Search Results (84)

Next-generation sequencing (NGS) has transformed the diagnostic landscape for inherited metabolic diseases by enabling high-resolution detection of pathogenic variants across genetically heterogeneous lysosomal pathways. This is particularly impactful for lysosomal diseases (LDs), including the mucolipidoses (ML I–IV), and for disorders involving lysosomal membranes, transporters, and lysosome-related organelles (LROs). These conditions often present with overlapping biochemical and clinical features that historically complicated accurate diagnosis. This review synthesizes current knowledge on the application of next-generation sequencing (NGS) technologies in the detection and interpretation of variants underlying mucolipidoses types I-IV and selected LRO and lysosomal membrane transport disorders. We summarize expanded variant catalogues, genotype–phenotype correlations, and functional evidence informing pathogenicity classification. In addition, we discuss the integration of NGS into newborn screening and population-level genomics. Collectively, these advances have refined disease definitions, resolved diagnostically challenging cases, and reshaped clinical workflows across the LD and LRO disease spectra. Full article

The Saudi Arabia National Newborn Screening (NBS) program is a pillar of public health, offering timely detection of treatable, life-threatening, or disabling conditions in neonates. This comprehensive review critically examines the current laboratory diagnostic practices employed for metabolite analysis within this program. It focuses primarily on biochemical NBS conducted via dried blood spot testing and evaluates the methodologies, technical challenges, and stringent quality assurance measures that underpin successful screening. This review examines the critical role of tandem mass spectrometry, sample integrity protocols, and the establishment of robust cutoff values. Furthermore, this review explores persistent challenges such as false-positive and false-negative results, ethical and logistical hurdles in global implementation, and the transformative potential of recent advancements, including the integration of genomics and high-resolution metabolomics. In addition, this review explores the future of the program, highlighting the transformative potential of high-resolution metabolomics and the integration of genomic sequencing to ensure early diagnosis and intervention. Full article

Neurodegenerative diseases (NDDs) in children represent a heterogeneous group of rare but collectively significant disorders characterized by progressive neurological decline, developmental regression, and substantial morbidity and mortality. Unlike adult-onset neurodegeneration, pediatric conditions are predominantly genetic and frequently arise from defects in fundamental cellular pathways, including lysosomal degradation, mitochondrial oxidative phosphorylation, peroxisomal lipid metabolism, and myelin maintenance. This comprehensive review synthesizes current knowledge regarding the epidemiology, molecular classification, pathophysiology, and emerging therapeutic strategies of major pediatric neurodegenerative disorders. Epidemiological data indicate a “rare-but-many” landscape, where individually uncommon diseases collectively impose a measurable population burden. Mechanistically, disease progression reflects converging processes such as toxic substrate accumulation, impaired autophagy–lysosome flux, mitochondrial bioenergetic failure, oxidative stress, neuroinflammation, and glial dysfunction. Representative groups discussed include lysosomal storage disorders, leukodystrophies, mitochondrial encephalopathies, peroxisomal disorders, and other monogenic neurodegenerative syndromes. Advances in next-generation sequencing, metabolic profiling, and neuroimaging have substantially improved diagnostic accuracy and enabled earlier detection, including through newborn screening programs. Therapeutic paradigms are shifting from primarily supportive care toward mechanism-based interventions, including enzyme replacement therapy, hematopoietic stem cell transplantation, substrate reduction strategies, and gene therapy approaches. Early molecular diagnosis is increasingly recognized as critical for optimizing outcomes, particularly in disorders amenable to presymptomatic intervention. Continued integration of genomic medicine, standardized epidemiologic surveillance, and translational research will be essential to refine disease classification, improve prognostication, and expand access to targeted therapies. Collectively, pediatric neurodegenerative diseases exemplify the intersection of developmental neurobiology and inherited metabolic dysfunction, underscoring the need for multidisciplinary, precision-based clinical strategies. Full article

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

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

Type 1 diabetes (T1D) is an autoimmune disease with a strong genetic component (~70% heritability). Early identification of individuals at risk is crucial for early intervention or risk assessment. Although polygenic risk scores (PRS) have shown promise in risk assessment, most current approaches remain constrained by linear assumptions and limited generalizability. We aimed to develop a neural network-driven classifier using T1D-associated single nucleotide polymorphisms (SNPs). In addition, we explored the inclusion of an entropy-derived feature as a complementary variable, representing the degree of genetic variability within an individual’s genotype profile across the 67 T1D-associated SNPs, to evaluate its potential additive contribution to the model performance. We analyzed genotype data from 11,909 individuals in the UK BioBank (546 T1D cases and 11,363 controls). Sixty-seven well-known SNPs associated with T1D were utilized as inputs to the model, using two distinct allele-encoding strategies. A feed-forward neural network was evaluated under varying case–control ratios through five-fold cross-validation. Performance was assessed using the area under the receiver operating characteristic curve (AUC) on a held-out test set and on an external European cohort as a validation cohort. Across five-fold cross-validation, the best configuration achieved a median AUC of 0.903. On the held-out UK Biobank test set, the model generalized well, with an AUC of 0.8889 (95% CI: 0.8516–0.9262). A probability-based risk framework, constructed using five risk groups (“very low”, “low”, “intermediate”, “high”, and “very high” risk), yielded a negative predictive value (NPV) of 98.9% for the “very low” risk group and a Positive Predicted Value (PPV) of 61.9% with a specificity of 97.3% for the “very high” risk group, assuming a 10% T1D prevalence. External validation in the German Diabetes Study reproduced clear case–control separation; for individuals with recent onset diabetes and glutamic acid decarboxylase antibodies (GADA+) vs. controls, specificity reached 91.9% in the “high” risk group (PPV of 94.3%) and 97.6% in the “very high” risk group (PPV of 95.7%). The proposed neural network reliably predicts T1D genetic risk using a compact SNP panel of 67 SNPs and maintains accuracy in both internal and external European cohorts. Its probabilistic output enables clinically interpretable risk thresholds, while entropy features contributed modestly to performance. These results demonstrate that a neural network-based approach achieves discriminative performance that is comparable to established T1D genetic risk models, while offering flexible probability-based risk stratification and architectural extensibility for future integration of additional features. Full article

To comprehend the current state and future of newborn screening (NBS), it is essential to understand its history. Over the past six decades, this well-established and exemplary population-based screening program has been guided by screening principles dating back more than half a century. Advances in laboratory and point-of-care testing, diagnostic methods, and a surge of available treatments and even cures have made it challenging to balance screening criteria that have not kept pace with the current landscape. The availability to screen as well as the demand from parents and stakeholders to screen for more and increasingly complex conditions while limiting the retention of NBS specimens and genetic material has been both exciting and challenging. This paper shares the history of NBS in the United States, followed by the development and integration of genomic sequencing as a complement to current practice. It explores evidence supporting the concomitant use of biomarker- and DNA-sequencing-based approaches for NBS, how disorders are selected for inclusion, and available treatments, and offers recommendations regarding what to consider and how to proceed in this ever-changing NBS landscape. Full article

In recent years, the development of new diagnostic technologies, such as tandem mass spectrometry (MS/MS) and next-generation sequencing (NGS), has caused a veritable revolution in the diagnosis of genetic diseases, reducing time, cost, and invasiveness associated with prior diagnostic techniques. While MS/MS laid the foundation for the development of numerous, usually institutionally based, neonatal screening programs, NGS has gained traction in newborn screening (NBS), primarily through pilot projects and private funding across different countries. As a result, the traditional Wilson and Jungner criteria have been supplemented by additional criteria, including considerations of equity and access, in response to emerging technologies. This review aims to provide an up-to-date overview of the global landscape of metabolic screening panels, highlight the major ongoing genomic screening projects, and outline the current models for integrating these two screening systems. Substantial differences exist across countries in the numbers and types of diseases included in national NBS programmes. In this context, Italy represents a prominent case, as its neonatal screening framework has seen significant expansion and development in recent years, reaching a particularly comprehensive metabolic screening panel. Nonetheless, a number of initiatives to incorporate genomic technologies into the NBS pathway are currently underway, primarily involving high-income countries. Nonetheless, unlike metabolomic-based NBS programs, no country has a government-mandated NGS program as first-tier testing for newborns. New evidence is emerging from ongoing models of integration of multi-omics approaches into NBS, including the use of AI and machine learning. Identifying the most appropriate system for this integration to reduce the false-positive and false-negative rates associated with both screening types, ensure more equitable access to screening, and facilitate faster access to treatment may represent a useful and foresightful way to conceptualize NBS in the future. This transitional phase should promote rigorous improvements before full-scale adoption. Full article

Background and Clinical Significance: Prader–Willi syndrome (PWS) is an imprinting disorder not typically associated with severe congenital sensorineural hearing loss (SNHL). When profound SNHL is present in an infant with a known syndrome, an independent monogenic etiology should be considered. We report the first molecularly confirmed case of PWS co-occurring with biallelic pathogenic TMC1 variants causing congenital SNHL, outlining diagnostic challenges, cochlear implant (CI) outcomes, and implications for blended phenotypes. Case Presentation: A male infant with PWS due to a paternal 15q11.2–q13 deletion failed newborn hearing screening. Diagnostic auditory brainstem response and auditory steady-state response confirmed bilateral severe-to-profound SNHL. Temporal bone CT/MRI were normal. Comprehensive genetic testing identified compound heterozygous TMC1 variants consistent with autosomal recessive DFNB7/11 hearing loss, plus two variants of uncertain significance in SERPINB6 and EPS8L2. Sequential bilateral cochlear implantation was performed (left ear at 14 months, right at 20 months), followed by auditory–verbal therapy. Over four years, the child showed steady improvements in hearing and early-speech development. Conclusions: Early genomic evaluation is essential when clinical features appear atypical for a known syndrome. Identifying TMC1-related deafness enabled timely cochlear implantation and measurable gains. This case highlights that severe congenital SNHL in a syndromic infant may reflect a distinct monogenic disorder rather than phenotypic expansion of the primary syndrome, emphasizing the importance of recognizing blended phenotypes to guide precision-care strategies in rare disorders. Full article

Background: Advances in genomic technologies combined with tandem mass newborn screening have enabled early detection and management of several common inborn errors of metabolism. Fructose-1,6-bisphosphatase deficiency, an autosomal recessive treatable disorder reported in around 150 patients worldwide, remains underdiagnosed despite an excellent prognosis with early detection. Although common in highly consanguineous populations, diagnosis is often delayed due to the non-specific clinical and biochemical profile. Methods: This report explores the diagnostic pathway using first-tier next-generation sequencing of three novel cases of fructose-1,6-bisphosphatase deficiency in a tertiary care center in Lebanon. Results: Two patients were diagnosed with first-tier exome sequencing within one month of presentation and had an excellent outcome at 6 years of follow-up. The third patient, undiagnosed for 10 years, suffered from neurological sequalae. The molecular profile was remarkable in two patients for exon 2 deletion in the FBP1 gene, a founder mutation reported in Turkish and Armenian patients, and a rare frameshift mutation in the third case. Conclusions: The use of next-generation sequencing as as a first-tier test for FBP deficiency is a non-invasive and rapid method for early diagnosis and management of this rare yet treatable disorder. It can detect both disease-causing variants and large deletions, founder mutations as well, delineating the molecular profile in populations where this disorder is highly prevalent. Full article

Newborn screening (NBS) is evolving as novel technologies offer the opportunities to include a broader range of treatable disorders in its programs. Multiplexable, high-throughput DNA-based technologies such as next-generation sequencing (NGS) are being explored to improve and expand disease detection, although several issues have been raised with its use. This scoping review aimed to identify multiplexable, high-throughput, DNA-based technologies that were used for screening or confirmatory testing of newborn disorders in published studies. Available evidence on the appropriateness of technologies in the NBS context was extracted. A literature search (Medline, Embase, and Web of Science) was performed from inception up to April 2024 in collaboration with a medical information specialist. After selection, 26 journal articles were included that used these technologies for either screening (n = 12) or confirmatory testing (n = 14). Five technologies were identified: whole-genome sequencing, whole-exome sequencing, targeted gene sequencing (TGS), quantitative polymerase chain reaction, and MassARRAY. The majority used TGS (n = 19, 73.08%). The data extracted concern mainly technical aspects, and these suggest that a combined approach, i.e., testing via NGS plus a biochemical test, in parallel or reflex, emerges as the optimal option. Ethical and economic evidence is limited and rarely reported in the reviewed articles. Full article

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

The expanded newborn screening (NBS) program in the Russian Federation, launched in 2023, includes the detection of severe forms of T- and B-cell immunodeficiencies via TREC/KREC quantification. We report a rare case of a male infant having multiple congenital anomalies and lymphopenia identified through this program. Genetic testing revealed a 25.8 Mb terminal deletion spanning 13q31.2–qter, consistent with 13q deletion syndrome. Initial NBS revealed reduced TREC levels, prompting further evaluation. The patient exhibited a complex phenotype, including central nervous system malformation (alobar holoprosencephaly), severe congenital heart disease, renal hypoplasia, limb and genitourinary anomalies, and facial dysmorphism. Postnatal complications included pneumonia, pleuritis, and chylothorax. Flow cytometry demonstrated mild T- and B-cell lymphopenia. The genomic defect was characterized using long-read third-generation sequencing, enabling precise breakpoint identification and accurate mapping of deleted genes. The deletion was confirmed via subtelomeric FISH analysis. The patient died at 7 months of age due to the progression of underlying congenital anomalies and associated complications. Our findings broaden the clinical characterization of distal 13q deletion syndrome and demonstrate the value of long-read sequencing in structural chromosomal analysis. They further highlight the difficulties of caring for neonates having complex malformations and immune dysfunction. Given the potential for both primary and secondary immune disturbances, comprehensive immunological evaluation should be considered in patients having 13q deletion syndrome to improve diagnostic accuracy and inform appropriate clinical management. Full article

Due to rapid technical advancements and increasing cost-effectiveness, the potential application of next-generation sequencing (NGS) in newborn screening (NBS) has raised great interest worldwide. Genomic NBS offers the possibility to improve current NBS programs when applied as follow-up tier, and, as first-tier, allows for inclusion of conditions lacking a detectable biomarker for conventional NBS. Obtaining enough high-quality DNA from typically limited dried blood spot (DBS) material to meet NGS requirements can be challenging. Selecting a DNA isolation method for genomic NBS requires balancing technical performance and laboratory feasibility with optimal cost-effectiveness. Ten DNA isolation protocols, including two column-based, five lysis-based, and three semi-automated magnetic bead-based protocols, were evaluated on technical outcomes and performance in targeted amplicon sequencing. Additionally, estimated costs, hands-on time, turnaround time, scalability, and plastic footprint were assessed. Although technical outcomes, including yield, purity, and molecular weight, differed between methods, qualitative results in amplicon sequencing, as defined by read output, mapping, and coverage depth, were found sufficient and comparable for various protocols. In conclusion, both technical requirements and operational parameters are crucial when selecting a DNA isolation protocol and will depend on the NGS application as well as the NBS approach, as either first-tier or follow-up tier. Full article