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At least 19 recordsLinked to original sources
PubMed2025

Assessment of the variant prioritization strategy for genomic newborn screening in the Generation Study.

PURPOSE: Genomic sequencing offers the opportunity to screen for hundreds of rare genetic conditions. To minimize potential negative impact on families and clinical services, it is crucial to reduce false-positive results while prioritizing clinical utility. We present an automated variant prioritization approach in the Generation Study, a research study investigating genomic sequencing in 100,000 newborns in England. Prioritized variants will subsequently undergo manual review by a registered clinical scientist and a specialist clinician before being reported back to parents. METHODS: We assessed specificity of our automated variant prioritization approach in 34,410 samples not enriched for rare diseases and sensitivity in 546 samples from patients with diagnostic variants in genes relevant to newborn screening. We used coverage and copy-number variants callability metrics to evaluate variant detection. RESULTS: We estimated that 3% to 5% of samples will have prioritized variants that require manual review and that <1% of cases will have reportable variants requiring further confirmation of the condition. Sensitivity in genes included in the Generation Study was estimated to be approximately 80%. Gene-level specificity results led to changes in variant prioritization rules and conditions that are included. CONCLUSION: Gene-specific assessment of variant prioritization is crucial to establish analytical validity prior to inclusion in genomic newborn screening.

Humans↗
PubMed2026

The costs of genomic newborn screening in England: A micro-costing analysis from the Generation Study.

PURPOSE: This study estimates the total cost per newborn of delivering genomic newborn screening (gNBS) within the Genomics England-led Generation Study. METHODS: A time-driven activity-based costing approach was used to estimate gNBS costs from recruitment to confirmatory testing. Resource use data were obtained through document review, semi-structured interviews with study staff, and direct observation across six English National Health Service Trusts. Inputs were categorized as labor, consumables, or equipment, with unit costs sourced from published pay scales, catalogs, or literature. Equipment costs were annualized at a discount rate of 3.5%. All costs were estimated in 2025 Great British Pounds (&#xa3;) from the healthcare providers perspective, including overheads and data storage. A one-way deterministic sensitivity analysis was conducted, varying key cost parameters (&#xb1;20%) and testing alternative delivery scenarios. RESULTS: gNBS costs &#xa3;1208 per newborn, with sequencing comprising 58% of the total costs, mainly consumables. The cost was reduced by 20% to &#xa3;963 when excluding research-specific recruitment and consent activities to reflect the delivery of gNBS as part of routine clinical care. CONCLUSION: This study provides an estimate of gNBS costs, highlighting sequencing as the main cost driver. Combined with evidence on outcomes and health care utilization, these findings will inform future cost-effectiveness analyses, supporting policy decisions regarding national implementation in England.

Neonatal Screening↗
PubMed2024

Estimating the sensitivity of genomic newborn screening for treatable inherited metabolic disorders.

PURPOSE: Over 30 research groups and companies are exploring newborn screening using genomic sequencing (NBSeq), but the sensitivity of this approach is not well understood. METHODS: We identified individuals with treatable inherited metabolic disorders (IMDs) and ascertained the proportion whose DNA analysis revealed explanatory deleterious variants (EDVs). We examined variables associated with EDV detection and estimated the sensitivity of DNA-first NBSeq. We further predicted the annual rate of true-positive and false-negative NBSeq results in the United States for several conditions on the Recommended Uniform Screening Panel. RESULTS: We identified 635 individuals with 80 unique IMDs. In univariate analyses, Black race (OR&#xa0;= 0.37, 95% CI: 0.16-0.89, P&#xa0;= .02) and public insurance (OR&#xa0;= 0.60, 95% CI: 0.39-0.91, P&#xa0;= .02) were less likely to be associated with finding EDVs. Had all individuals been screened with NBSeq, the sensitivity would have been 80.3%. We estimated that between 0 and 649.9 cases of Recommended Uniform Screening Panel IMDs would be missed annually by NBSeq in the United States. CONCLUSION: The overall sensitivity of NBSeq for treatable IMDs is estimated at 80.3%. That sensitivity will likely be lower for Black infants and those who are on public insurance.

Humans↗
PubMed2025

Data-driven consideration of genetic disorders for global genomic newborn screening programs.

PURPOSE: Over 30 international studies are exploring newborn sequencing (NBSeq) to expand the range of genetic disorders included in newborn screening. Substantial variability in gene selection across programs exists, highlighting the need for a systematic approach to prioritize genes. METHODS: We assembled a data set comprising 25 characteristics about each of the 4390 genes included in 27 NBSeq programs. We used regression analysis to identify several predictors of inclusion and developed a machine learning model to rank genes for public health consideration. RESULTS: Among 27 NBSeq programs, the number of genes analyzed ranged from 134 to 4299, with only 74 (1.7%) genes included by over 80% of programs. The most significant associations with gene inclusion across programs were presence on the US Recommended Uniform Screening Panel (inclusion increase of 74.7%, CI: 71.0%-78.4%), robust evidence on the natural history (29.5%, CI: 24.6%-34.4%), and treatment efficacy (17.0%, CI: 12.3%-21.7%) of the associated genetic disease. A boosted trees machine learning model using 13 predictors achieved high accuracy in predicting gene inclusion across programs (area under the curve = 0.915, R2 = 84%). CONCLUSION: The machine learning model developed here provides a ranked list of genes that can adapt to emerging evidence and regional needs, enabling more consistent and informed gene selection in NBSeq initiatives.

Humans↗
PubMed2025

The acceptability of blood spot screening and genome sequencing in newborn screening: a systematic review examining evidence and frameworks.

BACKGROUND: Population-wide newborn blood spot screening programmes are a successful public health intervention used to detect whether the baby is at risk of certain rare conditions, with the aim of earlier diagnosis and provision of optimal care and treatment. Evaluating candidate conditions to include in newborn blood spot and genetic sequencing raises questions regarding acceptability to parents/carers. METHODS: In the context of the possible expansion of the newborn blood spot screening programme in the United Kingdom, this review aimed to systematically review research on the acceptability to parents of newborn blood spot screening and genetic sequencing. A protocol was developed prior to commencing the review and was registered on the PROSPERO database. A team of researchers carried out the review, with checking at all stages carried out by at least two individuals. We included research published after 2013 with participants who were pregnant or a recent parent of a newborn and were resident in a high-income country. We included quantitative and qualitative studies that investigated the acceptability to parents/carers of newborn blood spot screening or genetic sequencing. Quantitative studies were narratively synthesised, and theories/frameworks identified and evaluated. Qualitative studies were analysed for recurring themes, and a meta-synthesis was carried out to compare and contrast these two types of data. We quality appraised included articles using tools appropriate for their study design. RESULTS: Searches were carried out in September to November 2023 and screening identified 25 relevant research articles. Just over half were from North America, with four existing reviews and nine qualitative studies. Domains of acceptability described in the literature were: support for screening; level of anxiety, information and knowledge; consent; views of the procedure; and support after screening. The research indicated consensus support for blood spot screening, and for expanding to some other conditions, although some parental anxiety was reported. Parents/carers mostly perceived that they had received sufficient information, but the timing of this could be improved. While parents indicated interest in genomic screening, studies highlighted the need for clearer consent procedures and greater support for parents following genomic screening than for blood spot screening. Only three included studies reported using any kind of theoretical framework. DISCUSSION: Most parents/carers found newborn blood spot screening programmes to be acceptable and favoured their large-scale implementation. A minority of parents/carers expressed concerns regarding the acceptability of processes underpinning newborn blood spot screening, such as consent, the timing of receiving information and support available after testing. More research is needed regarding the acceptability of newborn genomic sequencing screening programmes, which are less established compared with newborn blood spot screening programmes. LIMITATIONS: The over-representation of studies conducted in the United States has implications for the applicability of findings to other countries where testing is not typically mandatory and health systems differ considerably. Most studies were of cross-sectional design and there was limited representation of people from lower incomes and non-white ethnicity. While the inclusion of studies only in populations of future or very recent parents provided coherence to the findings, unclear reporting of participants may have resulted in under- or overinclusion of some studies. FUNDING: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR159927.

ACCEPTABILITY↗
PubMed2026

Parental Perspectives and Experiences with Genetic Testing and Surveillance for Cancer Predisposition in Healthy Young Children.

OBJECTIVES: To evaluate parental experiences following diagnosis of a cancer predisposition syndrome (CPS) in childhood and to assess parental perspectives on population-based genomic newborn screening (gNBS) for CPS. STUDY DESIGN: Participants were guardians of children diagnosed with a CPS by age 8, for whom cancer surveillance was recommended, and who had no history of cancer before the CPS diagnosis. Participants completed a demographic survey, genetic knowledge assessment, and a semistructured qualitative interview. Thematic analysis was performed on interview transcripts. Clinical data were abstracted from medical records. RESULTS: We enrolled 25 parents of children with 7 different CPS, including Li-Fraumeni syndrome (43%), familial adenomatous polyposis (14%), nevoid basal cell carcinoma syndrome (11%), and Beckwith-Wiedemann syndrome (11%). Parents characterized receiving a CPS diagnosis as emotionally challenging but also felt empowered by engagement in proactive cancer surveillance. They identified logistical, emotional, physical, and financial burdens of surveillance; however, most perceived that these burdens were outweighed by the medical and emotional advantages. The majority endorsed implementation of gNBS for pediatric cancer risk. CONCLUSIONS: Parents of presymptomatic children with a CPS experience both psychological distress and benefits following a genetic diagnosis. Despite the burdens of surveillance, parents express support for early genomic identification of cancer risk. These findings have implications for the care of children with CPS and inform implementation of population-based gNBS for CPS.

Humans↗
PubMed2026

Emerging Therapies for Angelman Syndrome.

Angelman syndrome (AS) is a complex neurogenetic disorder characterized by severe global developmental delay, motor dysfunction, and epilepsy, primarily resulting from the lack of functional ubiquitin protein ligase E3A (UBE3A) protein expression in neurons. While current management remains largely symptomatic, the therapeutic landscape for AS is rapidly evolving. Emerging strategies aim to restore UBE3A function through upstream interventions, such as gene replacement therapy or unsilencing of the imprinted paternal allele, which is present but transcriptionally silenced in neurons due to genomic imprinting. This imprinting is mediated by the distal portion of a long non-coding RNA known as the UBE3A-antisense transcript (UBE3A-ATS). This UBE3A-ATS has become a key therapeutic target, with several approaches developed to unsilence the paternal allele, including antisense oligonucleotides (ASOs), CRISPR-based editing, synthetic microRNA, and other modalities. To date, three ASO programs have demonstrated promising signals in early clinical development, with reported improvements in clinical outcomes and electroencephalography (EEG) biomarkers. Given the potential for improved outcomes with early intervention, the inclusion of AS in broader genomic newborn screening programs is currently being explored. An early-intervention approach, or combination of approaches, holds significant promise for transforming the lives of individuals affected by AS with outcomes dependent on their age or genotype.

Humans↗
PubMed2026

Newborn Screening: Equity for Aboriginal and Torres Strait Islander Families in the Context of Emerging Genomics.

Australia's newborn bloodspot screening (NBS) program is offered to every newborn. It screens for 34 rare conditions with the potential for hundreds more to be added using genomics. Despite NBS being available in Australia since the 1960s, there is a lack of evidence regarding the participation and experiences of Aboriginal and Torres Strait Islander peoples in NBS. As Australia considers a future where genomics might be used in NBS, there is a critical window of opportunity to understand and prioritise the perspectives, hopes and fears of Aboriginal and Torres Strait Islander peoples regarding the utility of genomics in NBS.

Humans↗
PubMed2025

Genetic Newborn Screening for Retinoblastoma: A Belgian Initiative Baby Detect.

Baby Detect Project, started in September 2022, aimed to create a newborn screening test using targeted next-generation sequencing for all early-onset, treatable, and serious conditions. The elaborated gene panel covers 405 genes, associated with 165 genetic conditions, and includes RB1, linked to retinoblastoma, the only oncological disease tested for. Germline RB1 mutations concern around 50% of all retinoblastoma cases and 100% of the most severe, bilateral cases. Ninety percent of them occur de novo, which delays the diagnosis by about a year with subsequent loss of vision and sometimes the eye itself. Detecting children with germline RB1 mutation at birth would greatly improve functional and anatomic outcomes, limiting invasive treatments and general anesthesias through early childhood. We discuss herein the novel approach of population screening, the rationale for newborn testing for RB1 mutations, the incidence of expected cases, the reliability of the test and its costs. The next step is to move to a nation-scale population; this initiative marks a landmark in retinoblastoma patients' care.

Humans↗
PubMed2025

Operationalizing the Wilson-Jungner principles for the genomics era: Consensus recommendations from the International Consortium on Newborn Sequencing.

PURPOSE: For decades, the selection of disorders included in newborn screening (NBS) programs has been guided by principles published by Wilson and Jungner in 1968. As research explores the expansion of conditions included in NBS through genomic sequencing, there is a critical need for updated recommendations to address the opportunities and complexities of genomic data. METHODS: The International Consortium on Newborn Sequencing includes leaders from over 16 research projects investigating genomic NBS across the United Kingdom, Europe, United States, and Oceania. Consortium members were invited to participate in a modified Delphi study, aggregating opinion on the selection of conditions for genomic NBS through 3 rounds of online questionnaires, with feedback provided to participants between rounds. RESULTS: In round 1, 94 participants completed the questionnaire, and 10 of 43 statements reached consensus. In round 2, 81 participants completed the questionnaire, and 14 of 27 statements reached consensus. In round 3, 68 participants completed the questionnaire, and all 10 statements reached 72% or more consensus. CONCLUSION: The 10 consensus recommendations developed in this study can guide future research and public health programs performing genomic NBS. This process also identified key areas of participant discordance, highlighting important topics for future research.

Humans↗
PubMed2025

Primary Care Provider Perspectives on Expanded Genomic Screening in Children.

OBJECTIVES: Expanding pediatric genomic screening beyond current newborn screening presents both opportunities and challenges to primary care providers. We are developing a novel paradigm called Age-Based Genomic Screening (ABGS), which will incorporate targeted genomic sequencing for select, highly actionable genetic conditions into routine care at relevant time-points throughout childhood. We surveyed pediatric primary care providers in North Carolina to identify potential ABGS implementation determinants and strategies to address them. STUDY DESIGN: We disseminated an electronic survey to family medicine and pediatric primary care clinicians. Survey items were modeled on constructs previously identified as important to genomic medicine and assessed perceived utility, benefits, barriers, and facilitators of implementing targeted genomic screening in pediatric primary care. Data were analyzed using descriptive statistics and content analysis, as appropriate. RESULTS: A total of 93 individuals completed the survey. Over 85% of respondents agreed that genomic screening was important and impactful in their patient care but about 30% lacked confidence in their ability to implement it in their practice. The most cited benefits of the ABGS program were related to readiness for implementation and the evidence, strength, and quality of the intervention. The most concerning barriers included cost for patients and available resources, with 87% and 75% of respondents having extreme or moderate concern for these barriers, respectively. CONCLUSIONS: Our findings have implications both for the design of the ABGS pilot program and directions for future research in genomic implementation. In particular, the blueprint for the pilot program must include specific plans for ensuring primary care providers have the time and resources available for shared decision making with their patients about engaging in genomic screening.

Journal Article↗
PubMed2026

Next-generation newborn screening: feasibility of combined genetic and biochemical testing for 95 treatable inherited metabolic disorders.

INTRODUCTION: Next-generation sequencing (NGS) is gaining attention in newborn screening (NBS) for its ability to detect treatable genetic disorders, especially those without a biochemical footprint. However, NGS-NBS requires interpreting variants without phenotype information or family trio analysis. Biochemical tests, preferably in dried blood spots (DBS), are therefore useful to confirm the pathogenicity of variants identified by NGS-NBS and increase its specificity and sensitivity. OBJECTIVES: We aimed to explore the potential of combined genetic-biochemical testing for 95 treatable Inherited Metabolic Disorders (IMD) considered eligible for NGS-NBS (100 genes) previously identified by our research group. METHODS: We reviewed the Collaborative Laboratory Integrated Reports (CLIR) and carried out systematic literature reviews in PubMed and Embase to identify biochemical tests for 95 IMD. Biochemical tests conducted on DBS were differentiated from tests that require referral. RESULTS: We identified DBS-biochemical tests for 72 of the 95 IMD (77/100 genes). DBS-based biochemical tests for 55 IMD (60 genes) are already implemented in NBS. For the other 23 IMD, biochemical tests in non-DBS specimens are reported, although some are less sensitive when measured at neonatal age in presymptomatic infants. CONCLUSION: We present a comprehensive overview of current biochemical tests for 95 IMD. These tests can be used to confirm inconclusive NGS-NBS results, and combined genetic-biochemical testing is expected to improve both the negative and positive predictive values of NBS programs.

Humans↗
PubMed2026

Inference of elevated mutation rates and variant effects using 700k exomes.

Genomic sequencing is now widely accessible for genetic diagnostics and is emerging as a component of newborn screening. This technological development generates the need to characterize incoming mutations, create comprehensive datasets of genes causing rare Mendelian disorders, and identify pathogenic variants. Large-scale exome sequencing datasets such as Genome Aggregation Database (gnomAD) have been assembled to help address these challenges. The recent release of gnomAD (v4; n = 730,947) uncovers millions of rare coding variants, many of which have arisen more than once by independent recurrent mutations in the rapidly growing recent human population. Here, we use newly developed theoretical understanding of sampling properties of rare variants to estimate key population genetics parameters of practical importance to human genetics such as demography history, mutation rate, and selection. Solely relying on population data, our method Population Inferred Estimates of Selection (PIES) identifies novel genes with loss-of-function mutational hotspots likely due to selection in spermatogonia. PIES efficiently estimates selection coefficients for heterozygous loss-of-function variants. Combining population genetics inference with variant effect predictors, PIES predicts pathogenic missense mutations and improves variant prioritization for genetic diagnostics and newborn screening.

Journal Article↗
PubMed2026

Characterization of a Novel BTD Hypomorphic Variant in a Patient with Complex Neurodevelopmental Delay: Resolving Actionable Metabolic Vulnerabilities Beyond Borderline Plasma Biochemistry.

Plasma biochemistry often presents significant limitations in diagnosing borderline metabolic disorders, particularly within complex neurodevelopmental phenotypes. Here, we present the clinical genomic evaluation of a six-year patient presenting with early-onset hypotonia and severe gastrointestinal complications whose newborn screening panel did not evaluate biotinidase (BTD) activity. While initial baseline plasma biochemistry yielded borderline residual BTD function (46% of the population mean), targeted sequencing identified a novel, compound heterozygous hypomorphic variant (p.Thr459Met) in trans with the common p.Asp424His allele. In vitro functional validation confirmed that p.Thr459Met induces severe protein misfolding and intracellular retention, impairing enzyme secretion. Biotin supplementation triggered a documented and favorable therapeutic improvement, establishing this borderline enzymatic background as an actionable metabolic vulnerability unmasked by chronic gastrointestinal stressors. This study underscores the critical value of functional genomic characterization over static enzymatic biomarkers to identify highly treatable metabolic components within heterogeneous clinical landscapes.

Humans↗
PubMed2026

An Update on Inborn Errors of V(D)J Recombination.

V(D)J recombination is the fundamental process by which developing T and B lymphocytes generate diverse antigen receptors, enabling adaptive immunity. This tightly regulated program operates exclusively in lymphoid precursors during G1 phase and depends on the lymphocyte-specific RAG1-RAG2 recombinase to introduce programmed DNA double-strand breaks at recombination signal sequences, followed by repair through the classical nonhomologous end joining (c-NHEJ) pathway. Disruption of any step in this molecular choreography compromises antigen receptor diversity and underlies a spectrum of inborn errors of immunity (IEIs), ranging from severe combined immunodeficiency (SCID) to immune dysregulation with autoimmunity and granulomatous disease. In this review, we place disorders of V(D)J recombination within the broader framework of T-cell development, detailing the temporal waves of recombinase activity, chromatin accessibility, and DNA damage responses that guide thymocyte differentiation. We discuss pathogenic variants affecting the cleavage phase [RAG1, RAG2, and the recently identified RAG cochaperone NudC domain-containing 3 (NUDCD3)], end processing (ARTEMIS), ligation and repair (LIG4, XLF, XRCC4, PRKDC), and genome surveillance pathways (ATM, MRN complex, RNF168), highlighting genotype-phenotype correlations and mechanisms driving immune deficiency and dysregulation. We briefly review recent diagnostic advances, including newborn screening using T-cell receptor excision circles, repertoire sequencing, and functional assays, alongside current therapeutic strategies. Finally, we outline key unanswered questions and argue that continued integration of clinical observation with molecular discovery is essential to improve outcomes and deepen understanding of adaptive immune development.

Humans↗