International Journal of Neonatal Screening最新文献

Newborn screening (NBS), one of the most important public health care prevention programs, aims at the early identification of asymptomatic newborns at increased risk for inherited disorders, facilitating timely intervention to reduce morbidity and mortality. NBS in Hungary is celebrating the 50th anniversary of the nationwide implementation of screening for phenylketonuria and galactosemia, as well as the 40th anniversary of congenital hypothyroidism screening. The present paper reviews the early years, the present situation, and future perspectives for the Hungarian NBS program. Today, screening for 27 disorders (opt-out) plus spinal muscular atrophy (opt-in) is supported by two centralized and well-equipped laboratories in Budapest and Szeged, in-depth laboratory knowledge, a robust follow-up system, and governmental financial support. Since 1975, 3,289 patients have been confirmed with a screened condition from over 5.6 million newborns screened. The 50-year anniversary of the Hungarian NBS program highlights the dedication of both past and current professionals, ongoing advancements in analytical methods and laboratory information management systems, and alignment with international standards. The equitable provision of screening services continues to be prioritized for all newborns nationwide and within the broader Euro-regional context.

This long-term observational study aimed to define the spectrum of genetic variation in a congenital hypothyroidism (CH) cohort and investigate the correlations between specific genotypes and clinical phenotypes, including treatment requirements and outcomes. We analyzed the maintenance dose of L-thyroxine (L-T4) at 6, 12, 18, and 24 months, alongside clinical outcomes after 3 years. Data were collected from the Neonatal Disease Screening Center at our hospital between January 2011 and March 2024. Of 247 patients with confirmed CH, 119 had available genetic testing and complete clinical information. The genetic positivity rate was 56.3% (67/119). DUOX2 was the most frequently mutated gene (28.57%), followed by TPO, TG, and TSHR. Phenotypic correlation analysis revealed that patients with DUOX2 variants had significantly lower initial screening TSH levels and required lower L-T4 maintenance doses at 12 months compared to those with TPO or TSHR variants. Patients with TPO and TSHR variants exhibited more severe clinical phenotypes and a higher prevalence of thyroid enlargement on ultrasound. Notably, no significant differences in biochemical data, L-T4 doses, or clinical outcomes were observed between patients with monoallelic and biallelic DUOX2 variations, or among the negative, monogenic, and oligogenic variation groups. This study establishes a high genetic diagnostic yield for CH in the studied cohort, with DUOX2 as the predominant genetic etiology. The findings demonstrate significant genotype-phenotype correlations, where variations in different genes are associated with distinct biochemical severities and treatment demands. Crucially, the lack of correlation between the number of affected DUOX2 alleles and disease severity highlights the complex genetic and phenotypic heterogeneity of CH. These results provide valuable insights for the precise management and prognostic counseling of patients with CH.

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.

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.

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.

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.

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) [...].

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.

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.

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.