International Journal of Neonatal Screening最新文献

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.