference ranges and were primarily composed of elevated free carnitine and reduced long-chain acylcarnitine levels. While low acylcarnitine concentrations are often not reported due to a lack of lower reference cutoffs, ratios involving these metabolites relative to short-chain acylcarnitines could aid in identifying CRD cases via NBS. When comparing this pattern to CPT-Ia cases, we confirmed a nearly identical acylcarnitine pattern between these, and thus support the need to consider CRD in cases with NBS results suggestive of CPT-Ia. This study is the first case series to characterize NBS patterns in patients with CRD and highlights the unique opportunity for early detection, particularly in cases that are neonatally asymptomatic and have unremarkable confirmatory biochemical results. Full article

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13 pages, 556 KB

Open AccessArticle

Evaluation of Implementation of Newborn Screening for Sickle Cell Disease Program in Selected Hospitals in Dar es Salaam, Tanzania

by Tunganege Matipa, Elia Nyangi, Agnes Jonathan, Mwashungi Ally, Lulu Chirande, Asteria Mpoto, Emmanuel Balandya and Gladys Reuben Mahiti

Int. J. Neonatal Screen. 2026, 12(2), 24; https://doi.org/10.3390/ijns12020024 - 15 Apr 2026

Abstract

Sickle cell disease (SCD) is a major public health concern in Tanzania where approximately 11,000 children are born with the condition annually. Newborn screening (NBS) enables early diagnosis and timely intervention. Despite the proven effectiveness of NBS in reducing early mortality from SCD, [...] Read more.

Sickle cell disease (SCD) is a major public health concern in Tanzania where approximately 11,000 children are born with the condition annually. Newborn screening (NBS) enables early diagnosis and timely intervention. Despite the proven effectiveness of NBS in reducing early mortality from SCD, implementation in Tanzania remains limited to pilot programs at facilities such as Temeke and Amana Regional Referral Hospitals (RRHs) in the city of Dar-es-salaam. This study evaluated the implementation of NBS for the SCD Program at Temeke and Amana RRHs. An explanatory mixed-methods process evaluation was conducted between January 2022 and December 2024. Quantitative data were extracted from hospital registries and REDCap, while qualitative data were obtained from key informant interviews with 17 healthcare workers. Quantitative data were analyzed using SPSS v29.0, while qualitative transcripts were thematically analyzed using NVivo software version 15 to explore operational factors influencing implementation. A total of 10,711 newborns were screened across the two hospitals. Seventy-four (0.70%) newborns had homozygous SCD (HbS/S), whereas 1325 (12.53%) had sickle cell trait (HbA/S). Enrolment of infants diagnosed with SCD into comprehensive care declined substantially over time, from 65.6% in 2022 to 10.5% in 2024 at Temeke RRH, while Amana RRH recorded no enrolments beyond the first year of implementation. Qualitative findings highlighted facilitators for NBS such as maternal awareness, interdepartmental collaboration, and the availability of trained staff. However, implementation was hindered by inadequate refresher training, delayed staff incentives, supply shortages, and parental hesitancy influenced by cultural beliefs. This evaluation found a substantial decline in enrolment of newborns diagnosed with SCD into comprehensive care, driven by key operational challenges. Although early implementation benefited from trained, committed staff and interdepartmental collaboration, sustainability was limited by inadequate refresher training, delayed incentives, supply shortages, and parental hesitancy. Addressing these gaps through regular capacity building, strengthened supply chains, timely incentives, and culturally sensitive community education is critical to improving enrolment, continuity of care, and informing national scale-up of NBS for SCD in Tanzania. Full article

(This article belongs to the Special Issue Newborn Screening for Sickle Cell Disease Between Point of Care Testing and Next Generation Sequencing – An Impossible Choice or Not?)

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12 pages, 942 KB

Open AccessTechnical Note

A Systematic Process to Accurately Link Large-Scale Research Consents to State Public Health Newborn Screening Samples

by Emily Cheves, Hannah E. Frawley, Angela You Gwaltney, Ana N. Forsythe, Samantha Scott, John Colin Mathews, Jake Dibble, Tanya Reeve, Vesselina Bakalov, Manisha Dass, Heidi L. Cope, Curt Scharfe and Holly Peay

Int. J. Neonatal Screen. 2026, 12(2), 23; https://doi.org/10.3390/ijns12020023 - 14 Apr 2026

Abstract

Research programs can interface with public health programs to generate innovation, yet it is critical to ensure processes that support research activities without infringing on protected data. Genomic newborn screening (gNBS) research programs require reliable methods to link parental consents to the correct [...] Read more.

Research programs can interface with public health programs to generate innovation, yet it is critical to ensure processes that support research activities without infringing on protected data. Genomic newborn screening (gNBS) research programs require reliable methods to link parental consents to the correct newborn screening (NBS) specimen. Early Check is a gNBS research program in North Carolina that uses the residual dried bloodspot (DBS) samples stored at the North Carolina State Laboratory of Public Health (NCSLPH) to screen babies for serious health conditions. Early Check created a systematic approach to match research consents with NBS DBS samples utilizing a fuzzy matching algorithm and manual review of prospective matches utilizing a decision tree. Between 28 September 2023, and 10 June 2025, Early Check received parental consents for 4279 newborns. Of those, 614 (14%) had discrepancies that required further review. More than half of these (349, 57%) required outreach to the consenting parent to resolve differences in information such as name, infant sex, or contact details. The use of probabilistic matching, a decision tree, and structured staff review provides a feasible approach for accurately identifying samples from consented NBS participants. Full article

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15 pages, 1440 KB

Open AccessArticle

Acid Sphingomyelinase Activity in Dried Blood Spot from Neonatal Intensive Care Unit–Admitted Neonates: A Pilot Study for Expanded Newborn Screening in Japan

by Akie Kato, Atsuko Noguchi, Hiroyuki Adachi, Kiichi Takahashi, Masato Ito, Tomoo Ito, Shozo Ota and Hirokazu Arai

Int. J. Neonatal Screen. 2026, 12(2), 22; https://doi.org/10.3390/ijns12020022 - 1 Apr 2026

Abstract

Acid sphingomyelinase deficiency (ASMD) is currently treatable with olipudase alfa, increasing the need for early newborn screening (NBS). We conducted a two-center pilot cohort study to characterize dried blood spot (DBS) acid sphingomyelinase (ASM) activity in Japanese neonates in the neonatal intensive care [...] Read more.

Acid sphingomyelinase deficiency (ASMD) is currently treatable with olipudase alfa, increasing the need for early newborn screening (NBS). We conducted a two-center pilot cohort study to characterize dried blood spot (DBS) acid sphingomyelinase (ASM) activity in Japanese neonates in the neonatal intensive care unit (NICU). ASM activity was measured by flow injection-tandem mass spectrometry in 244 NICU-admitted neonates (gestational age 25–41 weeks; birth weight 773–4201 g); longitudinal paired samples were available in 34 neonates with birth weight < 2000 g and concurrent hematology in 43 neonates. The mean ASM activity was 3.7 ± 1.2 μmol/h/L (95% confidence interval, 3.54–3.84; range, 1.7–11.6), with a right-skewed distribution. ASM activity correlated positively with birth weight (r = 0.184, p = 0.0039), gestational age (r = 0.219, p = 0.0006), and lymphocyte count (ρ = 0.394, p = 0.0089) and negatively with hematocrit (ρ = −0.372, p = 0.014). In neonates with a birth weight < 2000 g, ASM increased significantly on repeat sampling (mean difference, 1.60 μmol/h/L; p < 0.0001; Cohen’s d = 0.912). These findings support NICU-specific reference ranges, hematology-informed interpretations, repeat testing after maturation, and the use of second-tier biomarkers for ASMD NBS implementation in Japan. Full article

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

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11 pages, 603 KB

Open AccessArticle

Cost-Effectiveness of Newborn Screening for Infantile-Onset Pompe Disease in Japan

by Keiko Konomura, Motoko Tanaka, Go Tajima and Eri Hoshino

Int. J. Neonatal Screen. 2026, 12(2), 21; https://doi.org/10.3390/ijns12020021 - 31 Mar 2026

Abstract

We conducted a cost-effectiveness analysis of a universal newborn screening (NBS) program for infantile-onset Pompe disease (IOPD) compared with clinical identification in newborns. The analytical model combined a decision tree and a Markov model. The incremental cost-effectiveness ratio (ICER) was estimated over a [...] Read more.

We conducted a cost-effectiveness analysis of a universal newborn screening (NBS) program for infantile-onset Pompe disease (IOPD) compared with clinical identification in newborns. The analytical model combined a decision tree and a Markov model. The incremental cost-effectiveness ratio (ICER) was estimated over a lifetime horizon, applying a 2% annual discount rate from the public healthcare payer’s perspective. In a cohort of 727,288 individuals, 2.4 patients were expected to have IOPD. The cumulative quality-adjusted life years (QALYs) gained per patient were estimated to be 7.9 when clinically diagnosed and treated with enzyme replacement therapy, and 28.9 when identified through universal NBS. The ICER was 174 million JPY per QALY. Sensitivity and scenario analyses indicated that the parameters most affecting the ICER were the NBS test cost, the quality-of-life value for ambulatory patients, the prevalence of IOPD, and the cost of enzyme replacement therapy. Although considerable uncertainty exists in the analysis, the findings suggest that implementing NBS solely for detecting infantile-onset cases poses challenges in terms of cost-effectiveness, primarily due to the rarity of the disease and the high costs associated with testing and treatment. Full article

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

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9 pages, 211 KB

Open AccessArticle

A Survey of Current Australasian Practices in the Use of Residual Bloodspots for the Addition of a New Disorder to the Screening Panel

by Lawrence Greed, James Pitt, Ronda F. Greaves, Kate Coleman, Gabrielle Crisp, Enzo Ranieri, Mark de Hora, Dianne Webster and Natasha Heather

Int. J. Neonatal Screen. 2026, 12(2), 20; https://doi.org/10.3390/ijns12020020 - 30 Mar 2026

Abstract

Newborn screening (NBS) bloodspots are primarily used to test for a defined panel of conditions, yet screening expansion has necessitated the implementation of new tests. Integral to test implementation across all clinical laboratories is the need to evaluate the method with clinical samples, [...] Read more.

Newborn screening (NBS) bloodspots are primarily used to test for a defined panel of conditions, yet screening expansion has necessitated the implementation of new tests. Integral to test implementation across all clinical laboratories is the need to evaluate the method with clinical samples, and a common secondary use of residual bloodspots, which are samples that remain following conventional screening, is validating new testing methods by establishing “normal” analyte concentrations and setting action decision limits for NBS protocols prior to implementation. Analysis of de-identified residual bloodspots may potentially reveal an infant with a treatable condition, and re-identification and clinical notification of the infant may then be prudent. However, consent to test residual samples for conditions under implementation may not have been obtained. This ethical dilemma risks the inclusion of residual bloodspots in test development being declined by over-arching NBS authorities. Consequently, the Human Genetics Society of Australasia (HGSA) NBS Committee issued a survey to the Australasian NBS laboratories regarding the current practices of the use of residual bloodspots for new test implementation. The questionnaire revealed a consistent requirement for residual NBS bloodspot analysis to determine reference ranges and screening cutoffs for biochemical variants. If using de-identified residual samples as a component of test validation, re-identification of infants with out-of-range results for clinical referral was considered ethically justified for potentially treatable conditions. The survey results will be used to develop a consensus approach in the region that is both ethically and scientifically valid. Full article

15 pages, 1156 KB

Open AccessArticle

A Multi-Stakeholder Perspective on Integrating Genomic Sequencing into Newborn Screening: An Interview Study

by Saskia G. Smits, Suzanne M. Onstwedder, Tessel Rigter, Wendy Rodenburg and Lidewij Henneman

Int. J. Neonatal Screen. 2026, 12(2), 19; https://doi.org/10.3390/ijns12020019 - 26 Mar 2026

Abstract

Interest in the genomic sequencing of healthy newborns has raised a discussion on whether this technology should be introduced into existing newborn screening (NBS) programs. This qualitative study explores a multi-stakeholder perspective on the future of genomic sequencing in NBS. Semi-structured interviews were [...] Read more.

Interest in the genomic sequencing of healthy newborns has raised a discussion on whether this technology should be introduced into existing newborn screening (NBS) programs. This qualitative study explores a multi-stakeholder perspective on the future of genomic sequencing in NBS. Semi-structured interviews were conducted with 26 professionals involved in NBS or in clinical genome sequencing in the Netherlands. Participants highlighted opportunities such as the possibility to use one test for a wide range of genetic conditions, reducing diagnostic odyssey, expanding the scope of NBS, and increasing program efficiency. Challenges were raised regarding genetic variant interpretation, expected increased parental anxiety, data privacy issues, difficulties with information provision, and high costs. Three areas of tension between participants’ perspectives were identified: screening strategy, screening performance, and roles and responsibilities. It was emphasized that implementing genomic sequencing should not risk reducing the current high NBS participation, and that enhancing knowledge, communication, and collaboration between all stakeholders is needed. Although most participants did not believe genomic sequencing as a first-tier test is currently desirable and feasible, they acknowledged it has a role to play in the future of NBS. Future decision-making should consider the potential impact on the participation rate, program quality, and balancing benefits and harms. Full article

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12 pages, 577 KB

Open AccessArticle

Incorporating Next-Generation Sequencing in Newborn Screening for Organic Acidemias

by Yiming Lin, Jinping Zhong, Weilin Peng, Faming Zheng and Xudong Wang

Int. J. Neonatal Screen. 2026, 12(1), 18; https://doi.org/10.3390/ijns12010018 - 19 Mar 2026

Abstract

Organic acidemias (OADs) are a group of inherited metabolic disorders with a high false-positive rate in newborn screening. In this study, we aimed to evaluate the clinical performance of next-generation sequencing (NGS) as a combined genetic test for OADs. From September 2022 to [...] Read more.

Organic acidemias (OADs) are a group of inherited metabolic disorders with a high false-positive rate in newborn screening. In this study, we aimed to evaluate the clinical performance of next-generation sequencing (NGS) as a combined genetic test for OADs. From September 2022 to August 2025, 154,634 newborns underwent primary screening using tandem mass spectrometry (MS/MS). Among them, 151 neonates with suspected OADs underwent combined genetic screening using a pre-designed NGS panel. Of these, 55 cases tested positive on genetic screening, and 17 were ultimately diagnosed with OADs, yielding a prevalence of 1 in 9096. The positive predictive value of NGS was 30.91% (17/55). The genotypes of nine patients (9/17, 52.9%) were identified through NGS screening. Notably, one case of methylmalonic acidemia that would have been missed by MS/MS screening was successfully identified using the combined genetic screening. Additionally, 37 neonates with positive biochemical screening results were confirmed to be either carriers or unaffected individuals. Two cases of Wilson’s disease were also identified through combined genetic screening. Therefore, integrating NGS into conventional MS/MS-based screening can significantly reduce the false-positive rate and shorten the time from screening to definitive diagnosis. This approach provides a valuable model for improving the efficiency and accuracy of newborn genetic screening. Full article

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10 pages, 1917 KB

Open AccessArticle

Pathogenic Analysis of Two SLC22A5 Variants That Alter RNA Splicing in Patients with Primary Carnitine Deficiency

by Yiming Lin, Yanru Chen, Weihua Lin and Faming Zheng

Int. J. Neonatal Screen. 2026, 12(1), 17; https://doi.org/10.3390/ijns12010017 - 16 Mar 2026

Abstract

Functional analysis of SLC22A5 variants can improve diagnostic accuracy in patients with primary carnitine deficiency (PCD). Herein, we performed a genetic analysis of three neonates with PCD. Two of the patients harbored a novel synonymous SLC22A5 variant that has not been previously reported, [...] Read more.

Functional analysis of SLC22A5 variants can improve diagnostic accuracy in patients with primary carnitine deficiency (PCD). Herein, we performed a genetic analysis of three neonates with PCD. Two of the patients harbored a novel synonymous SLC22A5 variant that has not been previously reported, and the other patient harbored a classical splice site variant. The splicing patterns of the two SLC22A5 variants were evaluated using three in silico tools, and in vitro minigene analysis was performed to verify the impact of variants on RNA splicing mechanisms. All three in silico tools predicted that both SLC22A5 variants could alter normal RNA splicing. Functional studies using minigene assays demonstrated that the c.450C>T (p.F150=) leads to partial exon 2 skipping, and c.394-1G>A leads to intron 1 retention and exon 2 skipping. Intron 1 retention of 65 nucleotides and exon 2 skipping were confirmed by sequencing cDNA amplification products. These results, along with functional evidence, led to reclassification of c.450C>T (p.F150=) and c.394-1G>A as likely pathogenic and pathogenic, respectively. This is the first reported synonymous variant in the SLC22A5 gene that has been functionally validated to affect RNA splicing, thus enriching the variant spectrum of SLC22A5 and aiding accurate PCD diagnosis. Full article

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13 pages, 606 KB

Open AccessArticle

Clinical Experience of Timing Treatment in Newborns with Spinal Muscular Atrophy: A Call for Standardized Screening Practices in Italy

by Ilaria Bitetti, Rosa Iannaccone, Giovanna Margiotta and Antonio Varone

Int. J. Neonatal Screen. 2026, 12(1), 16; https://doi.org/10.3390/ijns12010016 - 9 Mar 2026

Abstract

Spinal muscular atrophy (SMA) is a rare neuromuscular disorder causing progressive muscle weakness. Severe SMA forms are typically observed up to six months postnatally. Disease-modifying therapies provide significant benefits, making newborn screening (NBS) essential for timely diagnosis and treatment initiation. The NBS programme [...] Read more.

Spinal muscular atrophy (SMA) is a rare neuromuscular disorder causing progressive muscle weakness. Severe SMA forms are typically observed up to six months postnatally. Disease-modifying therapies provide significant benefits, making newborn screening (NBS) essential for timely diagnosis and treatment initiation. The NBS programme evaluated infants born between April 2023 and October 2024 in the Campania region, Italy. DNA was amplified to detect homozygous deletion of the SMN1 gene by RT-PCR and SMN2 copy number using multiplex ligation-dependent probe amplification. Following treatment, motor functions were assessed using CHOP-INTEND and Bayley III scales. Among 62,801 infants screened for SMA, thirteen (11 females, 2 males) tested positive. The distribution of SMN2 copy numbers was as follows: eight patients had two copies, one patient had three, and four patients had four copies. One year after treatment, motor outcome data were available for four of the eight patients with two SMN2 copies. Among these patients, one achieved the milestones of walking without support, and three were standing with support. At 24 months, three of these patients were walking independently. Pre-symptomatic treatment markedly improves motor function development. This underscores the urgent need for large-scale newborn screening to prevent diagnostic delays and ensure timely, effective therapy. Validated care protocols must be established to facilitate early diagnosis and intervention. Full article

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8 pages, 640 KB

Open AccessArticle

Beyond Detection: Comparing State-Based Newborn Screening Methods for Effective Mucopolysaccharidosis I Diagnosis

by Rithika Thampy, Nishitha R. Pillai, Michael Evans, Chester B. Whitley, Paul J. Orchard, Matthew Ellinwood and Amy Gaviglio

Int. J. Neonatal Screen. 2026, 12(1), 15; https://doi.org/10.3390/ijns12010015 - 3 Mar 2026

Abstract

Mucopolysaccharidosis type I (MPS I) results in the accumulation of glycosaminoglycans (GAG) and, for the purposes of newborn screening, is differentiated into two forms: severe (Hurler syndrome) versus attenuated (encompassing Scheie and Hurler-Scheie syndromes). MPS I was added to the federal Recommended Uniform [...] Read more.

Mucopolysaccharidosis type I (MPS I) results in the accumulation of glycosaminoglycans (GAG) and, for the purposes of newborn screening, is differentiated into two forms: severe (Hurler syndrome) versus attenuated (encompassing Scheie and Hurler-Scheie syndromes). MPS I was added to the federal Recommended Uniform Screening Panel for newborn screening (NBS) in 2016, and as of December 2025, 45 of 54 programs in the United States (US) screen for MPS I. Within the newborn screening program, a second-tier analysis of GAG is thought to reduce false-positive rates, particularly through mitigating the detection of pseudodeficiency. However, there have been some concerns that the use of second-tier GAG analysis might inadvertently result in missed detection of attenuated cases. A survey of all US NBS programs was conducted requesting data on the total number of screen-positive NBS results for MPS I as well as the final diagnostic outcome from these results. Diagnostic outcomes after screening were classified as false-positive, pseudodeficiency, severe MPS I, attenuated MPS I, and MPS I of undetermined phenotype. Additionally, information on testing methodologies and dates of MPS I NBS implementation was collected. Responses were obtained from 32 NBS programs. The cohort of screening programs utilizing second-tier blood spot GAG determinations detected a higher proportion of severe cases than those not using this second-tier test (48% vs. 29%). The proportion of attenuated cases remained consistent between both groups (13% vs. 14%). The proportion of pseudodeficiency detection was only slightly lower in the cohort using second-tier GAG analysis (85% vs. 91%). Second-tier GAG analysis appears to reduce the detection of false-positive cases and improves the resolution of severe MPS I cases, though the proportion of pseudodeficiency was only slightly lower compared to the programs that do not use second-tier GAG analysis. Currently, the proportion of attenuated cases is comparable between the two cohorts, but the higher number of “undetermined phenotype” cases may eventually shift the balance toward states not using GAG analysis once the type is determined. 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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International Journal of Neonatal Screening

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