Journal of Medical Genetics最新文献

{"title":"Targeting autophagy in Duchenne muscular dystrophy: mechanistic insights and emerging therapeutic strategies.","authors":"Lakshmi Krishna, Ananyashree Srivathsa, Rhea Anand, Anagha Rao, Medha Karnik, Prashant Vishwanath, Chandan Dharmashekar, Yogish Kumar Honnavalli, Akila Prashant","doi":"10.1136/jmg-2025-111261","DOIUrl":"10.1136/jmg-2025-111261","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is a severe X-linked myopathy characterised by progressive skeletal and cardiac muscle degeneration, loss of ambulation, respiratory failure and premature mortality. Although corticosteroids and gene therapies have improved disease management, they are limited by significant side effects, mutation specificity and delivery challenges, underscoring the need for an alternative or an adjunctive strategy. Emerging evidence identifies autophagy dysregulation as a critical secondary pathological mechanism in DMD, contributing to impaired clearance of damaged organelles and toxic protein aggregates, exacerbating muscle atrophy and fibrosis.This review aims to acknowledge current insights into autophagy regulation in healthy muscle and its disruption in DMD, explore its crosstalk with key pathological pathways such as nuclear factor kappa B signalling, mitochondrial dysfunction and endoplasmic reticulum stress and critically evaluate emerging therapeutic strategies targeting autophagy.Autophagy, a fundamental cellular recycling process, is suppressed in DMD by hyperactivation of the Akt-mTOR pathway and dysregulated calcium homeostasis. This leads to mitochondrial dysfunction, oxidative stress and activation of inflammatory cascades. Recent preclinical studies highlight the therapeutic potential of pharmacological and dietary autophagy modulators, including rapamycin, 5-aminoimidazole-4-carboxamide ribonucleotide, low protein diets, SRT2104 and Givinostat, which improve autophagic flux, restore mitochondrial integrity and attenuate fibrosis. Lifestyle interventions and combinatorial approaches further underscore the importance of integrating multimodal strategies.Further research should focus on longitudinal studies to optimise therapeutic timing, validate dynamic biomarkers (LC-II, p62, miRNAs) and leverage artificial intelligence with multiomics integration for precision therapies. Targeting autophagy and its interconnected pathways holds promise for transforming DMD management and improving patient outcomes.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"205-215"},"PeriodicalIF":3.4,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13018805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145863123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel in-frame variant in DES (p.Glu353dup) causes myofibrillar myopathy: clinical, in silico and functional studies.","authors":"Sheila Lucia Castañeda, Guadalupe Amin, Maria Ines Freiberger, Federico Zabalegui, Sol Renes, Agata Fernandez, Alberto Luis Rosa, Claudia Cejas, Jose Manuel Pastor Rueda, Ariel Waisman, Diego Ferreiro, Gustavo Sevlever, Santiago Miriuka, Lucia Natalia Moro","doi":"10.1136/jmg-2025-110852","DOIUrl":"10.1136/jmg-2025-110852","url":null,"abstract":"<p><strong>Background: </strong>Desmin (DES) is a major intermediate filament protein involved in the structural integrity and function of striated muscles. Pathogenic mutations in DES are predominantly missense variants, causing isolated cardiomyopathy and combinations of myopathy and cardiomyopathy. In-frame insertions are very rare and usually classified as variants of uncertain significance or likely pathogenic due to limited predictive and/or experimental evidence.</p><p><strong>Methods: </strong>This study describes a novel heterozygous in-frame insertion in exon 6 of DES (RefSeq NM_001927.4:c.1059_1061dup) identified in an Argentine family with myofibrillar myopathy (MFM). This mutation results in the duplication of a glutamic acid residue at position 353 (NP_001918.3:p.(Glu353dup)), in the 2B subdomain of the central rod domain. Clinical, computational and functional analyses were performed to study the pathogenicity of this variant.</p><p><strong>Results: </strong>Clinically, the index patient exhibited hallmark MFM features, including progressive muscle weakness, atrophy and fatty muscle replacement. In silico analyses of molecular dynamics revealed that p.Glu353dup alters DES dimer assembly by stabilising an aberrant coiled-coil conformation, a mechanism not previously proposed for DES mutations. Functional studies in HEK293T cells and C2C12 myocytes suggested that the p.Glu353dup variant induces aberrant DES aggregation, confirming its detrimental effect on filament organisation.</p><p><strong>Conclusion: </strong>These findings are consistent with the idea that p.Glu353dup is a pathogenic variant, supported by clinical studies, in silico protein modelling and functional evidence, highlighting the impact of in-frame insertions on DES filament homeostasis. By providing computational and experimental evidence, this study expands our understanding of desminopathies and offers new perspectives for pathogenicity assessment of uncertain DES variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"216-224"},"PeriodicalIF":3.7,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refining the phenotypic spectrum of <i>PNKP</i>-related microcephaly: a study of 27 new patients.","authors":"Ghada M H Abdel-Salam, Mohamed S Abdel-Hamid, Sherif F Abdel-Ghafar, Marian Girgis, Maha S Zaki","doi":"10.1136/jmg-2025-111040","DOIUrl":"10.1136/jmg-2025-111040","url":null,"abstract":"<p><strong>Background: </strong>Biallelic pathogenic variants in <i>PNKP</i> are associated with microcephaly and early-onset seizures (MCSZ), ataxia with oculomotor apraxia type 4 and Charcot-Marie-Tooth disease type 2B2.</p><p><strong>Methods: </strong>We describe the clinical and neuroimaging features of 27 new patients with <i>PNKP</i> variants. All patients presented with early-onset seizures, congenital microcephaly and intellectual disability. In addition, we compared our results with data in the literature.</p><p><strong>Results: </strong>Twenty-five patients presented with the classic MCSZ phenotype, while two showed a more severe clinical phenotype. The brain imaging features of the 25 patients varied significantly, but widening of the frontal lobe gyri with frontal hypoplasia and prominent cerebellar folia (consistent with atrophy) could point to <i>PNKP-</i>related microcephaly . In contrast, the two patients with severe phenotype showed additional brain MRI features of white matter loss and pontocerebellar hypoplasia fulfilling the criteria of microlissencephaly. Exome sequencing identified seven different <i>PNKP</i> variants, including two novel ones. The c.1253_1269dup p.(Thr424GlyfsTer49) and c.1381_1383dup p.(Asn461dup) variants, each was recurrent in 10 patients (37%), while the c.1381_1383del p.(Asn461del) variant was recurrent in four patients (14.8%). Haplotype analysis confirmed that the p.Asn461dup variant has a founder effect in our population. No genotype-phenotype correlation was observed in our cohort.</p><p><strong>Conclusion: </strong>Our results provide 'microlissencephaly' as an emerging distinct phenotype linked to <i>PNKP</i> variants. As such, <i>PNKP</i> variants could be associated with four overlapping subgroups that lie along a unifying phenotypic continuum.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"250-258"},"PeriodicalIF":3.7,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145819665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical manifestations of chromosome 19p13.11 duplication.","authors":"Dibyendu Dutta, Megan Keeney, Nicole Matthews, Kristina Peron, Abdulrazak Alali, Ariel F Martinez, Bobbi McGivern, Claire Boring, Scott C Smith, Ria Garg","doi":"10.1136/jmg-2025-111154","DOIUrl":"10.1136/jmg-2025-111154","url":null,"abstract":"<p><strong>Background: </strong>Chromosome 19 is the most gene-dense chromosome in the human genome, with a high frequency of segmental duplications that predispose it to genomic rearrangements. While deletions of chromosome 19 have been associated with various clinical conditions, duplications remain poorly characterised. Here, we report three cases involving 19p13.11 duplication and describe the associated clinical phenotype.</p><p><strong>Methods: </strong>We describe three unrelated individuals with microduplications at 19p13.11 identified either via clinical whole-exome sequencing or chromosomal microarray. The probands underwent detailed clinical genetic evaluations, and CNVs were confirmed with parental testing when available. Sequencing reads were aligned to the GRCh37/hg19 human genome build.</p><p><strong>Results: </strong>All three probands exhibited neurodevelopmental delays, attention-deficit/hyperactivity disorder and speech delay. Additional overlapping features included joint hypermobility, short stature and craniofacial anomalies. Patient-specific manifestations included haematological abnormalities, musculoskeletal asymmetries and cardiac findings. Duplicated regions spanned 1.2-1.6 Mb and encompassed 41-49 protein-coding genes. Patients 2 and 3 have CNVs that overlap 76% with those of Patient 1. Several genes have predicted high triplosensitivity scores and are associated with autosomal dominant neurodevelopmental and skeletal disorders. Patient 1, with the largest duplication, had more extensive systemic involvement, likely reflecting the broader gene dosage effect.</p><p><strong>Conclusion: </strong>This is the first comprehensive clinical and molecular characterisation of 19p13.11 duplications, suggesting a recurring multisystem phenotype driven by gene dosage sensitivity. These findings support the inclusion of 19p13.11 duplications in diagnostic evaluations for neurodevelopmental and multisystem disorders.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"235-243"},"PeriodicalIF":3.4,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic <i>TTBK1</i> variant causes a severe syndromic neurodevelopmental disorder: clinical and genetic insights from two siblings.","authors":"Zehra Manav Yigit, Salih Burak Erarslan, Ayse Tosun, Gökay Bozkurt, Hilmi Bolat, Gul Unsel Bolat","doi":"10.1136/jmg-2025-111208","DOIUrl":"10.1136/jmg-2025-111208","url":null,"abstract":"<p><strong>Background: </strong>Tau-tubulin kinase 1 (<i>TTBK1</i>) is a neuron-enriched kinase implicated in τ phosphorylation and neurodegeneration. Human phenotypes associated with constitutional <i>TTBK1</i> variants remain undefined.</p><p><strong>Methods: </strong>Two siblings with a severe neurodevelopmental phenotype were assessed using quartet exome sequencing, segregation analysis and standardised clinical and neuroimaging evaluations.</p><p><strong>Results: </strong>Both children exhibited profound global developmental delay, non-ambulation, axial hypotonia with lower-limb spasticity and proportionate postnatal growth failure with microcephaly. Epilepsy was present in the older sibling. Brain MRI showed a thin brainstem and corpus callosum, periventricular T2 hyperintensities and mild cerebellar atrophy in the older sibling and external hydrocephalus in the younger. Exome sequencing identified a homozygous frameshift variant in <i>TTBK1</i> (NM_032538.3:c.1899del; p.Thr634Argfs*39) that segregated with the disease. The variant was absent from population databases and predicted to cause loss-of-function. According to the American College of Medical Genetics and Genomics criteria, it fulfils PVS1 and PM2_P.</p><p><strong>Conclusion: </strong>We report the two siblings with a neurodevelopmental disorder due to a biallelic <i>TTBK1</i> loss-of-function variant, establishing <i>TTBK1</i> as critical for human neurodevelopment. Together with preclinical data, these findings underscore its role in motor and cognitive circuits. Additional cases and functional studies will be essential to delineate the clinical spectrum and mechanistic basis of <i>TTBK1</i> deficiency.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"244-249"},"PeriodicalIF":3.4,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MITF (p.E318K) and renal cell carcinoma: current evidence does not support an effect.","authors":"Valentin Yves Walker, Hong Nhung Vu, Eiríkur Steingrímsson","doi":"10.1136/jmg-2025-111119","DOIUrl":"10.1136/jmg-2025-111119","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"275-276"},"PeriodicalIF":3.4,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13151504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How do clinician and parent-reported data differ? An analysis of similarity and difference in the datasets from a cross-syndrome genetics cohort study (GenROC).","authors":"Karen Jaqueline Low, Huw Day, Mevmi Lasanya Kodippuli Thanthilla, Charlotte Davis, Helen V Firth, Caroline Wright","doi":"10.1136/jmg-2025-111193","DOIUrl":"10.1136/jmg-2025-111193","url":null,"abstract":"<p><strong>Background: </strong>Parent/patient-reported (PRD) datasets provide ready access to phenotypic data for monogenic neurodevelopmental disorders, yet their concordance with clinical data is unclear.</p><p><strong>Methods: </strong>In the GenROC study, 547 children (mean age 7.6 years, balanced sex ratio) had parallel parent-reported web questionnaires and clinician-reported (CRD) Human Phenotype Ontology proformas. We compared the two sources per participant by system, gene and gene group and overall for quantity, detail and similarity.</p><p><strong>Results: </strong>547 probands were analysed ranging in age from infancy to 16 years (mean 7.6) with similar gender distribution. PRD provided more terms for dental, gastroenterology, immunology and respiratory systems and for vision (p<0.001 for all) and to a lesser degree for cardiac (p=0.0012). CRD provides more detail than PRD for most gene subgroups, combined systems and for neurology (p<0.001). Similarity scores were low overall per participant (mean 0.38 for combined). Similarity scores were highest for cardiac (mean 0.74) and lowest for Ear/Nose/Throat(ENT) (mean 0.34). There was minimal difference in similarity scores across gene groups or between the top 10 genes-scaffold adaptor gene groups had the highest (mean 0.43) as did <i>STXBP1</i> (mean 0.5) and <i>CACNA1A</i> (0.49). CRD is more similar to published syndrome phenotypes for syndromic genes.</p><p><strong>Conclusions: </strong>Parents reported more common childhood phenotypes, such as asthma and dental issues, while clinicians provided clinical phenotype descriptors, such as brain morphology and seizure semiology. It is important to understand the differences when designing studies and using datasets to appreciate their strengths and limitations.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"259-268"},"PeriodicalIF":3.4,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13018764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges associated with disclosing results from whole genome sequencing to diagnose paediatric rare diseases: analysis of parent-clinician interactions.","authors":"Holly Ellard, Jhumana Ali, Phoebe Buxton, Myra Bluebond-Langner, Celine Lewis","doi":"10.1136/jmg-2025-111137","DOIUrl":"10.1136/jmg-2025-111137","url":null,"abstract":"<p><strong>Background: </strong>Whole genome sequencing (WGS) has recently been introduced as a diagnostic test for patients with particular rare diseases in the National Health Service (NHS) in England. Little is known about the process of communicating results from WGS to families in practice.</p><p><strong>Methods: </strong>We audio-recorded clinicians and parents discussing the results of WGS for their child's rare disease diagnosis as part of a larger mixed-methods evaluation of the implementation of the NHS Genomic Medicine Service during its early years.</p><p><strong>Results: </strong>10 consultations were audio-recorded across four NHS Trusts. Clinical indications for WGS were related to neurological and developmental disorders. Seven parents received a genetic diagnosis for their child's condition, two received a variant of uncertain significance, and one received a no primary finding result. One parent also received an incidental finding for their child. Challenges in discussing results included (1) explaining a diagnosis when the genotype was established before detailed phenotyping, (2) navigating follow-up for an adult-onset condition identified in childhood, (3) disclosing an unexpected diagnosis for a parent from trio testing and (4) conveying a diagnosis with an uncertain prognosis.</p><p><strong>Conclusion: </strong>This study illustrates some of the issues that can arise from unexpected and uncertain information when returning results from broad-scope genomic testing for paediatric neurological and developmental disorders. Further study of actual interactions between clinicians and families discussing results from WGS across different specialities and conditions is needed to inform guidance on communication of results within this rapidly evolving area of medicine.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"174-183"},"PeriodicalIF":3.4,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7618969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association for Clinical Genomic Science (ACGS) guidelines for the classification of oncogenicity of somatic variants in cancer: recommendations by the UK somatic variant interpretation group (SVIG-UK).","authors":"George J Burghel, Joanne Mason, Kevin Baker, Kate Moloney, Claire Holt McKeeve, Ashley Cartwright, Ana M Brás-Goldberg, Debbie Travis, Siân Lewis, Jennifer A Fairley, Jonathan Williams, Kirsty Russell, Suzanne MacMahon, Christopher Wragg","doi":"10.1136/jmg-2025-111046","DOIUrl":"10.1136/jmg-2025-111046","url":null,"abstract":"<p><p>Comprehensive genomic testing in routine cancer care pathways has created the need to interpret the consequences of somatic (acquired) genomic variants beyond the currently well-characterised driver variants in cancer gene hotspots. While several guidelines have been published to determine the oncogenicity of somatic cancer gene variants, they lack a comprehensive and flexible approach that encompasses all available lines of evidence. Individual UK laboratories have developed local approaches to standardise somatic variant interpretation, often based on different sets of published guidelines, but a comprehensive national standardised framework is lacking. The absence of standardisation in approaches to somatic variant interpretation highlights a significant gap in the field of genomic medicine within the UK healthcare system. Key stakeholders from across the UK cancer genomics diagnostic community formed the UK Somatic Variant Interpretation Group (SVIG-UK) in September 2018 to develop a consensus approach for interpretation of somatic variants identified through genomic testing in patients with solid tumours and haematological malignancies. SVIG-UK scientists conducted a review of existing somatic variant interpretation classification systems and although they mostly agreed on evidence sources for variant interpretation, differences were identified in how the evidence should be used, weighted and combined. The SVIG-UK team subsequently developed a single, standardised UK-wide approach to somatic variant interpretation which encompassed both solid tumour and haematological cancer genomic testing. This framework was shared with stakeholders across the UK alongside variants for preliminary testing. Outcomes were then reviewed and following engagement sessions across the community, the variant interpretation recommendations were updated and ratified by the UK Association of Clinical Genomics Sciences. We present herein the SVIG-UK framework and recommendations, which provide a standardised, comprehensive and flexible approach for classifying the oncogenicity of somatic variants in cancer genes.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"147-156"},"PeriodicalIF":3.4,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13018753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145668789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sequencing every UK newborn: why cold storage economics should shape policy.","authors":"Timothy Hearn","doi":"10.1136/jmg-2025-111181","DOIUrl":"10.1136/jmg-2025-111181","url":null,"abstract":"<p><p>Whole-genome sequencing (WGS) for every UK newborn is hailed as a leap towards lifelong personalised medicine, yet policymakers have scarcely examined the informatics iceberg beneath the initiative: where, and at what cost, will millions of genomes be stored? This perspective contends that the research-era reflex of keeping raw reads and alignments in high-performance 'hot' cloud storage is incompatible with NHS budgets and net-zero targets. Drawing on the National Genomic Research Library's current practice (~80 GB per child), I estimate the UK government's 10-year rollout would accumulate more than 0.5 exabytes and incur ~£620 million in standard S3 fees-exceeding NICE's entire core budget over the same period-while driving up data-centre energy demand. By contrast, automatically migrating files to deep-archive tiers 3 months after newborn screening preserves future utility but cuts lifetime storage costs by 91% to about £18 per child and reduces operational power by an order of magnitude; 12-24 hour restore latencies remain clinically acceptable for episodic re-analysis. I argue that newborn sequencing is primarily a logistics challenge rather than a scientific one, and that a national 'screen-then-archive' policy, anchored by a retrieval service-level agreement, would safeguard public funds, support workforce expansion and honour NHS carbon commitments while allowing consent-based re-analysis at adolescence or adulthood. Embedding cold storage economics now will prevent the programme from sinking under an exabyte scale liability.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"184-186"},"PeriodicalIF":3.7,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145768483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}