Journal of Medical Genetics最新文献

{"title":"Long-read sequencing enables trio-assisted phasing of <i>de novo</i> variants in the imprinted gene <i>MAGEL2</i>.","authors":"Thomas W Laver, Preeah Sangha, Lucy Mallin, Michal Cohen, Yağmur Ünsal, Huseyin Demirbilek, Matthew N Wakeling, Jasmin J Bennett, Jayne A L Houghton, Jonna M E Männistö, Emma Dempster, Sarah E Flanagan","doi":"10.1136/jmg-2025-111282","DOIUrl":"10.1136/jmg-2025-111282","url":null,"abstract":"<p><p>Schaaf-Yang syndrome and Prader-Willi syndrome are imprinting disorders that result from the disruption of paternally expressed genes within the 15q11-q13 region. Both conditions present with overlapping clinical features including developmental delay, hypotonia and endocrine abnormalities. Schaaf-Yang syndrome specifically results from heterozygous variants in the paternally expressed <i>MAGEL2</i> gene. Because these variants are often <i>de novo</i>, determining that the variant is on the paternal allele is essential for a definitive diagnosis. Traditional methods, such as methylation-specific PCR, are labour-intensive, while it is challenging to phase variants separated by distances greater than the fragment length (~600 bp) using short-read sequencing. In this study, we used long-read Oxford Nanopore sequencing to perform trio-assisted phasing of a <i>de novo MAGEL2</i>, p.(Gln638Ter) variant identified in two unrelated probands referred for congenital hyperinsulinism genetic testing. Long reads spanning both the variant and informative parental heterozygous variants confirmed that the variant was on the paternal allele and was therefore pathogenic and causative of Schaaf-Yang syndrome and associated with hyperinsulinism in both individuals. Our findings demonstrate the clinical utility of long-read sequencing for enabling trio-assisted variant phasing in imprinting disorders, particularly when phenotypes are incomplete or overlapping. Our findings further highlight congenital hyperinsulinism as a rare but important feature associated with Schaaf-Yang syndrome.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"432-435"},"PeriodicalIF":3.4,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592657","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":"Expanded carrier screening in a Southwestern Chinese population indicates East Asian specific low-frequency pathogenic variants account for nearly half of the at-risk couple rate.","authors":"Sha Liu, Liyuan Cao, Victor Wei Zhang, Shuang Huang, Haipeng Liu, Xiang Wei, Yuan Luo, Yue Li, Lin Zhou, Linzhi Jiang, Qian Zhu, Hongqian Liu","doi":"10.1136/jmg-2025-111273","DOIUrl":"10.1136/jmg-2025-111273","url":null,"abstract":"<p><strong>Background: </strong>The optimal disease spectrum for carrier screening (CS) remains debated. We aimed to characterise the carrier landscape and quantify the at-risk couple rate (ACR) components in a Chinese population to guide panel design.</p><p><strong>Methods: </strong>Using a 334-gene expanded CS panel, we screened 3748 individuals from Sichuan, China. Pathogenic/likely pathogenic (P/LP) variants were classified by allele frequency and geographic specificity.</p><p><strong>Results: </strong>Overall, 65.55% of participants carried at least one P/LP variant. We identified 83 at-risk couples (ACR 5.19%), including 55 couples at risk for autosomal recessive (AR) disorders. We catalogued 1372 P/LP variants for AR conditions. Notably, 46 variants were classified as low frequency (minor allele frequency ≥0.1%). Among these 46 low-frequency variants, 54% (25/46) were identified as East Asian-specific. Strikingly, these 25 East Asian-specific variants contributed 41.8% (23/55) to the AR at-risk couples, whereas 11 globally shared alleles contributed only 9.1%. Three regionally enriched variants in <i>HBB</i>, <i>GJB2</i> and <i>SLC25A13</i> alone contributed 20% to the AR ACR.</p><p><strong>Conclusion: </strong>East Asian-specific low-frequency variants significantly contribute to the carrier burden in this population, accounting for nearly half of the AR risk. These findings provide empirical evidence that CS panels should prioritise population-specific carrier frequencies over global data to maximise clinical utility in regions with specific ethnic compositions.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"447-455"},"PeriodicalIF":3.4,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147615748","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":"<i>Retraction: multiple articles in volume 56, issue 1 (2019)</i>.","authors":"","doi":"10.1136/jmg-2026-56-1-2019ret","DOIUrl":"10.1136/jmg-2026-56-1-2019ret","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"466"},"PeriodicalIF":3.4,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147690509","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":"The SINEs were there: identification of a pathogenic Alu insertion in a patient with DICER1-related tumour predisposition.","authors":"Oluwatosin O Taiwo, Paola Angelini, Iman Awadh, Celine Domecq, William D Foulkes, Hood Mugalaasi, Henry Cope, Iryna Stasevich, Samuel E D Lawrence, Avgi Andreou, Suzanne Macmahon, Mikel Valganon-Petrizan, Helen Hanson","doi":"10.1136/jmg-2025-111365","DOIUrl":"10.1136/jmg-2025-111365","url":null,"abstract":"<p><p><i>DICER1</i>-related tumour predisposition (DRTP) is an autosomal dominant disorder marked by increased risk of benign and malignant tumours across multiple organ systems. A genetic diagnosis of DRTP requires identification of a (likely) pathogenic germline <i>DICER1</i> variant to confirm the diagnosis, and guide clinical management, including cascade testing and surveillance of at-risk relatives.We report a 14-year-old girl who developed multiple <i>DICER1</i>-associated tumours with high clinical suspicion of DRTP. Initial testing via next-generation sequencing and whole genome sequencing revealed only hotspot somatic <i>DICER1</i> variants, with no detectable germline variant, complicating the genetic diagnosis.A structural variant (SV) initially detected in a tumour sample prompted retrospective review of alignment data from all previously tested tumour, blood and normal tissue samples. This revealed a consistent SV across all samples. Short-read data suggested the SV was an Alu element insertion within the RNase IIIa domain of DICER1, but read length was insufficient for conclusive characterisation.Subsequent long-read nanopore sequencing confirmed a pathogenic AluY insertion, predicted to disrupt DICER1 function.This case highlights the importance of comprehensive genomic and functional analyses, especially in unresolved cases with strong clinical suspicion. It also demonstrates the value of long-read sequencing in identifying complex variants missed by conventional approaches.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"421-426"},"PeriodicalIF":3.4,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592609","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":"Perspectives of adolescents and young adults with advanced cancer on complete genomic analysis in standard oncology care.","authors":"Lina H Lankhorst, Milou J P Reuvers, Noor A A Giesbertz, Lizet E van der Kolk, Helle-Brit Fiebrich-Westra, Mathijs P Hendriks, Baukje Flameling, Lenneke Stabel, Madelief van de Ree, Jelmer Gietema, Winette T A van der Graaf, Olga Husson","doi":"10.1136/jmg-2025-111368","DOIUrl":"10.1136/jmg-2025-111368","url":null,"abstract":"<p><strong>Purpose: </strong>Tumour genomic profiling, including whole genome sequencing (WGS), offers opportunities for refined diagnosis and personalised treatment for adolescents and young adults (AYAs) with advanced or poor prognostic cancer. This study explores AYAs' attitudes towards receiving WGS in standard oncological care, their preferences for the communication of results and the perceived impact of these results.</p><p><strong>Methods: </strong>Semistructured interviews were conducted with AYAs (aged 18-39 years at initial cancer diagnosis). Interviews were transcribed and analysed thematically using an inductive approach in NVivo (V.12).</p><p><strong>Results: </strong>16 AYAs participated. Analysis revealed five themes: (1) confidence in the current WGS procedure; (2) challenges in understanding and communicating purpose and results of WGS; (3) dual emotional impact of WGS results; (4) high value placed on hereditary information for self and loved ones and (5) balancing altruism and personal risk in genomic data sharing.</p><p><strong>Conclusion: </strong>AYAs with advanced cancer generally value WGS, even when results have no immediate clinical consequences. They describe benefits such as hope, reassurance and the opportunity to help future patients. However, misunderstandings about its purpose, difficulties in interpreting genomic findings and limited awareness of potential hereditary implications may limit its optimal use. Strengthening communication with age-appropriate, accessible explanatory materials will be essential to ensure AYAs understand the purpose and potential outcomes of WGS and can fully benefit from its implementation.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"439-446"},"PeriodicalIF":3.4,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147529829","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":"<i>ACAN</i>-related disorder, antenatal presentation and phenotypic variability: a case series.","authors":"Nikhil Pattani, Anna Page, Joy L Barber, Juan Carlos Del Rey Jimenez, Suzanne Alsters, Assunta Albanese, Sahar Mansour","doi":"10.1136/jmg-2025-111354","DOIUrl":"10.1136/jmg-2025-111354","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic <i>ACAN</i> variants ('aggrecanopathies') are increasingly recognised as a non-syndromic cause of skeletal dysplasias and short stature. Unlike many other aetiologies, <i>ACAN</i>-related disorder is reportedly associated with advanced bone age due to early epiphysial fusion, although presentation can vary. This study aimed to further characterise skeletal findings in paediatric and adult patients.</p><p><strong>Methods: </strong>A retrospective study of confirmed <i>ACAN-</i>related disorder cases from a tertiary genetics centre in England was performed. Data collected included patient demographics, antenatal ultrasound imaging (where available), auxology, endocrine investigations, skeletal imaging and genetic variant analysis. Using the Tanner-Whitehouse III method, bone age was calculated from left hand/wrist radiographs.</p><p><strong>Results: </strong>Nine individuals from four families (paediatric=4, adult=5) were included. One individual presented antenatally with shortened long bones on ultrasound. The remaining cohort presented postnatally with short stature and unremarkable endocrine investigations. Of the paediatric patients, bone ages varied significantly: delayed (n=3) and advanced (n=1). Hypochondroplasia-like axial skeletal changes were more specific in affected parents than index children, for example, reduced interpedicular widening inferiorly in the lumbar spine and shortening of vertebral pedicles. Four had short fourth metacarpals. All individuals had pathogenic <i>ACAN</i> variants; two of the variants were novel.</p><p><strong>Conclusion: </strong>Advanced bone age is not a consistent finding and should not be considered pathognomonic of <i>ACAN</i>-related disorder. Hypochondroplasia is a differential diagnosis with similar radiological findings in the axial skeleton. A short fourth metacarpal is a feature of this condition. Although skeletal features may become more pronounced in adulthood, early diagnosis can maximise future possible interventions.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"456-462"},"PeriodicalIF":3.4,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645648","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":"Reverse haplotyping: taking full advantage of 25% risk testing for the 50% at-risk parent in Huntington's disease.","authors":"Emilia K Bijlsma, Tamara T Koopmann, Susanne T de Bot, Monique Losekoot","doi":"10.1136/jmg-2026-111509","DOIUrl":"10.1136/jmg-2026-111509","url":null,"abstract":"<p><p>Presymptomatic testing (PT) for Huntington's disease (HD) has been available for over 40 years. Individuals who opt for PT are typically at a 50% risk, though in rare cases, '25% at-risk individuals' request to know their genetic status. Family planning is one of the main reasons why predictive testing is requested and with the availability of a direct test, new choices regarding reproduction emerged. In pregnancies, couples of whom the at-risk parent (ARP) does not want to know their own status may opt for direct testing in the 25% at-risk fetus. However, this option has a significant disadvantage: in 25% of cases, the gene expansion will be detected in the fetus, simultaneously revealing the ARP's status. Nevertheless, there is a benefit to this approach that has not yet been well exploited: adding haplotyping to a normal prenatal test outcome may find the ARP (the 'linking pin') no longer at risk of developing HD. We have coined the term <i>reverse haplotyping</i> for this approach. Data from three families in which we applied this method are presented. Our aim is to raise awareness of the full potential of DNA analysis in this context.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"463-465"},"PeriodicalIF":3.4,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645623","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":"Molecular sleuthing: unmasking hidden lymphomas through plasma DNA sequencing.","authors":"Mathilde Bonnot, Pauline Bertin, Thibault Maillet, Nicolas Guyotat, Julliane Bloch, Steeve Chevreux, Isabelle Mosnier, Hervé Ghesquières, Audrey Pechenot, Virginie Desestret, Pierre Sujobert, Sarah Huet","doi":"10.1136/jmg-2025-111458","DOIUrl":"10.1136/jmg-2025-111458","url":null,"abstract":"<p><p>Diagnosing lymphomas can be challenging, particularly in atypical presentations lacking histological confirmation. We report two cases where next-generation sequencing of plasma cell-free DNA (cfDNA) enabled the early detection of diffuse large B-cell lymphoma, months before biopsy confirmation. cfDNA analysis identified key lymphoma-associated mutations, guiding diagnosis when conventional investigations were inconclusive. These findings highlight cfDNA's potential as a non-invasive diagnostic tool for occult lymphoma. While further validation is needed, cfDNA may facilitate earlier intervention in challenging cases, improving patient outcomes.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"436-438"},"PeriodicalIF":3.4,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592603","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":"<i>ATM</i> c.7374_7375insAlu is a French-Canadian founder pathogenic variant associated with predisposition to pancreatic and breast cancer.","authors":"Yifan Wang, Celine Domecq, Adeline Cuggia, Alejandro Mejia-Garcia, Joan Miguel Romero, Nancy Hamel, Rejean Lapointe, Diane Provencher, Anne-Marie Mes-Masson, Patricia N Tonin, Simon Gravel, George Zogopoulos, William D Foulkes","doi":"10.1136/jmg-2025-111441","DOIUrl":"10.1136/jmg-2025-111441","url":null,"abstract":"<p><p>Founder pathogenic variants (PVs) in <i>BRCA1</i>, <i>BRCA2</i> and <i>PALB2</i> increase lifetime risk of developing breast (BC), ovarian (OC) and pancreatic (PC) cancer. They have been identified in French-Canadians (FC), a population exhibiting genetic drift due to common ancestral origins. PVs in <i>ATM</i> also increase BC and PC risk; however, <i>ATM</i> founder PVs have not been described in FCs. Here, we report the identification of a germline <i>ATM</i> c.7374_7375insAlu in a FC family with BC and PC. Using a case-control study of 19 852 FC individuals, we show that heterozygous carriers of this variant are more prevalent in PC cases versus controls (6/325 (1.85%) vs 28/18 129 (0.15%), p<0.001) and BC cases versus female controls (5/858 (0.58%) vs 13/9768 (0.13%), p<0.001). There was no difference in the prevalence of heterozygous carriers in patients with endometrial cancer or OC compared to controls. <i>ATM</i>c.7374_7375insAlu carriers share a common haplotype, suggesting that the variant was inherited from a common FC ancestor, which originated approximately 10.53 generations (305 years) ago. Taken together, this study identifies <i>ATM</i> c.7374_7375insAlu as a novel FC founder PV that contributes to PC and BC predisposition. Improving carrier detection may identify at-risk relatives who may benefit from cancer-directed surveillance.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"427-431"},"PeriodicalIF":3.4,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592691","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":"Damaging missense variants in innate immunity genes are associated with earlier age of breast cancer onset in <i>BRCA1</i> 185delAG carriers.","authors":"Sapir Shemesh, Rinat Bernstein-Molho, Shelley Shoval, Yael Laitman, Dana Madorsky-Feldman, Eitan Friedman, Ran Elkon","doi":"10.1136/jmg-2025-111394","DOIUrl":"10.1136/jmg-2025-111394","url":null,"abstract":"<p><strong>Background: </strong>Penetrance of breast cancer (BC) among women who carry pathogenic variants (PVs) in <i>BRCA1</i> is incomplete, and the age at BC diagnosis varies considerably, even among carriers of the same PV, suggesting the involvement of genetic and non-genetic risk modifying factors. Polygenic Risk Score (PRS) models based on common sequence variants account for less than 10% of the total risk variability among <i>BRCA1</i> PV carriers, indicating that further genetic modifiers remain to be identified.</p><p><strong>Methods: </strong>Here, for the first time, we applied whole-exome sequencing for this challenge, investigating a cohort of 321 Israeli women carrying the <i>BRCA1</i> 185delAG founder PV.</p><p><strong>Results: </strong>In our cohort, we found that harbouring additional putatively damaging missense variants in genes involved in innate immunity was significantly associated with earlier BC onset. The HR for carrying a missense variant in genes annotated to the top-scoring immune-related gene set <i>NATURAL_KILLER_CELL_ACTIVATION</i> was 3.62 (95% CI 1.96 to 6.67; p=3.8×10^-5).</p><p><strong>Conclusion: </strong>These findings highlight a potential role for innate immune pathways as modifiers of <i>BRCA1</i> penetrance and support the development of more refined, personalised risk prediction models.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"415-420"},"PeriodicalIF":3.4,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592615","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}