Journal of Medical Genetics最新文献

{"title":"Clinically significant DNA variation from the GENCOV and HostSeq COVID-19 genome sequencing studies.","authors":"Erika Frangione, Radhika Mahajan, Juan De Los Rios, Selina Casalino, Navneet Aujla, Saranya Arnoldo, Alexandra Binnie, Bjug Borgundvaag, Marc Dagher, Luke Devine, Hanna Faghfoury, Steven Marc Friedman, Chun Yiu Jordan Fung, Zeeshan Khan, Gregory Morgan, David Richardson, Seth Stern, Ahmed Taher, Jennifer Taher, Jordan Lerner-Ellis","doi":"10.1136/jmg-2025-111029","DOIUrl":"10.1136/jmg-2025-111029","url":null,"abstract":"<p><strong>Background: </strong>Vast amounts of genome sequencing data generated from large-scale research studies like HostSeq provide an opportunity to summarise the spectrum of pathogenic variation in a subset of the Canadian population. Sharing variant-level data with public databases, like ClinVar, is crucial for advancing our understanding of genomic variants related to Mendelian diseases. However, such entries are often incomplete or contain discrepancies which render interpretation and classifications less useful.</p><p><strong>Methods: </strong>The GENCOV and HostSeq cohorts were annotated and summarised using custom workflows to identify variants with a pathogenic and likely pathogenic (P/LP) classification in ClinVar. These variants were further filtered using custom gene panels, gnomAD frequency, variant type, gene-disease relationship and the number of reputable ClinVar laboratory submissions. Manually assessed variants from the GENCOV study were compared with ClinVar classifications to identify discrepancies.</p><p><strong>Results: </strong>A total of 1956 unique variants were manually classified as P/LP through the GENCOV study. Of these, 65% (1276) were also identified in ClinVar, and among those, 69% (889) had concordant P/LP classifications. The manual assessment of unique exonic variants in GENCOV yielded a higher number of putative P/LP variants (1595), including truncating and missense variants compared with the 127 unique exonic P/LP variants in HostSeq.</p><p><strong>Conclusion: </strong>These results highlight that a large proportion of P/LP variation is either absent or has conflicting evidence for pathogenicity in ClinVar, emphasising the importance of periodic reassessment, discrepancy resolution and updates to ensure completeness and accuracy of public databases.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"299-307"},"PeriodicalIF":3.4,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147317429","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":"Frequency of familial hypercholesterolaemia-causing genetic variants in the 100 000 Genomes Project cohort: whole genome sequencing analyses of 77 260 participants.","authors":"Marta Futema, Martin Bird, Ash Haeger, Ellen Pinder, Anthony O'Rourke, Elijah R Behr, Steve E Humphries","doi":"10.1136/jmg-2025-111201","DOIUrl":"10.1136/jmg-2025-111201","url":null,"abstract":"<p><strong>Background: </strong>Heterozygous Familial Hypercholesterolaemia (HeFH) is caused by pathogenic variants in <i>LDLR</i>, <i>APOB</i>, <i>APOE</i> or <i>PCSK9</i>, leading to elevated low-density lipoprotein-cholesterol and increased cardiovascular risk. In the UK, HeFH affects ~1 in 288 individuals. The 100 000 Genomes Project (100KGP) generated whole genome sequencing (WGS) data from >85 000 participants recruited primarily with cancer or rare inherited disorders. We analysed WGS data to assess the prevalence and spectrum of FH-causing variants.</p><p><strong>Methods: </strong>Variants in <i>LDLR</i>, <i>APOB</i>, <i>APOE</i> and <i>PCSK9</i> were extracted from 100KGP WGS data and annotated using expert-reviewed ClinGen curation. Demographic, ancestry and linked health records were incorporated. Analyses were restricted to unrelated individuals.</p><p><strong>Results: </strong>Among 54 818 unrelated participants, 167 were heterozygote for an FH-causing variant, giving a prevalence of 1:328 (95% CI 1:285 to 1:386). Prevalence was similar across ancestries, including African (1:388) and South Asian (1:276). Variant distribution was: <i>LDLR</i> 67%, <i>APOB</i> 26.5%, <i>APOE</i> 3.5% and <i>PCSK9</i> 3%. Two individuals carried two FH variants, consistent with homozygous FH. Among 22 442 genetic relatives, 77 also carried an FH variant. Of all variant carriers, 53% were female, mean age at recruitment was 41.3 years, with 43 younger than 18 years, and 54.3% had documented hypercholesterolaemia.</p><p><strong>Conclusions: </strong>The prevalence and gene distribution of FH-causing variants in 100KGP are consistent with UK estimates. Differences in variant spectrum across ancestries were observed; however, FH prevalence was similar. Participants who consented to the return of actionable findings were informed, providing direct clinical benefit from genomic research.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"284-290"},"PeriodicalIF":3.4,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13151451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146157315","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":"Reclassification of variants of uncertain significance in type I collagen genes: a national reference laboratory experience.","authors":"Nurhaziqah Supari, Duncan Baker, Sylvia Keigwin, Sophie Delaney, Seiko Makino, Meena Balasubramanian","doi":"10.1136/jmg-2025-111334","DOIUrl":"10.1136/jmg-2025-111334","url":null,"abstract":"<p><strong>Background: </strong>The availability of large volumes of data from genetic testing has enabled the interpretation of more DNA variants, contributing to a greater number of identified variants of uncertain significance (VUS). The growing number of VUS causes a burden of inconclusive findings in clinical practice. Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder causing bone fragility and limb deformity. Pathogenic variants in two collagen genes, <i>COL1A1</i> and <i>COL1A2,</i> account for around 90% of all OI.</p><p><strong>Methods: </strong>Data mining of the variants from Sheffield Diagnostic Genetics Service, the national OI testing hub (UK), was conducted to collate all VUS in <i>COL1A1</i> and <i>COL1A2</i> identified. All VUS were then reclassified according to the latest 2024 ACGS (Association for Clinical Genomic Science) best practice guidelines.</p><p><strong>Results: </strong>A total of 161 VUS in <i>COL1A1</i> and 98 VUS in <i>COL1A2</i> were identified and reanalysed. For <i>COL1A1</i>, we found that 2% VUS were upgraded to likely pathogenic (LP), 23% of the VUS were downgraded to likely benign and benign, 12% were reclassified as hot VUS and the remaining 63% have not changed classification as VUS. With regard to <i>COL1A2</i>, only 1% of the VUS were upgraded to LP, 25% were downgraded to likely benign and benign, 13% were reclassified as hot VUS and 61% remained as VUS.</p><p><strong>Conclusion: </strong>From this study, we demonstrated that iterative reanalysis of VUS is crucial in clinical practice as new data and evidence become available. This dynamic process will significantly improve diagnostic accuracy and inform patient care decisions.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"277-283"},"PeriodicalIF":3.4,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146157259","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":"Inherited variants in autosomal dominant disease genes are a significant cause of fetal structural anomalies.","authors":"Sarah Anne Graham, Anne McCabe, Victoria Harrison, James Castleman, Sam Doyle, Stephanie Allen","doi":"10.1136/jmg-2025-111301","DOIUrl":"10.1136/jmg-2025-111301","url":null,"abstract":"<p><strong>Background: </strong>Monogenic disorders are a major cause of fetal structural anomalies. Most genetic diagnoses involve de novo, biallelic or X linked variants; however, inherited variants in autosomal dominant disease genes have been detected across multiple studies. The overall contribution of such variants to fetal structural anomalies is unclear and variant filtering strategies may exclude them. In this study, we aimed to characterise the inherited variants in autosomal dominant disease genes detected by prenatal exome sequencing in a large, well-phenotyped cohort.</p><p><strong>Methods: </strong>The outcomes of prenatal exome sequencing for fetuses with structural anomalies referred to our laboratory from April 2019 to February 2025 were reviewed.</p><p><strong>Results: </strong>Prenatal exome sequencing was carried out in 1185 fetuses, resulting in a diagnosis in 30.0% of cases. Autosomal dominant disorders accounted for 59.9% of diagnoses and a risk of recurrence was identified for 19.2% of these. Autosomal dominant conditions with an increased risk for recurrence were therefore identified in 3.5% of fetuses referred for sequencing, and accounted for 11.5% of prenatal exome sequencing diagnoses. Recurrent diagnoses involving inherited variants included rasopathies and type I/II collagen disorders.</p><p><strong>Conclusion: </strong>Inherited variants in autosomal dominant disease genes are a significant contributor to fetal structural anomalies and may have implications for parents' own health as well as management of the current pregnancy and reproductive options. The requirements for genomic counselling, clinical assessment and genetic testing of parents and family members following an inherited finding must be taken into account when planning delivery of a prenatal sequencing service.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"328-336"},"PeriodicalIF":3.4,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13151435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197839","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":"Later age of natural menopause among women with the pathogenic <i>CHEK2</i> c.1100delC variant: a validation study.","authors":"Maartje A C Schreurs, Antoinette Hollestelle, Muriel A Adank, Yvonne Louwers, Christi J van Asperen, Margreet G E M Ausems, Irma van de Beek, Margriet J Collee, Charlotte J Dommering, Encarna B Gómez García, Marijke R Wevers, Emma M Vieveen, Refika Yigit, Marjanka K Schmidt, Jenny A Visser, Maartje J Hooning","doi":"10.1136/jmg-2025-111339","DOIUrl":"10.1136/jmg-2025-111339","url":null,"abstract":"<p><strong>Background: </strong>The average age of natural menopause (ANM) for European women is 50-52 years. Reproductive risk and lifestyle factors have been found to be associated with ANM. Furthermore, a genome-wide association study found that women with a <i>CHEK2</i> variant reach ANM 3.49 years later than women without a <i>CHEK2</i> variant ('non-carriers'). With this study, we aim to validate this association within <i>CHEK2</i> c.1100delC families.</p><p><strong>Methods: </strong>As part of the HEreditary Breast and Ovarian cancer Netherlands (Hebon) study, all women who underwent genetic testing for pathogenic variants associated with breast or ovarian cancer were invited to participate and complete a questionnaire on established risk factors. We compared the reported ANM between groups and within selected birth cohorts. HRs and 95% CIs for the association of <i>CHEK2</i> status with ANM were estimated via Cox regression models, adjusted for age of menarche, parity, smoking status and hormonal contraceptive use.</p><p><strong>Results: </strong>We included 661 <i>CHEK2</i> c.1100delC heterozygotes, 175 non-carrier relatives and 8839 unrelated non-carriers. <i>CHEK2</i> c.1100delC women reached ANM at a significantly later age (51.8±4.8 years) compared with non-carrier relatives (50.3±4.0 years) and unrelated non-carriers (49.6±4.8 years). Similar patterns were found within the birth cohorts. In Cox regression analysis, heterozygotes were associated with a later ANM compared with unrelated non-carriers (HR 1.58; 95% CI 1.21 to 2.08) and non-carrier relatives (HR 1.83; 95% CI 1.13 to 2.95).</p><p><strong>Conclusion: </strong><i>CHEK2</i> c.1100delC is associated with 1.5-2.2 years later ANM compared with non-carriers, underlining the independence of <i>CHEK2</i> c.1100delC irrespective of heritability of ANM within families.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"291-298"},"PeriodicalIF":3.4,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13151450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197777","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":"Evaluating the efficiency of nanopore adaptive sampling sequencing in detecting balanced translocation.","authors":"Meng Gao, Jun Ren, Cuiting Peng, Xijing Liu, Jiemei Zheng, Han Chen, Xinlian Chen, Jiamin Wang, Yi Lai, Ting Hu, Shanling Liu","doi":"10.1136/jmg-2025-111347","DOIUrl":"10.1136/jmg-2025-111347","url":null,"abstract":"<p><strong>Background: </strong>Balanced translocation (BT) carriers have a high risk of recurrent miscarriage and abnormal offspring due to unbalanced gamete production. Clinical genetic testing often fails to detect BTs that fall below microscopic resolution or occur in repetitive genomic regions. Long-read sequencing technologies can overcome these limitations by spanning large genomic segments, but whole-genome long-read sequencing remains costly and data-intensive. Nanopore adaptive sampling sequencing, a computational enrichment technique, enables selective sequencing of target regions, offering a cost-effective and flexible alternative. We aimed to assess the efficacy of adaptive sampling for detecting BTs.</p><p><strong>Methods: </strong>Fourteen participants from eight families with suspected BTs were recruited. Peripheral blood samples from parents were subjected to nanopore adaptive sampling sequencing. Karyotyping and Sanger sequencing were performed to confirm the detected breakpoints.</p><p><strong>Results: </strong>Adaptive sampling accurately identified all BT breakpoints in eight families, with translocated fragment sizes ranging from 0.8 to 18 Mb. Our data suggested that a 500 kb flanking region at 20X depth was sufficient for detection, while a 5 Mb region at 15X depth provided enough efficiency. The method achieved comparable sequencing depth to whole-genome long-read sequencing but with reduced data output and lower cost.</p><p><strong>Conclusion: </strong>Nanopore adaptive sampling sequencing enables high-resolution, cost-effective detection of submicroscopic BTs, offering a practical alternative to whole-genome long-read sequencing. This clinical workflow is suitable for cases in which candidate BT regions have been indicated by prior genetic testing.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"317-327"},"PeriodicalIF":3.4,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147306859","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":"Mosaic variegated aneuploidy as a novel feature in patients with Mulibrey nanism and <i>TRIM37</i> variants.","authors":"Anna H Hakonen, Susann Karlberg, Kirsi Kiiski, Marita Lipsanen-Nyman, Carola Saloranta, Minna Pekkinen, Saila Laakso, Johanna Lehtonen, Janna Saarela, Anna-Kaisa Anttonen, Eveliina Jakkula, Kristiina Aittomäki, Outi Mäkitie","doi":"10.1136/jmg-2025-111325","DOIUrl":"10.1136/jmg-2025-111325","url":null,"abstract":"<p><p>Mulibrey nanism is a rare disorder caused by biallelic tripartite motif containing protein 37 (<i>TRIM37</i>) variants and characterised by prenatal onset growth failure, dysmorphic features, restrictive heart disease and predisposition to tumours. TRIM37 has been linked to regulation of centrosome functions. In chromosomal analysis of two siblings with Mulibrey nanism, we observed mosaic variegated aneuploidies. This prompted us to investigate karyotypes of 10 additional patients with Mulibrey, using fibroblast cultures. In the index patients, the prenatal samples and a postnatal skin biopsy showed a heterogeneous mix of aneuploidies in 7-36% of metaphases. Fibroblast karyotypes of the 10 other patients, who were phenotypically comparable to the index patients, showed clinically relevant, low-level abnormalities in one subject. This is the first report on low-level mosaic aneuploidies in Mulibrey amniocytes and neonatal fibroblasts, detectable by conventional karyotyping. The results are in line with previous observations of segregation errors in human cell lines with <i>TRIM37</i> defects. Further studies are required to elucidate the prevalence and implications of mosaic aneuploidies in Mulibrey nanism.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"308-311"},"PeriodicalIF":3.4,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146213476","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":"Test the grandfather! Incidental in-frame <i>DMD</i> deletions in three asymptomatic families.","authors":"Dorsa Kord, Victoria M Siu","doi":"10.1136/jmg-2025-111103","DOIUrl":"10.1136/jmg-2025-111103","url":null,"abstract":"<p><p>The <i>DMD</i> gene, the largest gene in the human genome, is particularly prone to exonic deletions or duplications due to recombination events during gametogenesis, with frameshift deletions typically seen in Duchenne muscular dystrophy (DMD) and in-frame deletions with Becker muscular dystrophy or X-linked dilated cardiomyopathy. Dystrophic changes in the muscles result in elevated creatine kinase levels. <i>DMD</i> deletions are also associated with cognitive challenges. In this case series, we present three unrelated families with the incidental finding of in-frame <i>DMD</i> deletions on chromosome microarray, two involving exons 49-51 and one involving exons 45-60. All of the children are asymptomatic or minimally symptomatic with normal echocardiograms and inherited the deletion from their maternal grandfathers who are asymptomatic into their 60s.The identification of incidental <i>DMD</i> deletions on chromosome microarray can have important implications in terms of diagnosis, screening and follow-up, prognostication and family planning. The finding of a familial in-frame <i>DMD</i> deletion in an asymptomatic maternal grandfather is reassuring with regard to prognosis and disease course. When a maternally inherited in-frame <i>DMD</i> deletion is identified in an asymptomatic young male, or unexpectedly at the time of invasive prenatal testing, it is crucial to test both maternal grandparents.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"312-316"},"PeriodicalIF":3.4,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146219987","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":"Catatonia and regression in an autism spectrum disorder patient harbouring a <i>BRSK2</i> frameshift mutation.","authors":"Andrea Laurato Sertié, Raphaella Josino, Vitória Rezende Goll, Ana Luiza Nunes Goussain Filippo, Gabriele da Silva Campos, Francisco do Rego, Ellen de Souza Siqueira, Najila Farias de Alcântara, Elaine Cristina Zachi, Maria Rita Passos-Bueno","doi":"10.1136/jmg-2025-111102","DOIUrl":"10.1136/jmg-2025-111102","url":null,"abstract":"<p><p>Deleterious variants in the <i>BRSK2</i> gene, which encodes a serine/threonine kinase crucial for neuronal polarisation and brain development, have recently been linked to the pathogenesis of autism spectrum disorder (ASD). However, comprehensive clinical descriptions of individuals with pathogenic <i>BRSK2</i> variants remain limited, and the molecular and cellular consequences of these mutations are poorly understood. This case report provides a detailed clinical, cognitive and molecular characterisation of a male patient with ASD harbouring a de novo <i>BRSK2</i> frameshift variant, who developed catatonia, developmental regression and cognitive decline during early adolescence. To assess the functional impact of the variant, induced pluripotent stem cells (iPSCs) and iPSC-derived neural organoids were generated from the patient. Molecular analyses revealed a significant reduction in <i>BRSK2</i> transcript and protein levels. Sequencing of <i>BRSK2</i> mRNA showed exclusive expression from the wild-type allele, consistent with degradation of the mutant transcript via nonsense-mediated decay. These findings broaden the mutational and phenotypic spectrum associated with <i>BRSK2</i>-related neurodevelopmental disorders and provide functional evidence supporting the pathogenicity of the identified variant. Furthermore, this report demonstrates the role of <i>BRSK2</i> in complex neuropsychiatric features-such as catatonia and cognitive deterioration, which remain underreported in the existing literature-and emphasises the importance of longitudinal cognitive and behavioural monitoring in individuals with <i>BRSK2</i> mutations.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"269-274"},"PeriodicalIF":3.7,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145804649","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":"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}