International Journal of Neonatal Screening

13 pages, 4376 KB

Open AccessArticle

Validation on the First-Tier Fully Automated High-Throughput SMN1, SMN2, TREC, and RPP30 Quantification by Quadruplex Droplet Digital PCR for Newborn Screening for Spinal Muscular Atrophy and Severe Combined Immunodeficiency

by Chloe Miu Mak, Timothy Yiu Cheong Ho, Man Kwan Yip, Felicite Enyu Song, Raymond Chiu Mo Tam, Leanne Wing Ying Yu, Ann Anhong Ke, Eric Chun Yiu Law, Toby Chun Hei Chan and Matthew Chun Wing Yeung

Int. J. Neonatal Screen. 2025, 11(4), 97; https://doi.org/10.3390/ijns11040097 - 19 Oct 2025

Abstract

Newborn screening (NBS) for spinal muscular atrophy (SMA) and severe combined immunodeficiency (SCID) faces challenges. Accurate and precise SMN1 and SMN2 copy number determination, confirmed by two orthogonal methods, are vital for SMA prognostication and treatment. Single SMN1 copy detection also enables the [...] Read more.

Newborn screening (NBS) for spinal muscular atrophy (SMA) and severe combined immunodeficiency (SCID) faces challenges. Accurate and precise SMN1 and SMN2 copy number determination, confirmed by two orthogonal methods, are vital for SMA prognostication and treatment. Single SMN1 copy detection also enables the further feasibility to screen for compound heterozygotes. In SCID, low-level T-cell receptor excision circle (TREC) quantification by quantitative PCR is imprecise, necessitating replicates for reliable results. An assay with enhanced accuracy, precision, and high throughput is warranted for NBS SMA and SCID. False positive of SMN1 deletions due to allele dropout are also a potential pitfall in PCR-based methods. We evaluated a first-tier fully automated quadruplex droplet digital PCR (ddPCR) assay detecting SMN1, SMN2, TREC, and RPP30 using dried blood spots together with a second-tier Sanger sequencing to exclude SMN1 allele dropout. Five proficiency test samples and six patient samples with known SMN1 and SMN2 copy numbers confirmed by multiplex ligation-dependent probe amplification were used for accuracy evaluation with full concordance. The ddPCR assay showed high precision for SMN1 and SMN2 (<7% coefficient of variation (CV) for ≥0 copy) and TREC (14.6% CV at 37 copies/µL blood). Second-tier Sanger sequencing identified all SMA cases with homozygous deletions. Accuracy for TREC classification was concordant with 10 proficiency samples. The reference interval of TREC concentration was established for newborns ≥ 34 weeks (n = 1812) and the 2.5th percentile was 57 copies/µL blood. A two-tiered approach with fully automated quadruplex ddPCR and Sanger sequencing delivers accurate and precise quantitation for NBS SMA and SCID, enabling early treatment and counseling. Full article

(This article belongs to the Special Issue Selected Papers from 13th ISNS European Regional Meeting—Celebrating 10 Years of IJNS)

► Show Figures

Figure 1

18 pages, 1659 KB

Open AccessSystematic Review

Methodological and Procedural Considerations for Developing Decision Analytic Models to Assess the Health Economic Impacts of Newborn Bloodspot Screening: A Systematic Methodological Review

by Jim Chilcott, Alice Bessey, James R. Bonham, Iván Castilla-Rodríguez, Sarah Davis, David Elliman, Sara Hunt, Chris Hyde, Silvia Lombardo, Jason Madan, John Marshall, Joan Morris, Katherine Payne, Oliver Rivero-Arias, Bethany Shinkins, Graham Shortland, Susan Spillane, Anthea Sutton, Sian Taylor-Phillips and Cristina Visintin

Int. J. Neonatal Screen. 2025, 11(4), 96; https://doi.org/10.3390/ijns11040096 - 17 Oct 2025

Abstract

This methodological review identifies challenges in the development of health economic evaluations of newborn bloodspot screening (NBS) interventions and their consideration in NBS policy making. A systematic review of health economics methodological studies in NBS and stakeholder consultation was undertaken. The intervention under [...] Read more.

This methodological review identifies challenges in the development of health economic evaluations of newborn bloodspot screening (NBS) interventions and their consideration in NBS policy making. A systematic review of health economics methodological studies in NBS and stakeholder consultation was undertaken. The intervention under examination was defined as health economic decision analytic modelling used as decision support to NBS policy makers. An iterative search strategy was used to identify studies, and a data extraction framework was based upon a simple decision analytic model structure for the NBS decision problem. Synthesis was facilitated by two stakeholder workshops, which focused on ensuring the complete identification of challenges and developing recommendations. Sixteen methodological studies were identified. Data were extracted on challenges in decision criteria, decision variables, decision problem scope, defining model structure, selecting modelling method, the target condition, the screening test/protocol, outcome nodes, and other categories. Recommendations are made concerning supporting NBS decision making, NBS economic model structure and methods, data and estimation of model parameters, and overarching considerations. Recommendations for decision processes and methods research are put forward for the consideration of NBS policy makers and commissioners of research. Full article

► Show Figures

Figure 1

14 pages, 427 KB

Open AccessArticle

Challenges Faced by Healthcare Professionals in Screening Newborns for Congenital Heart Defects in Pakistan

by Ijaz ul Haq, Muhammad Imran Khan, Amir Muhammad, Majid Ali, Xiaojing Hu and Guo-Ying Huang

Int. J. Neonatal Screen. 2025, 11(4), 95; https://doi.org/10.3390/ijns11040095 - 15 Oct 2025

Abstract

Early and timely screening for congenital heart disease (CHD) is one of the key challenges for healthcare professionals (HPs). This study aimed to identify barriers to the screening of CHD among healthcare professionals in Khyber Pakhtunkhwa, Pakistan. A qualitative cross-sectional study was conducted [...] Read more.

Early and timely screening for congenital heart disease (CHD) is one of the key challenges for healthcare professionals (HPs). This study aimed to identify barriers to the screening of CHD among healthcare professionals in Khyber Pakhtunkhwa, Pakistan. A qualitative cross-sectional study was conducted among HPs working in public and private hospitals, and data were analyzed thematically using NVivo 10.0 software until saturation following Braun and Clarke’s framework. Data were reported according to the Standards for Reporting Qualitative Research (SRQR). Participants reported critical gaps in CHD screening, including scarce resources such as a lack of pulse oximeters and echocardiography machines, inadequate training, and overburdened staff struggling with high patient volumes. Emotional distress was common when diagnosing severe CHDs, compounded by parental reluctance due to low awareness and socioeconomic barriers, including costs and travel distances. Operational inefficiencies, such as inconsistent protocols, weak referral systems, and paper-based record-keeping, further delayed diagnoses. Despite these challenges, HPs emphasized the potential of standardized screening tools, interdisciplinary coordination, and community education to improve detection rates. CHD screening in Pakistan is impeded by resource limitations, systemic fragmentation, and sociocultural factors. Prioritizing equipment procurement, HP training, public awareness campaigns, and policy-mandated screening protocols could enhance early detection. Full article

10 pages, 1084 KB

Open AccessArticle

Next-Generation Sequencing for Cystic Fibrosis: Florida Newborn Screening Experience

by Deanna M. Green, Jean Polasky, Mark Weatherly, Heather Stalker, Colleen Blanchard, Cheryl Kushner, Marisa Couluris, Patricia Ryland, Iruvanti Sunitha, Joseph Fong, Sandra Crump, Emily Reeves and Kristin Barnette

Int. J. Neonatal Screen. 2025, 11(4), 94; https://doi.org/10.3390/ijns11040094 - 14 Oct 2025

Abstract

Cystic fibrosis (CF) is an autosomal recessive genetic condition affecting nearly 1 in 4000 newborns. Early diagnosis and treatment have been shown to improve the care of individuals with CF, which is enhanced through newborn screening (NBS). The state of Florida has been [...] Read more.

Cystic fibrosis (CF) is an autosomal recessive genetic condition affecting nearly 1 in 4000 newborns. Early diagnosis and treatment have been shown to improve the care of individuals with CF, which is enhanced through newborn screening (NBS). The state of Florida has been performing CF NBS since 2007, and in 2022, Florida implemented enhanced next generation sequencing (NGS). The goal of this change was to identify individuals from under-represented racial and ethnic groups, who may have rare or de novo variants. NBS screening for CF involved a first tier with immunoreactive trypsinogen (IRT) ≥ 50 or the top 4% of daily specimens, whichever is lower, reflexing to a second tier. As of 2022, the second tier has evolved to an expanded sequence with an Agena 74-variant panel. Single variants would then reflex to the third tier utilizing NGS. NGS is able to confirm what is detected in second-tier testing, adding variants not included in the Agena panel, and refining the TG replications for Poly-T variants to determine pathogenicity of 5T results. When there is a variant of varying clinical consequence between the two databases, the most conservative classification is selected. Individuals with variants would then be referred to one of the contracted CF NBS referral centers for confirmatory sweat chloride testing (sweat). With implementation of NGS, referrals nearly tripled in 2022–2024, with 538 referrals in 2019; 485 in 2020; and 805 in 2021; followed by 1223 referrals made in 2022; 1146 in 2023; and 1294 in 2024. In 2022–2024, 71% of referrals to the contracted NBS CF referral centers were for single variant results, and no cases of CF were identified from these referrals. The number of CF cases remained about the same, ranging from 23 to 40 through the years 2019–2024. The number of CRMS/CFSPID cases, however, tripled going from 10 to 12 in 2019–2022 to over 100 in 2024. The reason for this change seems to be related to complex heterozygous genetic variants as opposed to abnormal sweat. Implementation of NGS for CF in Florida led to a significant increase in the identification of CFTR variants which affected all aspects of the NBS CF process, from an increased workload on the NBS laboratory and follow-up staff, to an increase in referrals to the NBS CF referral centers. The majority of referrals were for single-variant results, which meant the infants had a very low likelihood of having CF. It is recommended that when an algorithm involving NGS is utilized, one should verify that there are appropriate processes for sweat, including the manner in which single-variant CF results are handled, avoiding unnecessary healthcare utilization. Full article

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

► Show Figures

Figure 1

2 pages, 141 KB

Open AccessEditorial

Congenital Hypothyroidism: Moving Ahead, but a Long Way Still to Go

by Ernest M. Post and Natasha L. Heather

Int. J. Neonatal Screen. 2025, 11(4), 93; https://doi.org/10.3390/ijns11040093 - 13 Oct 2025

Abstract

Newborn screening (NBS) for congenital hypothyroidism (CH) has been going on for more than fifty years, but we are still learning more about the process and the disease(s) [...] Full article

(This article belongs to the Special Issue Newborn Screening for Congenital Hypothyroidism)

17 pages, 335 KB

Open AccessReview

Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions

by Eva Thimm, Anselma Riederer, Jerry Vockley, Dries Dobbelaere, Monique Williams, Anita MacDonald, Katharina Dokoupil, Ulrich A. Schatz and Regina Ensenauer

Int. J. Neonatal Screen. 2025, 11(4), 92; https://doi.org/10.3390/ijns11040092 - 10 Oct 2025

Abstract

Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading to an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids. The clinical presentation is [...] Read more.

Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading to an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids. The clinical presentation is highly variable, ranging from life-threatening metabolic crises with metabolic acidosis and hyperammonemia to a clinically asymptomatic only biochemical phenotype. Newborn screening for IVA has been established in many countries. Treatment consists of a protein-restricted diet combined with supplementation of carnitine and/or glycine and emergency treatment in catabolic episodes. Still, evidence-based recommendations for the diagnosis and management of IVA patients with various phenotypes are lacking. Therefore, a systematic search and review of the literature was conducted to make suggestions for the care of patients with IVA based on both the available scientific evidence and consensus-derived expert conclusions. Based on a comprehensive set of literature data published between 1966 and 2024, 15 statements were phrased on the presentation, diagnosis, management, and outcome of IVA involving clinical, biochemical, and nutrition expertise. These statements can serve as a basis for more standardized care for IVA. Full article

22 pages, 1591 KB

Open AccessArticle

Analytical Validation of a Genomic Newborn Screening Workflow

by Kristine Hovhannesyan, Laura Helou, Benoit Charloteaux, Valerie Jacquemin, Flavia Piazzon, Myriam Mni, Charlotte Flohimont, Corinne Fasquelle, Davood Mashhadizadeh, Tamara Dangouloff, Vincent Bours, Laurent Servais, Leonor Palmeira and François Boemer

Int. J. Neonatal Screen. 2025, 11(4), 91; https://doi.org/10.3390/ijns11040091 - 10 Oct 2025

Abstract

Newborn screening (NBS) has evolved significantly since its inception, yet many treatable rare diseases remain unscreened due to technical limitations. The BabyDetect study used gene panel sequencing to expand NBS to treatable conditions not covered by conventional biochemical screening. We present here the [...] Read more.

Newborn screening (NBS) has evolved significantly since its inception, yet many treatable rare diseases remain unscreened due to technical limitations. The BabyDetect study used gene panel sequencing to expand NBS to treatable conditions not covered by conventional biochemical screening. We present here the analytical validation of this workflow, assessing sensitivity, precision, and reproducibility using dried blood spots from newborns. We implemented strict quality control thresholds for sequencing, coverage, and contamination, ensuring high reliability. Longitudinal monitoring confirmed consistent performance across more than 5900 samples. Automation of DNA extraction improved scalability, and a panel redesign enhanced the coverage and selection of targeted regions. By focusing on known pathogenic/likely pathogenic variants, we minimized false positives and maintained clinical actionability. Our findings demonstrate that gene panel sequencing-based NBS is feasible, accurate, and scalable, addressing critical gaps in current screening programs. Full article

► Show Figures

Figure 1

10 pages, 216 KB

Open AccessArticle

Caregivers’ Emotional Responses Triggered by a False-Positive VLCADD in Newborn Screening in Oita Prefecture

by Sakura Morishima, Yumi Shimada and Kenji Ihara

Int. J. Neonatal Screen. 2025, 11(4), 90; https://doi.org/10.3390/ijns11040090 - 8 Oct 2025

Abstract

Neonatal screening programs for inborn errors of metabolism are essential for early diagnosis and intervention. However, false-positive results can cause unnecessary psychological stress for caregivers. This study investigated the emotional impact on a small number of caregivers in Oita Prefecture in Japan, whose [...] Read more.

Neonatal screening programs for inborn errors of metabolism are essential for early diagnosis and intervention. However, false-positive results can cause unnecessary psychological stress for caregivers. This study investigated the emotional impact on a small number of caregivers in Oita Prefecture in Japan, whose infants received false-positive screening results for very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). Particular attention was given to caregivers’ concerns regarding episodes of transient fasting suggestive of nutritional deficiency, as well as their perspectives on appropriate feeding practices for newborns. Nineteen infants in Oita Prefecture were identified as having elevated acylcarnitines, which were later confirmed as false positives. Of these cases, 11 mothers consented to participate in a survey and long-term growth evaluation using health check records. Thirty children with normal screening results were included as controls. While no differences in physical growth were found between groups by 3.5 years of age, some mothers of false-positive infants reported persistent anxiety. Their concerns included regret for inadequate breastfeeding and latent adverse effects on long-term growth or development. Conversely, caregivers’ anxiety diminished over time as they directly observed their infants’ normal growth and development. No regret was expressed regarding breastfeeding, and concerns about VLDCAD were not observed. Caregivers’ responses may help reduce their psychological burden. Full article

11 pages, 859 KB

Open AccessArticle

Quebec Spinal Muscular Atrophy Newborn Screening Program: The First Year Experience

by Emilie Groulx-Boivin, Ariane Belzile, Cam-Tu Émilie Nguyen, Amélie Gauthier, Nicolas Chrestian, Catherine Michaud-Gosselin, Yves Giguère, Marie-Thérèse Berthier, Jean-François Soucy, Anne-Marie Laberge and Maryam Oskoui

Int. J. Neonatal Screen. 2025, 11(4), 89; https://doi.org/10.3390/ijns11040089 - 5 Oct 2025

Abstract

Clinical trials in spinal muscular atrophy (SMA) have shown that early treatment improves outcomes, prompting inclusion in newborn screening (NBS) programs worldwide. The province of Quebec launched its SMA NBS program in October 2023, with a rapidly progressive implementation. We describe the program’s [...] Read more.

Clinical trials in spinal muscular atrophy (SMA) have shown that early treatment improves outcomes, prompting inclusion in newborn screening (NBS) programs worldwide. The province of Quebec launched its SMA NBS program in October 2023, with a rapidly progressive implementation. We describe the program’s first-year experience, focusing on screening yield, birth prevalence, clinical outcomes, and challenges. In the first year, 6 of 67,933 newborns screened positive for SMA, all subsequently confirmed by diagnostic testing. Of these, 4 newborns (67%) had two SMN2 copies and 2 newborns (33%) had four copies. Additionally, one symptomatic compound heterozygote infant presented during this period, indicating a provincial birth prevalence of 1 in 9705 live births (95% CI: 1:20,032–1:4701). Two newborns with two SMN2 copies were symptomatic at initial consultation; one transitioned to palliative care and died at 43 days of life. Surviving newborns initiated treatment at a median age of 30 days (range: 9–103 days), with four receiving onasemnogene abeparvovec and one nusinersen. Motor outcomes at three or six months were stable or improved among treated infants. Overall, the Quebec SMA NBS pilot program successfully identified affected newborns, facilitated early access to therapy, and provided the first provincial estimate of SMA birth prevalence. Improved sample shipping and processing times are needed to maximize the program’s impact, which is expected with full automation. Full article

► Show Figures

Figure 1

22 pages, 1531 KB

Open AccessCommentary

Reflections on 50 Years of Cystic Fibrosis Newborn Screening Experience with Critical Perspectives, Assessment of Current Status, and Predictions for Future Improvements

by Philip M. Farrell

Int. J. Neonatal Screen. 2025, 11(4), 88; https://doi.org/10.3390/ijns11040088 - 30 Sep 2025

Abstract

The morbidity/mortality risks of cystic fibrosis (CF) with a delayed diagnosis have made newborn screening (NBS) attractive for the past 50 years. Initial efforts focused on meconium analyses, but these proved unsatisfactory. After dried blood spot specimens became valuable for NBS applied to [...] Read more.

The morbidity/mortality risks of cystic fibrosis (CF) with a delayed diagnosis have made newborn screening (NBS) attractive for the past 50 years. Initial efforts focused on meconium analyses, but these proved unsatisfactory. After dried blood spot specimens became valuable for NBS applied to other genetic disorders and immunoassay methods became routine, the discovery of immunoreactive trypsinogen (IRT) led to numerous CF NBS programs around the world. Excellent laboratorians led the way, but CF clinicians rightly questioned the benefit–risk relationship and unanswered questions about IRT. These issues were resolved by the combination of a positive randomized clinical trial and the discovery of the cystic fibrosis transmembrane conductance regulator gene (CFTR) and its principal pathogenic variant, F508del. Recommendations for universal screening and then the proliferation of IRT/DNA screening programs followed. But more knowledge has brought more complexity, including an enigmatic, distracting condition known as cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS) or cystic fibrosis screen positive, inconclusive diagnosis (CFSPID). Recently, with the recognition that CF is not a “white person’s disease,” and that over 1000 CFTR pathogenic variants occur, attention has turned to achieving equity and timeliness for all babies. Continuous quality improvement has characterized the past decade, as greatly expanded CFTR panels in the DNA tier through next-generation sequencing offer promise and raise the prospect of a primary genetic screening test. Full article

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

► Show Figures

Figure 1

15 pages, 2219 KB

Open AccessArticle

Evaluating Georgia’s Cystic Fibrosis Newborn Screening Algorithm to Inform Improvement Recommendations

by Brittany Truitt, Eileen Barr, Angela Wittenauer, Andrew Jergel, Shasha Bai, Rossana Sanchez Russo, Kathryn E. Oliver, Kathleen McKie and Rachel W. Linnemann

Int. J. Neonatal Screen. 2025, 11(4), 87; https://doi.org/10.3390/ijns11040087 - 29 Sep 2025

Abstract

Early diagnosis by newborn screening (NBS) has contributed to improved outcomes in children with cystic fibrosis (CwCF). Georgia’s two-tiered algorithm consists of a fixed immunoreactive trypsinogen (IRT) cut-off followed by a 39-variant CFTR genetic panel. We conducted a retrospective review of CwCF born [...] Read more.

Early diagnosis by newborn screening (NBS) has contributed to improved outcomes in children with cystic fibrosis (CwCF). Georgia’s two-tiered algorithm consists of a fixed immunoreactive trypsinogen (IRT) cut-off followed by a 39-variant CFTR genetic panel. We conducted a retrospective review of CwCF born in Georgia from 2007 to 2022 to evaluate false negative NBS frequency. We characterized CwCF whose diagnosis was delayed beyond 28 days of age despite positive NBS. Six cases were detailed demonstrating the impact of missed and delayed diagnoses. We examined IRT trends from 2018 to 2022 and cut-off approaches. Missed case detection by expanded CFTR variant assays was assessed. Of 390 CwCF born in Georgia, 18 (4.6%) had false negative NBS—6 due to lack of CFTR variant detection and 12 due to low IRT values. Thirty children had delayed diagnosis, with the majority related to sweat testing. Minoritized children made up 19% of the population but 43% of missed and 44% of delayed diagnoses. Black and Hispanic infants had higher odds of missed or delayed diagnosis compared to non-Hispanic White infants (OR = 2.7, p = 0.027 and OR = 6.1, p < 0.001, respectively). Average IRT values varied across kits and were lower in warmer seasons. Expanded CFTR assays would reduce missed cases. Our results informed recommendations for improvement at multiple steps in the NBS process. Full article

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

► Show Figures

Figure 1

19 pages, 632 KB

Open AccessArticle

Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) Newborn Screening in Italy: Five Years’ Experience from a Nationwide Program

by Margherita Ruoppolo, Cristina Cereda, Teresa Giovanniello, Sabrina Malvagia, Sara Boenzi, Francesca Teofoli, on behalf of the SIMMESN Italian Newborn Screening Group and Alberto Burlina

Int. J. Neonatal Screen. 2025, 11(4), 86; https://doi.org/10.3390/ijns11040086 - 26 Sep 2025

Abstract

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of fatty acid oxidation that can have life-threatening consequences if not promptly treated. Early diagnosis by means of newborn screening (NBS) has the potential to reduce morbidity and mortality. This study investigates the [...] Read more.

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of fatty acid oxidation that can have life-threatening consequences if not promptly treated. Early diagnosis by means of newborn screening (NBS) has the potential to reduce morbidity and mortality. This study investigates the incidence and molecular characteristics of MCADD in Italy over a five-year period within the framework of the expanded NBS program. Between January 2019 and December 2023, a total of 1,976,473 newborns were screened. Ninety unrelated neonates were diagnosed with MCADD, providing an estimated incidence of 1/21,960 live births (95% CI: 1:17,780–1:27,200), comparable to rates reported in other Mediterranean populations. Molecular analysis identified c.985A>G (p.Lys329Glu) as the most frequent pathogenic ACADM gene variant, observed in 56 patients (63%), including eighteen patients (20%) who were homozygous and thirty-eight (43%) who were compound heterozygotes for this variant. To our knowledge, this study represents the first comprehensive investigation to document the high prevalence of MCADD among the Italian population. Full article

► Show Figures

Figure 1

14 pages, 3285 KB

Open AccessArticle

CFTR Variant Frequencies and Newborn Screening Panel Performance in the Diverse CF Population Receiving Care in the State of Georgia

by Eileen Barr, Brittany Truitt, Andrew Jergel, Shasha Bai, Kathleen McKie, Rossana Sanchez Russo, Kathryn E. Oliver and Rachel W. Linnemann

Int. J. Neonatal Screen. 2025, 11(4), 85; https://doi.org/10.3390/ijns11040085 - 26 Sep 2025

Abstract

Cystic fibrosis (CF) newborn screening (NBS) aims to improve outcomes through early diagnosis, yet disparities in time to diagnosis remain. This study examines CFTR allele frequencies and variant panel performance among a diverse CF population in Georgia to inform recommendations for updating the [...] Read more.

Cystic fibrosis (CF) newborn screening (NBS) aims to improve outcomes through early diagnosis, yet disparities in time to diagnosis remain. This study examines CFTR allele frequencies and variant panel performance among a diverse CF population in Georgia to inform recommendations for updating the NBS algorithm and improving equity. This cross-sectional study includes 969 people with CF (PwCF) from Georgia’s accredited CF centers. CFTR variant frequencies were calculated according to race and ethnicity. Panel performance was evaluated for Georgia’s current Luminex-39 variant test and three expanded panels. Statistical analyses compared detection rates across panels and demographic groups. Georgia’s diverse CF population demonstrates a unique CFTR allelic variability compared to national data. Increasing panel size enhances case identification. A panel including 719 CF-causing variants from the CFTR2 database significantly improves case detection from 93% to 97% (p = 0.002), as well as two-variant detection from 69% to 86% (p < 0.001). Detection of minoritized PwCF also improves with increasing panel size. However, even using the 719-variant panel, detection of non-Hispanic Black PwCF remains significantly lower compared to non-Hispanic White PwCF (case detection: p = 0.003; two-variant detection: p < 0.001). In conclusion, the use of expanded CFTR panels for NBS in Georgia would enhance timely diagnosis and improve equity. Full article

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

► Show Figures

Figure 1

19 pages, 1554 KB

Open AccessArticle

Newborn Screening of X-Linked Adrenoleukodystrophy in Italy: Clinical and Biochemical Outcomes from a 4-Year Pilot Study

by Eleonora Bonaventura, Fabio Bruschi, Luisella Alberti, Clara Antonello, Filippo Arrigoni, Marina Balestriero, Barbara Borsani, Laura Cappelletti, Elisa Cattaneo, Matilde Ferrario, Giulia Fiore, Maria Iascone, Giana Izzo, Simona Lucchi, Cecilia Parazzini, Michela Perrone Donnorso, Luigina Spaccini, Ylenia Vaia, Pierangelo Veggiotti, Elvira Verduci, Gianvincenzo Zuccotti, Cristina Cereda, Davide Tonduti and XALD-NBS Study Group Show full author list Hide full author list

Int. J. Neonatal Screen. 2025, 11(4), 84; https://doi.org/10.3390/ijns11040084 - 24 Sep 2025

Abstract

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, caused by mutations in the ABCD1 gene. Early diagnosis is critical to manage adrenal insufficiency and cerebral forms of the disease. Since 2021, a pilot newborn screening (NBS) program for X-ALD has been launched [...] Read more.

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, caused by mutations in the ABCD1 gene. Early diagnosis is critical to manage adrenal insufficiency and cerebral forms of the disease. Since 2021, a pilot newborn screening (NBS) program for X-ALD has been launched in Lombardy, Italy. From September 2021 to June 2025, 138,116 newborns (≥37 weeks’ gestational age) were screened for elevated C26:0-lysophosphatidylcholine (C26:0-LPC) levels using a two-tier algorithm. Genetic testing was performed in non-negative cases. Males found to be ABCD1 variant carriers were enrolled in multidisciplinary follow-up, including neurological, endocrinological, and nutritional assessments. Eleven individuals (six males, five females) carried pathogenic or likely pathogenic ABCD1 variants. Three males were diagnosed with adrenal insufficiency and started hydrocortisone therapy between 1 and 2 years of age. Growth parameters were within normal range overall, but two children showed signs of stunting associated with poor dietary compliance. Additionally, three patients were diagnosed with Zellweger spectrum disorders (ZSDs). No patients affected with Aicardi-Goutières Syndrome were identified. Newborn screening for X-ALD in Italy is feasible and enables early detection and intervention. Biochemical markers and genetic analysis are reliable tools for identifying affected males and female carriers. Multidisciplinary management is essential to address medical and psychosocial challenges during follow-up. Full article

► Show Figures

Figure 1

12 pages, 691 KB

Open AccessArticle

Prevalence and Mutation Analysis of Medium-Chain Acyl-CoA Dehydrogenase Deficiency Detected by Newborn Screening in Hefei, China

by Haili Hu, Qingqing Ma, Yong Huang, Wangsheng Song, Hongyu Xu, Peng Zhu and Yan Wang

Int. J. Neonatal Screen. 2025, 11(3), 83; https://doi.org/10.3390/ijns11030083 - 22 Sep 2025

Abstract

Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) is a metabolic disorder caused by mutations in the ACADM gene, leading to impaired fatty acid oxidation. The present study aims to analyze the prevalence and genetic mutation characteristics of MCADD among newborns in Hefei, China, providing insights [...] Read more.

Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) is a metabolic disorder caused by mutations in the ACADM gene, leading to impaired fatty acid oxidation. The present study aims to analyze the prevalence and genetic mutation characteristics of MCADD among newborns in Hefei, China, providing insights for the diagnosis, treatment, and prevention of MCADD. A retrospective analysis was conducted on data from newborns diagnosed with MCADD at the Hefei Newborn Disease Screening Center between January 2016 and December 2024. Screening was performed using tandem mass spectrometry (MS/MS), complemented by next-generation sequencing (NGS) for genetic testing. Out of 880,224 screened newborns, 16 cases of MCADD were diagnosed, resulting in a prevalence of 1 in 55,014. A total of 31 mutation sites in the ACADM gene were identified, with 18 different mutation types. The hotspot mutations were c.449-452del (p.T150Rfs*4) and c.1085G>A (p.G362E), each with a mutation frequency of 16.13% (5 out of 31). Additionally, three novel mutations were identified: c.468+5G>A, c.854C>G, and c.428_431delinsTCTTCTTTTGTT. Following diagnosis, patients received health education, dietary guidance, and symptomatic treatment, all resulting in favorable prognoses without any acute metabolic decompensation events. The prevalence of MCADD is lower in Asia compared to Europe and America. The hotspot mutations for MCADD in Hefei are c.449-452del and c.1085G>A. Diagnosis should integrate results from both octanoylcarnitine (C8) levels and genetic testing. Early screening, diagnosis, treatment, and scientific prevention strategies are essential for reducing adverse outcomes in children with MCADD. Full article

► Show Figures

Figure 1

12 pages, 1335 KB

Open AccessArticle

The Impact of Cystic Fibrosis Algorithm Changes: A Case Study of Challenges and Strategies

by Jerusalem Alleyne, Kenneth Coursey, Kimberly Noble Piper, Cynthia Cass and Michael Pentella

Int. J. Neonatal Screen. 2025, 11(3), 82; https://doi.org/10.3390/ijns11030082 - 19 Sep 2025

Abstract

The State Hygienic Lab at the University of Iowa (SHL) performs newborn blood spot screening (NBS) for IA, AK, ND, and SD. In October 2022, we halted in-house CFTR DNA testing due to the unexpected nonperformance of our newly expanded variant panel. Samples [...] Read more.

The State Hygienic Lab at the University of Iowa (SHL) performs newborn blood spot screening (NBS) for IA, AK, ND, and SD. In October 2022, we halted in-house CFTR DNA testing due to the unexpected nonperformance of our newly expanded variant panel. Samples were sent to a reference laboratory to ensure uninterrupted testing and by December 2022, SHL had selected an alternative test that enabled CFTR panel expansion as envisioned. However, due to circumstances beyond our control, test implementation was severely delayed, and in-house testing was paused. These events were consequential. Firstly, our prolonged utilization of reference labs and fees was a financial strain on the lab. Secondly, our timeliness decreased significantly, and lastly, these issues were burdensome for staff. The lab overcame these problems using three strategies: effective communication; technical expertise; and staff perseverance. Finally, in Aug 2023, SHL successfully resumed in-house testing. As state labs ponder major CFTR algorithm changes, such as the addition of next generation sequencing, the strategies we utilized can be useful during sudden setbacks. Our experience of replacing our CFTR assay underscores the importance of emergency preparedness and partnership within the NBS community. Full article

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

► Show Figures

Figure 1

11 pages, 1333 KB

Open AccessArticle

Early Screening for Developmental Dysplasia of the Hip: Sonographic Reference Values, Risk Factors, and Treatment Considerations

by Bjoern Vogt, Stella S. Tureck, Georg Gosheger, Adrien Frommer, Andrea Laufer, Henning Tretow, Robert Roedl and Gregor Toporowski

Int. J. Neonatal Screen. 2025, 11(3), 81; https://doi.org/10.3390/ijns11030081 - 19 Sep 2025

Abstract

Developmental dysplasia of the hip (DDH) is a common neonatal musculoskeletal disorder. In Germany, sonographic screening is recommended at 1–10 days of life for neonates with specific risk factors. This study aims to determine reference values for early sonographic screening and to evaluate [...] Read more.

Developmental dysplasia of the hip (DDH) is a common neonatal musculoskeletal disorder. In Germany, sonographic screening is recommended at 1–10 days of life for neonates with specific risk factors. This study aims to determine reference values for early sonographic screening and to evaluate associated risk factors. Between 2007 and 2022, 3383 neonates (6766 hips) underwent hip ultrasound according to Graf. Of these, 967 neonates were screened universally (2007–2015) and 1900 based on predefined risk factors (2015–2022). DDH was defined as ≥type IIc, according to Graf. A subgroup of 20 neonates with borderline alpha angles (51–52°) was followed up after 3–6 weeks. The mean alpha angle was 61.2° ± 5.3° (range 50.5–71.9°), and beta angle 70.8° ± 8.6° (range 53.6–88.0°). DDH prevalence was 2.5% in the universal and 3.2% in the risk-based cohort (p = 0.350). Logistic regression revealed associations with abnormal birth presentation (OR = 3.09, p < 0.001) and female sex (OR = 3.77, p < 0.001), not with Cesarean section or familial predisposition. In the follow-up subgroup, all hips showed a sufficient maturation to an alpha angle of 61.0° (range 57–66°). This study provides reference values for early DDH screening and confirms abnormal birth presentation and female sex as relevant risk factors. Full article

► Show Figures

Graphical abstract

4 pages, 149 KB

Open AccessOpinion

Newborn Screening—A Worldwide Endeavour to Protect

by James R. Bonham, Dianne Webster, Amy Gaviglio, Aysha Habib Khan, R. Rodney Howell and Peter C. J. I. Schielen

Int. J. Neonatal Screen. 2025, 11(3), 80; https://doi.org/10.3390/ijns11030080 - 18 Sep 2025

Abstract

For more than 60 years, newborn (or neonatal) screening has flourished through global collaboration, demonstrating that collective action is key to success. This unity proved to be especially vital during the COVID-19 pandemic, when, despite severe disruptions, NBS services were largely preserved, reflecting [...] Read more.

For more than 60 years, newborn (or neonatal) screening has flourished through global collaboration, demonstrating that collective action is key to success. This unity proved to be especially vital during the COVID-19 pandemic, when, despite severe disruptions, NBS services were largely preserved, reflecting the high value placed on early detection and care for vulnerable newborns. Today, the International Society for Neonatal Screening (ISNS) recognises that NBS programmes face increasing challenges due to global instability. While direct assistance is not always possible, ISNS emphasises the strength of the international NBS community—scientists, clinicians, patient groups, and industry partners—who are committed to mutual support and knowledge-sharing. Building on the proud legacy inspired by pioneers like Bob Guthrie, this community is enriched by diverse voices and is unified by a shared vision: to ensure that all children with rare disorders have access to life-saving screening and care. Safeguarding and advancing this foundation is a responsibility owed to future generations. Full article

7 pages, 1699 KB

Open AccessCase Report

The Success of Newborn Screening Beyond War: An International Collaborative Case of Purine Nucleoside Phosphorylase (PNP) Deficiency

by Alessandra Bettiol, Roberta Damiano, Nataliia Mytsyk, Nataliia Samonenko, Gabriella Cericola, Carsten Speckmann, Nataliia Olkhovich, Renzo Guerrini and Giancarlo la Marca

Int. J. Neonatal Screen. 2025, 11(3), 79; https://doi.org/10.3390/ijns11030079 - 16 Sep 2025

Abstract

Ukraine’s healthcare system has shown remarkable resilience in continuing newborn screening (NBS), beyond the challenges of war. Amid the conflict, a Ukrainian newborn screened positive for an extremely rare severe combined immunodeficiency (SCID)–purine nucleoside phosphorylase (PNP) deficiency. Ukraine successfully carried out NBS on [...] Read more.

Ukraine’s healthcare system has shown remarkable resilience in continuing newborn screening (NBS), beyond the challenges of war. Amid the conflict, a Ukrainian newborn screened positive for an extremely rare severe combined immunodeficiency (SCID)–purine nucleoside phosphorylase (PNP) deficiency. Ukraine successfully carried out NBS on a neonatal dried blood spot (DBS) by real-time PCR, which showed remarkably reduced T-cell receptor and kappa-deleting recombination excision circles (TREC/KREC). Retesting was delayed due to communication difficulties with the family. Whole exome sequencing on a new DBS confirmed the diagnosis. The newborn was a candidate for allogeneic hematopoietic stem cell transplantation (HSCT), the only curative treatment. HSCT is a complex procedure still ongoing in Ukraine despite the conflict. However, due to the psychosocial strain, the family sought medical support in Germany, where HSCT was performed successfully at 6 months. As part of a collaborative initiative with Italy, PNP biomarkers were quantified on the same DBSs using tandem mass spectrometry, according to the protocols established for SCID NBS in Tuscany, serving as a proof of concept of its diagnostic performance. This case highlights the importance of sustaining preventive and life-saving healthcare services, and reflects the key role of international partnerships in upholding the right to healthcare in times of crisis. Full article

► Show Figures

Figure 1

Journal Description

International Journal of Neonatal Screening

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI