Genetics in Medicine最新文献

{"title":"ACMG SF v3.3 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG)","authors":"Kristy Lee , Noura S. Abul-Husn , Laura M. Amendola , Kyle B. Brothers , Wendy K. Chung , Michael H. Gollob , Adam S. Gordon , Steven M. Harrison , Ray E. Hershberger , Marilyn Li , Deborah Ondrasik , C. Sue Richards , Andrew Stergachis , Douglas R. Stewart , Christa Lese Martin , David T. Miller , ACMG Secondary Findings Working Group","doi":"10.1016/j.gim.2025.101454","DOIUrl":"10.1016/j.gim.2025.101454","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 8","pages":"Article 101454"},"PeriodicalIF":6.6,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144338932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imprecision medicine: Systematic gaps in reporting variants of uncertain significance (VUS) and their reclassifications.","authors":"Andrew Folta, Adriana E Sedeño Cortés, Pankhuri Gupta, Abbye E McEwen, Eric Y Kao, Martha Horike-Pyne, Jeremy Stone, Brian H Shirts, Marianne E Dubard-Gault, Douglas M Fowler, Lea M Starita, Fuki M Hisama, Andrew B Stergachis","doi":"10.1016/j.gim.2025.101501","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101501","url":null,"abstract":"<p><strong>Purpose: </strong>Variants of uncertain significance (VUS) are frequently encountered during clinical genetic testing. To explore the clinical burden of VUS, we developed the Brotman Baty Institute Clinical Variant Database (BBI-CVD), which is an Electronic Health Record (EHR)-linked database of clinical germline genetic variant information from patients with rare genetic disorders seen at two tertiary academic medical centers.</p><p><strong>Methods: </strong>We retrospectively reviewed EHRs and genetic testing reports from 5,158 patients seen across diverse adult genetics practices at these institutions from 2015 to 2024. We also compared these EHR-based variant classifications to those in ClinVar.</p><p><strong>Results: </strong>The number of reported VUS relative to Pathogenic or Likely Pathogenic variants can vary by over 14-fold depending on the primary indication for genetic testing and 3-fold depending on self-reported race. Furthermore, at least 1.6% of variant classifications used in the EHR for clinical care are outdated based on ClinVar variant classifications, including 26 instances where the testing lab updated ClinVar, but the reclassification was never communicated to the patient.</p><p><strong>Conclusions: </strong>Our findings reveal that the clinical burden of VUS in adult medical genetics is unequally distributed across patients. We also highlight a deficiency in existing systems for communicating variant reclassifications to ClinVar, patients, and providers.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101501"},"PeriodicalIF":6.6,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gaucher disease Type 3: classification of the chronic neuronopathic variant informed by genotype in a phenotypically diverse cohort.","authors":"Aimée Donald, Simon A Jones, Derralynn A Hughes, Heather J Church, Timothy M Cox","doi":"10.1016/j.gim.2025.101502","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101502","url":null,"abstract":"<p><strong>Purpose: </strong>Type 3 Gaucher disease, the chronic neuronopathic form caused by biallelic pathogenic variants in GBA1, is clinically heterogeneous and there have been few comprehensive studies of its natural history and phenotypic diversity. The greatest unmet clinical need is for disease-modifying treatment for the neurological manifestations, but the inability to identify unifying features in the existing nomenclature that would facilitate establishment of eligibility criteria and suitable endpoints in clinical trials, is a major challenge for therapeutic development.</p><p><strong>Methods: </strong>A multi-centre cohort study in England, GAUCHERITE, undertook retrospective and prospective clinical evaluation of patients with Gaucher disease; this sub-study is focussed on patients with nGD. The research cohort is registered with ClinicalTrials.gov, NCT code, 03240653.</p><p><strong>Results: </strong>42 patients with neuronopathic GD were recruited; 16 male and 26 female; nine patients had died (age of death 4 - 28 years), living patients aged 6-61yrs. We categorise them clinically (\"attenuated\", \"intermediate\" and \"severe\") and on the basis of defined pathogenic variants in GBA1. Childhood disease manifestations provide prognostic utility, especially in context of genotype.</p><p><strong>Conclusions: </strong>This work captures the full phenotypic spectrum and striking clinical diversity of neuronopathic Gaucher disease not encompassed by the existing nomenclature. We propose a novel descriptive system of phenotypic cateogrization: while this requires refinement and validation across the global population, it seeks to stimulate further exploration of disease behaviours that can be clearly stratified. By these means, we contend that identification of disease manifestations likely to respond to interventions with distinct modes of action in appropriate patient groups, will enhance the value of clinical trial programs and accelerate much needed therapeutic development.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101502"},"PeriodicalIF":6.6,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Clinician-reported Genetic testing Utility InDEx for neonatal intensive care (C-GUIDE NICU): Quantifying Genome-wide Sequencing Utility in the NICU.","authors":"Lena I Dolman, Joyce Yan, Stephanie Luca, Bowen Xiao, Salma Shickh, Elise Poole, Lauren Chad, Wendy J Ungar, Martin Offringa, Robin Z Hayeems","doi":"10.1016/j.gim.2025.101503","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101503","url":null,"abstract":"<p><strong>Purpose: </strong>Use of genomic sequencing (GS) in neonatal intensive care units (NICUs) has increased with improved diagnostic yield. However, uncertainty persists regarding when and for whom GS is most useful. Since a standardized approach to assessing utility is lacking, we developed a novel version of the Clinician-reported Genetic testing Utility InDEx (C-GUIDE^TM) to quantify the utility of GS in NICUs.</p><p><strong>Methods: </strong>Informed by a scoping review, we developed a draft C-GUIDE NICU tool to quantify utility which underwent iterative revisions through feedback from clinician interviews and questionnaires on item relevance, comprehensibility, and comprehensiveness. We finalized the expert-informed C-GUIDE NICU using an international Delphi consensus process.</p><p><strong>Results: </strong>Scoping review (n=25 articles) and interviews (n=21) revealed key themes of utility. Guided by qualitative feedback and item scoring, C-GUIDE was iteratively reduced to include 21, 18, and 14 items. The Delphi consensus process with 22 experts achieved item consensus and stability, yielding a final 10-item tool.</p><p><strong>Conclusion: </strong>Using a rigorous process, we developed a consensus-based standardized method for capturing the clinical utility of GS in NICUs. C-GUIDE NICU can be used by clinicians, researchers, and payers to assess GS value to patient care, and will be available for licensed use following reliability and validity testing.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101503"},"PeriodicalIF":6.6,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency: From metabolism to clinical implications.","authors":"Sarah C Grünert, Matthias R Baumgartner, Juliette Bouchereau, Alberto Burlina, Peter T Clayton, Javier de Las Heras, Carlo Dionisi-Vici, Corinne Gemperle-Britschgi, Claudia Haase, Stanley H Korman, Johannes Krämer, Eva Kühlwein, Esther M Maier, Arianna Maiorana, Manuel Schiff, Carl Ulrich Schmid, Trine Tangeraas, Raina Yamamoto, Johannes Zschocke, Jörn Oliver Sass","doi":"10.1016/j.gim.2025.101484","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101484","url":null,"abstract":"<p><strong>Purpose: </strong>Ketone bodies represent an important energy source and can contribute much to the energy supply of the brain. Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency (HMGCS2D) is an autosomal recessive disorder of ketogenesis caused by biallelic variants in HMGCS2. Only 59 patients with this disorder have been reported so far.</p><p><strong>Patients and methods: </strong>We performed a comprehensive literature search to identify all published cases of HMGCS2D (n=59). Additionally, data of 16 yet undescribed patients with this disorder were collected. Clinical course, biochemical findings and mutation data are highlighted and discussed. An overview on all HMGCS2 variants reported in patients is provided.</p><p><strong>Results: </strong>Sixty-eight patients (91%) presented with an acute metabolic decompensation, mostly within the first year of life, but beyond the neonatal period. Asymptomatic individuals were identified in several families. Six patients (8%) had died, mainly during the initial metabolic crisis. The neurologic long-term outcome of surviving patients was favorable with almost all patients (98%) showing normal development. Only one variant was identified to be common, (HMGCS2) NM_005518.4: c.634G>A, p.(Gly212Arg), and found in 6 families. No genotype-phenotype correlation can be established.</p><p><strong>Discussion: </strong>This comprehensive data analysis provides an overview on all published patients reported with HMGCS2D including a list of HMGCS2 variants identified in affected individuals.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101484"},"PeriodicalIF":6.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Medicaid claims from 2008 to 2016 indicate low rates of genetic testing among children with intellectual disability and autism spectrum disorder.","authors":"Tashalee R Brown, Wei-Lin Lee, Jonas Ventimiglia, Audrey Thurm, Tess Levy, Victoria Yuan, Julian A Martinez-Agosto, Lindsay L Shea","doi":"10.1016/j.gim.2025.101451","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101451","url":null,"abstract":"<p><strong>Purpose: </strong>Little is known nationally about the clinical implementation of existing genetic testing medical guidelines for children with autism spectrum disorder (ASD) and/or intellectual disability (ID) among those enrolled in Medicaid or Children's Health Insurance Program plans.</p><p><strong>Methods: </strong>Children with diagnosis codes for ASD-only, ID-only, and ASD + ID were identified using established algorithms with 2008 to 2016 Medicaid claims data. The outcome measure is the cumulative proportion of individuals with genetic testing procedure codes.</p><p><strong>Results: </strong>The cohort consisted of 241,060 children aged 7 to 17 years. The frequency of genetic testing was low across diagnoses, with ASD + ID showing the highest frequency of 25.94%. The ASD + ID cohort had the highest odds of genetic testing (aOR = 29.43 [95% CI 27.57-31.41]) compared with a random sample of children without ASD or ID. Cytogenetics and Fragile X testing were the predominant testing types used up to 2013, followed by increasing use of chromosomal microarray analysis and gene panels in 2014 to 2016.</p><p><strong>Conclusion: </strong>The results suggest that the clinical implementation of genetic testing in children with neurodevelopmental disabilities in the Medicaid-enrolled population was low in frequency compared with the eligible population with neurodevelopmental disorders. Further research could identify facilitators and barriers to the clinical use of genetic testing in this population.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101451"},"PeriodicalIF":6.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing participant and community engagement in cancer genomic sequencing research.","authors":"Norah L Crossnohere, Anne L R Schuster, Cindy K Blair, Hasani Bland, John D Carpten, Elizabeth B Claus, Graham A Colditz, Diane Diehl, Li Ding, Bettina F Drake, Ryan C Fields, Suzanne George, Katherine Janeway, Hyoshin Kim, Heinz-Josef Lenz, Jennifer W Mack, Charité Ricker, Mariana C Stern, Andrew Sussman, Jeffrey Trent, Eliezer Van Allen, Roel Verhaak, Cheryl Willman, John F P Bridges, Shiraz I Mishra, Bethany M Kwan","doi":"10.1016/j.gim.2025.101483","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101483","url":null,"abstract":"<p><strong>Purpose: </strong>We describe strategies implemented across research centers of the Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network to optimize engagement of participants and communities in cancer genomics research. We also present consensus definitions of engagement and engagement optimization, informed by our shared experiences in the Network.</p><p><strong>Methods: </strong>Key informant interviews and a document review identified engagement and optimization strategies across PE-CGS research centers. Findings were synthesized using qualitative content analysis. Consensus on definitions of engagement and optimization were developed through iterative review by PE-CGS members.</p><p><strong>Results: </strong>PE-CGS research centers adopted tailored strategies based on community needs and scientific gaps. Engagement strategies included community-based efforts (e.g., advisory boards, newsletters) and participant-focused approaches (e.g., enhanced informed consent, decision-support tools). Optimization strategies leveraged scientific methods (e.g., randomized controlled trials, surveys) to evaluate engagement. Engagement was described as the sustained and meaningful interactions between researchers, participants, and communities. Optimization was described as the application of scientific methods to refine and improve engagement and research processes and outcomes.</p><p><strong>Conclusions: </strong>Engagement and optimization strategies have informed research planning, conduct, and dissemination across PE-CGS. These approaches and definitions provide a foundation for developing evidence-based practices to strengthen participant and community involvement in cancer genomics research.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101483"},"PeriodicalIF":6.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The importance of residual newborn screening dried blood spots, 2025 revision: A position statement of the American College of Medical Genetics and Genomics (ACMG).","authors":"Nancy C Rose, Michele Caggana, Mary Beth Dinulos, Leslie Francis, Michele A Lloyd-Puryear, Andrea Matthews, Michelle L McClure, Cynthia M Powell, Changrui Xiao","doi":"10.1016/j.gim.2025.101433","DOIUrl":"10.1016/j.gim.2025.101433","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101433"},"PeriodicalIF":6.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Statement of ACMG, ACMGF, and Drs. Muenke and Williams.","authors":"","doi":"10.1016/j.gim.2025.101468","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101468","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101468"},"PeriodicalIF":6.6,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Costs and cost-effectiveness of returning secondary findings from genomic sequencing based on the return of additional findings in the 100,000 Genomes Project.","authors":"Emma J Smith, Melissa Hill, Lyn S Chitty, Stephen Morris","doi":"10.1016/j.gim.2025.101479","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101479","url":null,"abstract":"<p><strong>Purpose: </strong>To assess costs and cost-effectiveness of returning additional findings from genome sequencing (GS) using data from the 100,000 Genomes Project (100kGP).</p><p><strong>Methods: </strong>A model-based cost-utility analysis combining yield, consent rates and cost data from the 100kGP with published estimates of downstream costs and quality-adjusted life years (QALYs) expected to accrue over a lifetime, following identification of a pathogenic variant.</p><p><strong>Results: </strong>The cost of returning additional findings to participants in the 100kGP was £7.1m or £81 per participant, with a yield of 0.85% for consented participants. The estimated lifetime incremental cost per participant was £125 and QALYs 0.004, giving an ICER of £28,830. Implementing a policy of returning additional findings is unlikely to be cost-effective (ie, 13%) at a willingness-to-pay threshold of £20,000. A short-term cost of returning findings of £43 per participant or lower (compared to the base case of £81) would result in an ICER of less than £20,000. Alternatively, cost-effectiveness may be improved by returning AFs to younger patient populations.</p><p><strong>Conclusion: </strong>Return of additional findings following GS for this group of conditions may not be a cost-effective use of healthcare system resources. Our cost-effectiveness outcomes rely on published estimates and should be validated through long-term follow-up data.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101479"},"PeriodicalIF":6.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}