European Journal of Human Genetics最新文献

{"title":"Penetrance and pleiotropy in ATXN2-related amyotrophic lateral sclerosis","authors":"Andrew G. L. Douglas","doi":"10.1038/s41431-025-01882-1","DOIUrl":"10.1038/s41431-025-01882-1","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 9","pages":"1093-1095"},"PeriodicalIF":4.6,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01882-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208089","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":"MYBPC3 c.2309-2A>G: exploring a founder variant in Italian hypertrophic cardiomyopathy patients.","authors":"Marco Fabiani, Caterina Micolonghi, Silvia Caroselli, Camilla Savio, Simona Petrucci, Giacomo Tini, Beatrice Musumeci, Erika Pagannone, Ludovica De Fazio, Aldo Germani, Vincenzo Visco, Antonio Pizzuti, Liana Veneziano, Enrica Marchionni, Ruggiero Mango, Laura Pezzoli, Irene Bottillo, Camilla Lucca, Agnese Scatigno, Lucrezia Goisis, Francesca Cappuccini, Maria Pia Ciccone, Adelaide Ballerini, Alessia Gozzini, Valerio Onofri, Carlotta Pia Cristalli, Andrea Latini, Daniela D'Angelantonio, Francesca Gualandi, Giada Tortora, Monia Magliozzi, Antonio Novelli, Cesare Rossi, Paola Grammatico, Federica Sangiuolo, Francesca Girolami, Maria Iascone, Iacopo Olivotto, Camillo Autore, Speranza Rubattu, Maria Piane","doi":"10.1038/s41431-025-01873-2","DOIUrl":"https://doi.org/10.1038/s41431-025-01873-2","url":null,"abstract":"<p><p>MYBPC3 pathogenic variants are the most common cause of hypertrophic cardiomyopathy (HCM) and are associated with significant phenotypic heterogeneity. Despite their pathogenic potential, MYBPC3 founder variants persist within specific populations. This study investigates the MYBPC3 c.2309-2 A > G splice variant hypothesizing its founder origin in central Italy. The aim was to confirm the presence of a common haplotype, assess its molecular and clinical impact, and compare the phenotype with that of other MYBPC3 founder variants. Among the 5251 HCM patients recruited at eight Italian referral centers, 1108 probands (21.1%) were identified as carriers of pathogenic or likely pathogenic MYBPC3 variants, and among these, 11.6% carried the c.2309-2 A > G variant. Haplotype reconstruction using short tandem repeats and tag-SNPs revealed a unique 5.2 Mb haplotype segregating with the c.2309-2 A > G variant in all carriers. Age estimation suggested that the variant originated approximately 481 years ago, likely in the Lazio region with clustering in Rome. Clinically, carriers exhibited variable expressivity with age-and sex-dependent penetrance. Males showed earlier onset, higher penetrance and greater disease severity compared to females. RNA analysis showed the retention of both introns 23 and 24, and significantly reduced MYBPC3 expression consistent with haploinsufficiency. Comparative analysis with other MYBPC3 founder variants highlighted differences in phenotypic expression, particularly in left ventricular wall thickness and clinical outcomes. This study establishes c.2309-2 A > G as an Italian MYBPC3 founder mutation, enhancing the understanding of HCM genetics and regional founder effects. These findings emphasize the importance of targeted genetic screening and personalized management for MYBPC3 c.2309-2 A > G carriers.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191662","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":"The development and usability of ‘The Genetics Navigator’: a digital solution for adult and paediatric clinical genetics services","authors":"Saumeh Saeedi,&nbsp;Daena Hirijkaka,&nbsp;Marc Clausen,&nbsp;Stephanie Luca,&nbsp;Emma Reble,&nbsp;Rita Kodida,&nbsp;Daniel Assamad,&nbsp;Lauren Chad,&nbsp;Gregory Costain,&nbsp;Hanna Faghfoury,&nbsp;Josh Silver,&nbsp;Serena Shastri-Estrada,&nbsp;Maureen Smith,&nbsp;Robin Z. Hayeems,&nbsp;Yvonne Bombard,&nbsp;The Genetics Navigator Study Team","doi":"10.1038/s41431-025-01871-4","DOIUrl":"10.1038/s41431-025-01871-4","url":null,"abstract":"Clinical genetic services address diverse genetic testing needs, but there is no comprehensive digital solution to meet this variety. We aimed to develop and test the usability of the Genetics Navigator (GN), a platform designed to enhance genetic services for paediatric and adult patients. The GN prototype was created with input from a patient and clinician advisory board, informed by prior research. Usability testing involved genetics patients (N = 14), parents of paediatric patients (N = 4), and the general public (N = 10). Participants provided feedback using the ‘think aloud’ method when using the platform. We used the System Usability Scale (SUS) for quantitative evaluation. Qualitative data were coded by platform section, item, and identified key areas for improvement. Building on the Genetics Adviser platform, we added video and written content for various genetic conditions and patient groups, including pre-test education, counselling, decision support, history collection, post-test result disclosure, and management. Key feedback during rounds of usability testing emphasized the need for a supportive design, seamless workflow, and engaging experience of the tool. The tool was modified to reflect the feedback, and the GN achieved an average SUS score of 87.7 ± 10.9 (N = 28), indicating above-average usability. Future research will evaluate its clinical and cost-effectiveness in a randomized trial.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 9","pages":"1188-1193"},"PeriodicalIF":4.6,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186845","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":"Workflow analysis and evaluation of a next-generation phenotyping tool: A qualitative study of Face2Gene","authors":"Katharina Wenderott,&nbsp;Jim Krups,&nbsp;Fiona Zaruchas,&nbsp;Peter Krawitz,&nbsp;Matthias Weigl,&nbsp;Hellen Lesmann","doi":"10.1038/s41431-025-01875-0","DOIUrl":"10.1038/s41431-025-01875-0","url":null,"abstract":"The diagnosis of rare genetic disorders often involves prolonged delays, with facial features serving as key diagnostic clues. Next-Generation Phenotyping (NGP) tools, such as Face2Gene, utilize Artificial Intelligence (AI)-driven algorithms to analyze patient photographs and list differential diagnoses based on facial dysmorphism. Despite their growing use and proven clinical value, their integration into clinical workflows remains poorly understood. This study evaluates Face2Gene’s implementation into routine clinical care with barriers and facilitators to successful adoption. We conducted a literature review, followed by in-depth interviews with 15 geneticists across university hospitals in Germany. Results showed an overall positive appraisal of the tool among clinicians with emphasis on its usability. Key workflow barriers comprised IT integration and patient consent process. Despite being an additional step in the diagnostic pathway, Face2Gene has been effectively incorporated into geneticists’ diagnostic routines, facilitating decision processes, and potentially expediting diagnoses for some patients. Our findings contribute to the existing literature on NGP technologies by demonstrating that effective integration of Face2Gene can enhance clinicians’ efficiency and quality of work. To maximize impact of NGP technologies in genetic medicine, future implementation efforts should strive for clinicians’ acceptance particularly through user-friendly design and sustained organizational support in course of workflow implementation. Study registration: German Register for Clinical Trials (DRKS) DRKS00032436","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 10","pages":"1333-1341"},"PeriodicalIF":4.6,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01875-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132290","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":"Biallelic loss-of-function variants in ZNF142 are associated with a robust DNA methylation signature affecting a limited number of genomic loci","authors":"Mathis Hildonen,&nbsp;Andrea Ciolfi,&nbsp;Marco Ferilli,&nbsp;Camilla Cappelletti,&nbsp;Chadi Al Alam,&nbsp;David J. Amor,&nbsp;Tahsin Stefan Barakat,&nbsp;Valérie Benoit,&nbsp;Ohad Shmuel Birk,&nbsp;Bert Callewaert,&nbsp;Ana Cazurro-Gutiérrez,&nbsp;Matthias De Wachter,&nbsp;Martine Doco-Fenzy,&nbsp;Paulino Gómez-Puertas,&nbsp;Trine Bjørg Hammer,&nbsp;Rami Abou Jamra,&nbsp;Rauan Kaiyrzhanov,&nbsp;Shinichi Kameyama,&nbsp;Boris Keren,&nbsp;Christina Kresge,&nbsp;Ilona Krey,&nbsp;Damien Lederer,&nbsp;Iñigo Marcos-Alcalde,&nbsp;Reza Maroofian,&nbsp;Naomichi Matsumoto,&nbsp;Takeshi Mizuguchi,&nbsp;Lip-Hen Moey,&nbsp;Angela Morgan,&nbsp;Francina Munell,&nbsp;Konrad Platzer,&nbsp;Beth A. Pletcher,&nbsp;David Ros-Pardo,&nbsp;Lynne Rumping,&nbsp;Katalin Szakszon,&nbsp;Kristof Van Schil,&nbsp;Edgard Verdura,&nbsp;Julie Vogt,&nbsp;Evangeline Wassmer,&nbsp;Mina Zamani,&nbsp;Zeynep Tümer,&nbsp;Marco Tartaglia","doi":"10.1038/s41431-025-01876-z","DOIUrl":"10.1038/s41431-025-01876-z","url":null,"abstract":"Biallelic inactivating variants in ZNF142 underlie a clinically variable neurodevelopmental disorder. ZNF142 is a zinc-finger transcription factor with potential roles on chromatin organization, implying a possible association of ZNF142 loss of function with perturbed genome-wide DNA methylation (DNAm) pattern. We performed EPIC array-based methylation profiling of peripheral blood-derived DNA samples from 27 individuals with biallelic ZNF142 inactivating variants, together with 6 heterozygous carriers and 40 controls. A DNAm signature discovery pipeline was applied by using 440 controls for discovery and validation analyses, and a machine-learning model was trained to classify 8 individuals carrying ZNF142 variants of uncertain clinical significance. Analyses directed to explore the genome-wide DNAm landscape in affected individuals revealed 88 differentially methylated probes constituting the minimal informative set specific to ZNF142 loss of function. This reproducible pattern of DNAm changes involved regulatory regions of a small number of genes. The DNAm signature derived from peripheral blood allowed us to diagnose individuals carrying biallelic inactivating ZNF142 variants when applied to fibroblasts. Our findings provide evidence that biallelic loss-of-function ZNF142 variants result in a specific and robust DNAm signature. The identified DNAm pattern suggests occurrence of a methylation disturbance involving a small number of loci that appears to be shared by different cell lineages.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 7","pages":"896-903"},"PeriodicalIF":3.7,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132060","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":"View of healthcare professionals on ultra-rapid genome sequencing and its future implementation in clinical practice for critically ill children","authors":"Claire Caillot,&nbsp;Etienne Javouhey,&nbsp;Stéphane Hays,&nbsp;Evan Gouy,&nbsp;Pauline Monin,&nbsp;Gaetan Lesca,&nbsp;Damien Sanlaville,&nbsp;Nicolas Chatron","doi":"10.1038/s41431-025-01869-y","DOIUrl":"10.1038/s41431-025-01869-y","url":null,"abstract":"The clinical utility of ultra-rapid genome sequencing (urGS) in neonatal and paediatric intensive care situations has been demonstrated, and barriers to its implementation in clinical practice studied. A 38-item questionnaire was distributed via medical professional learned societies to identify the views of French healthcare professionals in the field prior to its implementation. Overall, 116 responses were received: 35% from healthcare professionals working in clinical genetics, 19% in laboratory genetics, and 32% in paediatric or neonatal intensive care units (NICU/PICU). Nearly all (97%) respondents agreed that healthcare professionals should receive specific training before a first test order; 94% considered urGS useful, and 97% that the results would likely modify a decision to withdraw life-sustaining treatment. A multidisciplinary approval of the urGS request was considered necessary by 87% of respondents, and multidisciplinary discussion of the result by 84%; joint disclosing of results by a clinical geneticist and NICU/PICU physician was considered ideal for 91% of respondents, and 78% were against additional findings being disclosed at the same time as the result. For 99% of respondents, psychological assistance was crucial after the result. Based on the results, we propose a workflow to facilitate implementation in a broad range of centres.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 7","pages":"937-944"},"PeriodicalIF":3.7,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-025-01869-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132287","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":"Determining a role for Patient and Public Involvement and Engagement (PPIE) in genomic data governance for cancer care.","authors":"Katherine Sahan, Lesley Turner, Nina Hallowell, Michael Parker, Anneke Lucassen","doi":"10.1038/s41431-025-01866-1","DOIUrl":"10.1038/s41431-025-01866-1","url":null,"abstract":"<p><p>Comprehensive collections of cancer data, including genomic data, are needed to improve cancer risk prediction and treatments. A recent government review, Better, Broader, Safer: Using health data for research and analysis, has argued for high-quality Patient and Public Involvement and Engagement (PPIE) for ethical data use. In this paper we determine a role and justification for PPIE to govern uses of genomic data in fields like cancer. First, we analyse two public attitudes studies about the role of PPIE in genomics governance. Second, we characterise two ethically-significant features of the context of governing genomic data: 1) data aggregation leading to novel group formation, and 2) the hybrid territory of genomic cancer data uses. Thirdly, we bring together these aspects to describe a fully determined role for PPIE within an approach to governing cancer genomic data, which is tailored to major areas of ethical consideration. Our account is a novel interpretation of what PPIE is for in governance, how it may foster public support and how its success in so doing depends on it being tailored to context.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132138","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":"Impact of rapid genomic testing on clinical outcomes of acutely unwell children presenting with severe epilepsy","authors":"Erina Sasaki,&nbsp;Philip Millington,&nbsp;Taisiia Sazonova,&nbsp;Lucy Hanington,&nbsp;Andrew Parrish,&nbsp;Benito Banos-Pinero,&nbsp;Helen Lord,&nbsp;John Taylor,&nbsp;Ramanand Jeeneea,&nbsp;Charlotte Sherlaw-Sturrock,&nbsp;Amitav Parida,&nbsp;Julie Vogt,&nbsp;Swathi Naik,&nbsp;Mario Sa,&nbsp;Usha Kini","doi":"10.1038/s41431-025-01870-5","DOIUrl":"10.1038/s41431-025-01870-5","url":null,"abstract":"About 30% of epilepsy patients remain unresponsive to standard antiseizure treatment. Increasing evidence suggests that genetic epilepsies may respond better to targeted management. In this study, we therefore evaluate the therapeutic benefits of rapid genetic testing in children with severe epilepsy. Methods: the clinical data of patients with epilepsy referred for rapid whole-exome sequencing were systematically collected at two large paediatric/neurogenetic centres (Birmingham/Oxford) in the United Kingdom over 3 years (2019–2022), with follow-up at 12 months post-diagnosis. The demographics, diagnostic yield, management by gene function and seizure group (SZ-seizures only or SZ+ seizures with co-morbidities) were explored. Results: among the 106 eligible patients, the age at testing ranged from 0 to 16 years with a median of 7 months. Underserved ethnic groups, e.g., British Asians and Black British, were well-represented. Thirty-nine genes affecting 49 patients were identified, giving an overall diagnostic yield of 46%, which was further enhanced to 51% (31/61) in the SZ+ group. Twenty percent of genes identified affect ion channels and patients were more likely to present early (&lt;6 months old) and respond to a gene-directed treatment (p = 0.004483). Seizures secondary to metabolic disorders responded to bespoke therapy. A fifth (22/106) of tested patients and 45% (22/49) of those diagnosed had their management impacted. At the 12-month follow-up, 9/15 (60%) patients remained seizure-free following gene-targeted management. Conclusion: this study demonstrates high diagnostic yield and significant therapeutic benefit from rapid genetic testing in patients with epilepsy. The gene function categories were statistically significant predictors of management change.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 10","pages":"1324-1332"},"PeriodicalIF":4.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41431-025-01870-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119229","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":"Tools used to appraise the quality of studies included in systematic reviews and meta-analyses in human genetics: a systematic review.","authors":"Carmen Lindsay, Ingeborg Blancquaert, François Rousseau","doi":"10.1038/s41431-025-01861-6","DOIUrl":"https://doi.org/10.1038/s41431-025-01861-6","url":null,"abstract":"<p><p>Quality assessment of primary studies is an essential component of systematic reviews (SRs). This methodological review systematically examines the choice, format and utilization of critical appraisal (CA) tools in SRs with or without meta-analyses in the field of human genetics. We searched MEDLINE, Embase, Web of Science, and PubMed up to January 2024. Two reviewers independently performed title, abstract, full-text screening and data extraction. This PROSPERO registered methodological review followed PRISMA guidelines. Meta-analysis and full-scale risk-of-bias assessment of SRs were not relevant. Among 149 randomly selected SRs, 136 mentioned CA tools (156 citations). Nineteen different generic tools constituted 71.2% of citations. NOS, QUADAS and the Cochrane risk-of-bias tool represented 36.5, 11.5, and 8.3% of tools, respectively. Ninety-three reviews stated following reporting guidelines, with 22 PRISMA checklists accessible. Detailed presentation of results was observed for 65.8% of generic and 37.8% of customized tools (p = 0.0013). Results for NOS were less often detailed than for other generic tools (p < 0.0001). Few SRs used CA results for study selection, data analysis, or discussion of findings. In conclusion, this first review of CA tools in human genetics SRs highlights a lack of transparency regarding utilization of CA tools and deficiencies in reporting of CA results.Registration: PROSPERO (CRD42023449349).</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119230","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":"Expanding the understanding of DDX3X-related neurodevelopmental disorder in males","authors":"Silvia De Rubeis","doi":"10.1038/s41431-025-01879-w","DOIUrl":"10.1038/s41431-025-01879-w","url":null,"abstract":"","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 8","pages":"978-979"},"PeriodicalIF":4.6,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110151","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}