European Journal of Human Genetics最新文献

{"title":"Vascular Ehlers Danlos Syndrome and Chromosome 2q32 Microdeletion Syndrome.","authors":"Claire E Green, Shadi Albaba, Glenda J Sobey, Jessica M Bowen, Deirdre E Donnelly, Marina Colombi, Marco Ritelli, Athalie Melville, Neeti Ghali, Fleur S van Dijk, Emma Hobson, Jessica A Radley, Esther Kinning, Abhijit Dixit, Simon McCullough, Duncan Baker, Diana S Johnson","doi":"10.1038/s41431-025-01849-2","DOIUrl":"https://doi.org/10.1038/s41431-025-01849-2","url":null,"abstract":"<p><p>Interstitial deletions of 2q32 are typically identified after investigation for developmental delay. Two genes associated with Ehlers Danlos Syndrome (EDS); COL3A1 and COL5A2 associated with vascular EDS and classical EDS respectively, may be incorporated in the region. Although many reports of 2q32 microdeletion patients exist, there is little mention of these genes with only a few reports highlighting features potentially linked with EDS. This paper reviews the literature and presents eleven new patients with 2q32 deletions that encompass COL3A1 and COL5A2. We describe their clinical manifestations with a particular focus on the EDS phenotype. Most patients showed some minor features of vascular EDS and one patient had vessel rupture at a young age. Analysis of skin biopsy findings from two patients showed features consistent with vascular EDS but no features of classical EDS. The findings from this cohort provide additional evidence that haploinsufficiency is an important disease mechanism in COL3A1 but not COL5A2. We highlight the importance of pre-test counselling for incidental findings from broad genetic testing and appropriate post-test counselling to ensure follow up is provided to manage the implications of a vascular EDS diagnosis.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Empowering human research ethics committees to review genomics applications: evaluating the utility of a custom online education resource","authors":"Ella McGahan,&nbsp;Jennifer Berkman,&nbsp;David Milne,&nbsp;Bronwyn Terrill,&nbsp;Russell Gear,&nbsp;Susan Gardiner,&nbsp;Lisa Eckstein,&nbsp;Dianne Nicol,&nbsp;Natalie Taylor,&nbsp;Ingrid Winship,&nbsp;Rebekah McWhirter,&nbsp;Amy Nisselle,&nbsp;Jason Lodge,&nbsp;Aideen McInerney-Leo","doi":"10.1038/s41431-025-01846-5","DOIUrl":"10.1038/s41431-025-01846-5","url":null,"abstract":"Complex genomic technologies are increasingly utilised in research. However, human research ethics committee (HREC) members lack confidence reviewing genomics applications. This study developed and evaluated the acceptability and utility of an online educational resource on genomics and the ethical considerations for HREC members. Resource development and evaluation was theoretically informed. Qualitative semi-structured interviews with HREC members and subject experts were transcribed and deductively analysed. Participants (n = 29) found the content to be comprehensive, appropriately pitched, and optimal in quantity. Most reported the resource was easy to access and intuitive to navigate. HREC members reported improved confidence in reviewing genomics ethics applications and intentions to re-access as needed. Most (n = 28/29) would recommend to other HREC members, and some volunteered that they would recommend to researchers. Suggested navigation improvements included a progress bar, active learning elements, and a more clearly visible menu. Content suggestions included more detail on data storage/management and considerations when engaging diverse communities. This is the first study to develop and evaluate a genomic educational resource tailored to ethics committees. Following refinement and quantitative evaluation, it is hoped that this resource will increase HREC member confidence in reviewing genomics ethics applications and the quality of researchers’ submissions.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 7","pages":"945-955"},"PeriodicalIF":3.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-025-01846-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cost-effectiveness of population-based expanded reproductive carrier screening for genetic diseases in Australia: a microsimulation analysis.","authors":"Deborah Schofield, Evelyn Lee, Jayamala Parmar, Adriana Castelo Taboada, Matthew Hobbs, Nigel Laing, Rupendra Shrestha","doi":"10.1038/s41431-025-01835-8","DOIUrl":"https://doi.org/10.1038/s41431-025-01835-8","url":null,"abstract":"<p><p>Using the Australian Census survey 2021 as base population, a microsimulation model, PreconMOD was developed to evaluate the cost-effectiveness of population-based expanded reproductive carrier screening (RCS) for 569 recessive conditions from the health service and societal perspectives. The model simulated the effect of expanded RCS including the downstream interventions for at-risk couples on cost and outcomes. The comparators were (i) no population screening (ii) limited screening for cystic fibrosis, spinal muscular atrophy, and fragile X syndrome and (iii) a 300 conditions screening panel. Averted affected births and health service cost with expanded RCS were projected to year 2061. At a 50% uptake, our model predicts that expanded RCS is cost saving (i.e., higher quality-adjusted life-years and lower costs) compared with other screening strategies in the model from the health service and societal perspectives. The number of affected births averted in a single cohort would increase from 84 [95% confidence interval (CI) 60-116] with limited screening to 2067 (95%CI 1808-2376) with expanded RCS. Expanded RCS was cost-saving compared to the 300-conditions screening panel. Indirect cost accounted for about one-third of the total costs associated with recessive disorders. Our model predicts that the direct treatment cost associated with current limited 3 genes screening would increase by 20% each year to A$73.4 billion to the health system by 2061. Our findings contribute insights on the cost burden of genetic diseases and the economic benefits of expanded RCS to better informed resource allocation decisions.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What’s new in April’s EJHG?","authors":"Alisdair McNeill","doi":"10.1038/s41431-025-01842-9","DOIUrl":"10.1038/s41431-025-01842-9","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 4","pages":"393-394"},"PeriodicalIF":3.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-025-01842-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benchmark of computational methods to detect digenism in sequencing data","authors":"Marie-Sophie C. Ogloblinsky,&nbsp;Donald F. Conrad,&nbsp;Anaïs Baudot,&nbsp;Elisabeth Tournier-Lasserve,&nbsp;The FrEx Consortium,&nbsp;Emmanuelle Génin,&nbsp;Gaëlle Marenne","doi":"10.1038/s41431-025-01834-9","DOIUrl":"10.1038/s41431-025-01834-9","url":null,"abstract":"Digenic inheritance is characterized by the combined alteration of two different genes leading to a disease. It could explain the etiology of many currently undiagnosed rare diseases. With the advent of next-generation sequencing technologies, the identification of digenic inheritance patterns has become more technically feasible, yet still poses significant challenges without any gold standard method. Here, we present a comprehensive overview of the existing methods developed to detect digenic inheritance in sequencing data and provide a classification in cohort-based and individual-based methods. The latter category of methods appeared the most applicable to rare diseases, especially the ones not needing patient phenotypic description as input. We discuss the availability of the different methods, their output and scalability to inform potential users. Focusing on methods to detect digenic inheritance in the case of very rare or heterogeneous diseases, we propose a benchmark using different real-life scenarios involving known digenic and putative neutral pairs of genes. Among these different methods, DiGePred stood out as the one giving the least number of false positives, ARBOCK as giving the greatest number of true positives, and DIEP as having the best balance between both. By synthesizing the state-of-the-art techniques and providing insights into their practical utility, this benchmark serves as a valuable resource for researchers and clinicians in selecting suitable methodologies for detecting digenic inheritance in a wide range of disorders using sequencing data.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 7","pages":"831-841"},"PeriodicalIF":3.7,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ethics in editorship: lessons from a major retraction incident","authors":"Joris A. Veltman","doi":"10.1038/s41431-025-01847-4","DOIUrl":"10.1038/s41431-025-01847-4","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 5","pages":"561-562"},"PeriodicalIF":3.7,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-025-01847-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The value of large-scale programmes in human genomics","authors":"Ruth Horn,&nbsp;Angeliki Kerasidou,&nbsp;Jennifer Merchant,&nbsp;The UK-FR+GENE (Genetics and Ethics Network) Consortium","doi":"10.1038/s41431-025-01844-7","DOIUrl":"10.1038/s41431-025-01844-7","url":null,"abstract":"Large national genomic programmes have been created in many countries, including France, England and Germany, to advance the realisation of the potential genomic medicine holds to significantly contribute to society by improving health, and driving science, innovation and the economy. To reach this ambition, these programmes collect, manage and analyse big genomic datasets. While there is much talk about the promises, and hence the importance of genomics, there is little in-depth analysis of the actual contribution or value—here understood as benefits—of genomics for society at large. To explore the issue of the value of large-scale genomic programmes for society, UK-FR-D+ GENE held an international workshop focusing on a variety of levels—societal, economic, clinical, scientific, and population-wide level—at which such benefits might be observed. First, the broader societal implications of large genome programmes and their impact for public trust were discussed. Second, the meaning of fair and just allocation of public resources, based on considerations of the economic costs and benefits of genomic innovations, was examined. Third, the benefits of these innovations for stakeholders (clinicians, patients, and families) at the clinical level were investigated. Fourth, the scope and limitations of genomics at the scientific level were discussed. Finally, the potential of genomics to improve health at the population level was explored. Providing an insight into the benefits of large genomic programmes on various levels, the workshop concluded by defining several criteria that should be considered to ensure benefits for society when implementing large genomic programmes.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 5","pages":"563-569"},"PeriodicalIF":3.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-025-01844-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Structural variant calling and clinical interpretation in 6224 unsolved rare disease exomes.","authors":"German Demidov, Steven Laurie, Annalaura Torella, Giulio Piluso, Marcello Scala, Manuela Morleo, Vincenzo Nigro, Holm Graessner, Siddharth Banka, Katja Lohmann, Stephan Ossowski","doi":"10.1038/s41431-025-01841-w","DOIUrl":"https://doi.org/10.1038/s41431-025-01841-w","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perinatal genetic diagnostic yield in a population of fetuses with the phenotype arthrogryposis multiplex congenita: a cohort study 2007-2021.","authors":"Arda Arduç, Johanna I P De Vries, Maria B Tan-Sindhunata, Quinten Waisfisz, Eva Pajkrt, Ingeborg H Linskens","doi":"10.1038/s41431-025-01848-3","DOIUrl":"10.1038/s41431-025-01848-3","url":null,"abstract":"<p><p>Arthrogryposis multiplex congenita (AMC) presents challenges for prenatal detection due to its heterogeneous etiology, onset, and phenotypical manifestations. This study aims to describe the genetic diagnostic yield in a population of fetuses with detailed phenotypic description over a 15-year period (2007-2021) at the Fetal Medicine Unit of Amsterdam UMC, the Netherlands. The fetal and neonatal phenotypes were classified into three clinical AMC Groups, with the exception that Groups 1 and 2 were combined in the prenatal classification. Group 1 involves limb involvement primarily, Group 2 includes musculoskeletal involvement plus other system anomalies, and Group 3 involves musculoskeletal involvement with central nervous system disability, lethality, fetal akinesia deformation sequence, and/or intellectual disability. The cohort consisted of 64 consecutive cases, 13 in Groups 1 + 2 and 51 in Group 3. Perinatal genetic testing occurred in all cases: prenatally in 56 of the 64 (88%), postnatally in 36 of the 64 (56%), and combined testing in 28 of the 64 cases (44%). The overall genetic diagnostic yield was 28% (18/64), and it increased over the 5-year period from 14% to 50%. Whole exome sequencing had the highest yield (41.7%). The yield per phenotype was 30.8% (4/13) for AMC Group 1 + 2 and 27.4% (14/51) for AMC Group 3. Detailed fetal phenotyping and perinatal genetic testing in all cases showed improved diagnostic yield over time, likely due to the introduction of Next-generation sequencing-based tests. The availability of stored DNA will be beneficial for future investigations since further improvements in genetic testing possibilities are expected.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reanalysis of unsolved prenatal exome sequencing for structural defects: diagnostic yield and contribution of postnatal/postmortem features","authors":"Christel Thauvin-Robinet,&nbsp;Aurore Garde,&nbsp;Maud Favier,&nbsp;Julian Delanne,&nbsp;Caroline Racine,&nbsp;Thierry Rousseau,&nbsp;Sophie Nambot,&nbsp;Ange-Line Bruel,&nbsp;Sébastien Moutton,&nbsp;Chloé Quelin,&nbsp;Cindy Colson,&nbsp;Anne-Claire Brehin,&nbsp;Anne-Marie Guerrot,&nbsp;Caroline Rooryck,&nbsp;Audrey Putoux,&nbsp;Patricia Blanchet,&nbsp;Sylvie Odent,&nbsp;Elise Schaefer,&nbsp;Odile Boute,&nbsp;Alice Goldenberg,&nbsp;Agnes Guichet,&nbsp;Carine Abel,&nbsp;Godelieve Morel,&nbsp;Melanie Fradin,&nbsp;Bertrand Isidor,&nbsp;Marie Vincent,&nbsp;Christine Francannet,&nbsp;Gabriella Vera,&nbsp;Florence Petit,&nbsp;Mathilde Nizon,&nbsp;Constance Wells,&nbsp;Mederic Jeanne,&nbsp;Caroline Deiller,&nbsp;Alban Ziegler,&nbsp;Manon Godin,&nbsp;Pascale Saugier-Veber,&nbsp;Kevin Cassinari,&nbsp;Pierre Blanc,&nbsp;Emmanuel Simon,&nbsp;Christine Binquet,&nbsp;Yannis Duffourd,&nbsp;Hana Safraou,&nbsp;Anne-Sophie Denomme-Pichon,&nbsp;Antonio Vitobello,&nbsp;Christophe Philippe,&nbsp;Laurence Faivre,&nbsp;Frédéric Tran-Mau-Them,&nbsp;Nicolas Bourgon","doi":"10.1038/s41431-025-01823-y","DOIUrl":"10.1038/s41431-025-01823-y","url":null,"abstract":"In 30–40% of fetuses with structural defects, the causal variant remains undiagnosed after karyotype, chromosomal microarray, and exome sequencing. This study presents the results of a reanalysis of unsolved prenatal ES (pES) cases and investigates how postnatal/postmortem phenotyping contributes to identifying relevant variants. pES data was prospectively reanalyzed for unsolved cases enrolled in the AnDDI-Prénatome cohort study. Postnatal/postmortem data were included with prenatal features using Human Phenotype Ontology terms up to 3 years after pES. The reanalysis involved updating bioinformatic processing and querying raw data using a GREP query. We reanalyzed 58/94 (62%) unsolved pES cases, including 8 variants of unknown significance. Data for clinical examination at birth was available for all live newborns, and postmortem examination was available in 12 terminated fetuses. Additional features were identified at birth in 27/58 cases (44%): 9 terminated fetuses, 2 stillbirths, and 16 live newborns. One diagnosis (SNAPC4) was obtained through a periodic query following recent associations with human disease, and without additional clinical data. Three additional VUS were identified through reanalysis with the addition of new clinical features, illustrating the limited contribution of updated postnatal/postmortem phenotyping in identifying relevant variants after negative pES. In conclusion, the benefit of prospective reanalysis of unsolved pES is limited, even over time. Postnatal genome sequencing may be a more appropriate option than reanalysis with postnatal/postmortem phenotyping to establish a causal diagnosis.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 5","pages":"675-682"},"PeriodicalIF":3.7,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}