Genetics in Medicine最新文献

{"title":"Statement of ACMG, ACMGF, and Drs. Muenke and Williams","authors":"ACMG and ACMGF Board of Directors","doi":"10.1016/j.gim.2025.101468","DOIUrl":"10.1016/j.gim.2025.101468","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101468"},"PeriodicalIF":6.6,"publicationDate":"2025-07-01","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":"Patterns of X-linked inheritance: A new approach for the genome era","authors":"Sanjana Basava ,&nbsp;Charles J. Billington Jr. ,&nbsp;Laura Carrel ,&nbsp;Leslie G. Biesecker ,&nbsp;William B. Dobyns","doi":"10.1016/j.gim.2025.101384","DOIUrl":"10.1016/j.gim.2025.101384","url":null,"abstract":"<div><h3>Purpose</h3><div>The concepts of X-linked (XL) dominant and recessive inheritance originated long before dosage compensation for X chromosome genes was understood, but now have no scientific basis. However, misunderstanding of the underlying biology persists, prompting our reassessment of XL inheritance.</div></div><div><h3>Methods</h3><div>We reviewed data on penetrance, expressivity, and X chromosome inactivation (XCI) for 55 XL genes and 57 XL disorders, and examined variations in inheritance based on disease severity, XCI status, cell selection, and other factors.</div></div><div><h3>Results</h3><div>Our analysis demonstrated widely varying penetrance among heterozygous females that was related to severity of the phenotype particularly in males, the degree of cell selection shown by XCI patterns, cell autonomous or non-cell autonomous function of the gene product, and rare cellular interference.</div></div><div><h3>Conclusion</h3><div>The conventional classification of XL inheritance into dominant and recessive subtypes is biologically flawed and should be retired. A more nuanced framework for understanding XL disorders is needed that accounts for the underlying biological complexity, and we propose 4 new groups of XL disorders with different patterns that should improve genetic diagnosis and counseling in families with XL disorders.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101384"},"PeriodicalIF":6.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440638","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":"Implementing secondary findings analysis in a genetic and environmental research study","authors":"Jennifer J. Johnston ,&nbsp;Julie C. Sapp ,&nbsp;Seeley Yoo ,&nbsp;Zara Wermers ,&nbsp;Sophia Hernandez ,&nbsp;Alison Motsinger-Reif ,&nbsp;Adam Burkholder ,&nbsp;David Fargo ,&nbsp;Jennifer L. Emerson ,&nbsp;Janet E. Hall ,&nbsp;Leslie G. Biesecker","doi":"10.1016/j.gim.2025.101515","DOIUrl":"10.1016/j.gim.2025.101515","url":null,"abstract":"<div><h3>Purpose</h3><div>Optimizing return of secondary findings (SFs) in research settings requires an understanding of the complexities and challenges.</div></div><div><h3>Methods</h3><div>Genome sequence was generated for 4737 participants in a genetic and environmental health study, and 4630 of them consented to SF return. Variants in the American College of Medical Genetics and Genomics v3.0 genes were classified using the American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria with ClinGen-approved modifications.</div></div><div><h3>Results</h3><div>Eighty-six variants were eligible for return to 102 participants. Average time to initial recontact attempt was 5.8 years. Recontact attempts reached 95 of 102 individuals. Results were returned to 57 participants. The remainder passively declined (25), actively declined (11), were lost to follow-up (5), were deceased (3), or had prior knowledge of the result (1). Return of results was positively associated with education status (2 × 3 C², <em>P</em> = .0035).</div></div><div><h3>Conclusion</h3><div>The interest in receiving SFs was high at the time of consenting, but a clinically validated result was returned to just over half of the individuals with an SF. Approximately 1 in 3 participants with an SF who had consented to receive them subsequently actively or passively declined receipt of the result. Given the health importance of return of SF, minimizing the time from consent to results return and tailoring outreach to education level may optimize uptake of SF return.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 9","pages":"Article 101515"},"PeriodicalIF":6.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559981","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":"Addendum: Laboratory analysis of organic acids, 2018 update: A technical standard of the American College of Medical Genetics and Genomics (ACMG)","authors":"Suzette M. Huguenin,&nbsp;Tina M. Cowan,&nbsp;M. Laura Duque Lasio,&nbsp;Marzia Pasquali,&nbsp;Ross A. Rowsey,&nbsp;Ross Ridsdale,&nbsp;Jing Xiao,&nbsp;Troy Coody,&nbsp;Jerry Vockley,&nbsp;ACMG Laboratory Quality Assurance Committee∗","doi":"10.1016/j.gim.2025.101434","DOIUrl":"10.1016/j.gim.2025.101434","url":null,"abstract":"<div><div>This document was reaffirmed by the ACMG Board of Directors as of 24 February 2025 with the following addendum:</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 7","pages":"Article 101434"},"PeriodicalIF":6.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144535186","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":"Bi-allelic loss-of-function variants in POC5 cause a syndromic retinal, endocrine, and neuromuscular ciliopathy","authors":"Anneke T. Vulto-van Silfhout ,&nbsp;Ingrid M. Jazet ,&nbsp;Suzanne Yzer ,&nbsp;Jeroen Pas ,&nbsp;Serwet Demirdas ,&nbsp;Elisabeth F.C. van Rossum ,&nbsp;Alberta A.H.J. Thiadens ,&nbsp;Ronald van Beek ,&nbsp;Lonneke Haer-Wigman ,&nbsp;Daniela Q.C.M. Barge-Schaapveld ,&nbsp;Charlotte Brasch-Andersen ,&nbsp;Simon Frost ,&nbsp;Miriam Bauwens ,&nbsp;Elfride De Baere ,&nbsp;Irina Balikova ,&nbsp;Filip Van den Broeck ,&nbsp;Monika Weisz-Hubshman ,&nbsp;Pascal Joset ,&nbsp;Peter Miny ,&nbsp;Isabel Filges ,&nbsp;Machteld M. Oud","doi":"10.1016/j.gim.2025.101513","DOIUrl":"10.1016/j.gim.2025.101513","url":null,"abstract":"<div><h3>Purpose</h3><div>A homozygous loss-of-function (LoF) variant in <em>POC5</em> was previously described in an individual with retinitis pigmentosa. We identified <em>POC5</em> variants in 12 probands with a syndromic phenotype. We aim to define the phenotype spectrum and molecular mechanism associated with biallelic <em>POC5</em> LoF variants.</div></div><div><h3>Methods</h3><div>We studied a cohort of 12 families with bi-allelic LoF <em>POC5</em> variants and performed detailed phenotype analysis. POC5 localization studies were performed in 3 proband-derived fibroblast cell lines.</div></div><div><h3>Results</h3><div>Detailed phenotyping of probands with <em>POC5</em> variants expands the phenotype spectrum beyond ocular manifestations. This syndrome causes not only rod-cone dystrophy but also diabetes mellitus with severe insulin resistance and partial lipodystrophy, kidney disease, and muscle cramps.</div><div>The POC5 protein plays an essential role during cell cycle and cilium formation. Interestingly, POC5 localization studies in 3 proband-derived fibroblast cell lines show aberrant localization suggesting a ciliary defect. The phenotypes of the 12 families in this study fit well within the ciliopathy phenotype spectrum, except for lipodystrophy, which is not common in ciliopathies.</div></div><div><h3>Conclusion</h3><div>We describe a multiorgan syndrome caused by bi-allelic LoF variants in <em>POC5</em>. This underscores the pleiotropic effects of <em>POC5</em> variants and highlights the significance of adipose tissue and metabolic dysfunction in ciliopathies.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 10","pages":"Article 101513"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539985","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":"ELFN1 deficiency: The mechanistic basis and phenotypic spectrum of a neurodevelopmental disorder with epilepsy","authors":"Rhys Dore ,&nbsp;Chu-Ting Chang ,&nbsp;Amber Declève ,&nbsp;Gloria Brunori ,&nbsp;W. Grant Ludlam ,&nbsp;Alden Huang ,&nbsp;Mojtaba Movahedinia ,&nbsp;Nadirah S. Damseh ,&nbsp;Ijaz Anwar ,&nbsp;Mohammad Yahya Vahidi Mehrjardi ,&nbsp;Annelii Ny ,&nbsp;Mehdi Khorrami ,&nbsp;Majid Kheirollahi ,&nbsp;Helen Frederiksen ,&nbsp;Fatemeh Eghbal ,&nbsp;Mohammad Reza Mirjalili ,&nbsp;Mohammadreza Dehghani ,&nbsp;Ehsan Ghayoor Karimiani ,&nbsp;Sergey Oreshkov ,&nbsp;Cesar Alves ,&nbsp;Reza Maroofian","doi":"10.1016/j.gim.2025.101506","DOIUrl":"10.1016/j.gim.2025.101506","url":null,"abstract":"<div><h3>Purpose</h3><div>Synaptic communication deficits are central to many neurodevelopmental disorders. However, for rare monogenic conditions, these disorders remain poorly defined, with limited understanding of their molecular etiology. A homozygous frameshift variant in the synaptic cell adhesion molecule ELFN1 was reported in a family with 3 affected siblings with epileptic encephalopathy, alongside a missense variant of uncertain significance in a cohort study involving a family with intellectual disability. Therefore, we sought to evaluate the role and mechanism of biallelic <em>ELFN1</em> variants in disease pathogenesis.</div></div><div><h3>Methods</h3><div>We describe 8 newly identified individuals from 5 unrelated families, all carrying homozygous <em>ELFN1</em> variants, including frameshift and in-frame deletions. By integrating data from these cases with clinical details from 6 previously reported individuals, we delineate the phenotypic spectrum associated with <em>ELFN1</em> variants.</div></div><div><h3>Results</h3><div>Clinical features include varying degrees of developmental delay/intellectual disability, epilepsy, and movement disorders. Molecular investigations reveal that these variants disrupt ELFN1 protein trafficking to the cell surface, resulting in loss of function. Functional modeling in mice and zebrafish demonstrates the role of Elfn1 loss in motor activity abnormalities and seizures.</div></div><div><h3>Conclusion</h3><div>Our findings establish <em>ELFN1</em> deficiency as the cause of a distinct, rare neurodevelopmental disorder, providing a foundation for future investigations into its pathophysiology and therapeutic strategies.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 9","pages":"Article 101506"},"PeriodicalIF":6.2,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505530","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":"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 ,&nbsp;Noura S. Abul-Husn ,&nbsp;Laura M. Amendola ,&nbsp;Kyle B. Brothers ,&nbsp;Wendy K. Chung ,&nbsp;Michael H. Gollob ,&nbsp;Adam S. Gordon ,&nbsp;Steven M. Harrison ,&nbsp;Ray E. Hershberger ,&nbsp;Marilyn Li ,&nbsp;Deborah Ondrasik ,&nbsp;C. Sue Richards ,&nbsp;Andrew Stergachis ,&nbsp;Douglas R. Stewart ,&nbsp;Christa Lese Martin ,&nbsp;David T. Miller ,&nbsp;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":"Eugenics and polygenic embryo screening: Public, clinician, and patient perceptions of conditions versus traits","authors":"Dorit Barlevy ,&nbsp;Rémy A. Furrer ,&nbsp;Asha Kalapatapu ,&nbsp;Abigail Martinez ,&nbsp;Todd Lencz ,&nbsp;Shai Carmi ,&nbsp;Gabriel Lázaro-Muñoz ,&nbsp;Stacey Pereira","doi":"10.1016/j.gim.2025.101507","DOIUrl":"10.1016/j.gim.2025.101507","url":null,"abstract":"<div><h3>Purpose</h3><div>Polygenic embryo screening (PES) estimates an embryo’s genetic chances of developing complex conditions (eg, cancer) and traits (eg, height). Stakeholders have raised concerns that PES promotes eugenic practices and ideology.</div></div><div><h3>Methods</h3><div>We surveyed a nationally representative sample of the US public on approval of screening embryos for 12 conditions and 12 traits and examined the association between disapproval and concern about eugenics. We also conducted semistructured interviews with US-based reproductive endocrinology and infertility specialists and patients undergoing in vitro fertilization on their perspectives toward PES.</div></div><div><h3>Results</h3><div>Among the US public (<em>n</em> = 1423), disapproval of screening embryos for traits has a stronger association with concern that PES promotes eugenics than disapproval of screening embryos for conditions. Interviews with reproductive endocrinology and infertility specialists (<em>n</em> = 27) and patients undergoing in vitro fertilization (<em>n</em> = 26) suggest that perceptions of PES as eugenic were more common when discussing screening and selecting for or against traits versus selecting against conditions.</div></div><div><h3>Conclusion</h3><div>Results suggest PES for traits is more frequently associated with eugenics and perceived often as unacceptable, whereas PES for conditions is perceived sometimes as acceptable. Future research should explore whether the distinction between conditions and traits is meaningful in the definition of eugenics and/or approval of genomics-based embryo selection and how that influences clinical practices and policy.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 9","pages":"Article 101507"},"PeriodicalIF":6.6,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484130","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 ,&nbsp;Adriana E. Sedeño Cortés ,&nbsp;Pankhuri Gupta ,&nbsp;Abbye E. McEwen ,&nbsp;Eric Y. Kao ,&nbsp;Martha Horike-Pyne ,&nbsp;Jeremy Stone ,&nbsp;Brian H. Shirts ,&nbsp;Marianne E. Dubard-Gault ,&nbsp;Douglas M. Fowler ,&nbsp;Lea M. Starita ,&nbsp;Fuki M. Hisama ,&nbsp;Andrew B. Stergachis","doi":"10.1016/j.gim.2025.101501","DOIUrl":"10.1016/j.gim.2025.101501","url":null,"abstract":"<div><h3>Purpose</h3><div>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, which is an electronic health record (EHR)-linked database of clinical germline genetic variant information from patients with rare genetic disorders seen at 2 tertiary academic medical centers.</div></div><div><h3>Methods</h3><div>We retrospectively reviewed EHRs and genetic testing reports from 5158 patients seen across diverse adult genetics practices at these institutions from 2015 to 2024. We also compared these EHR-based variant classifications with those in ClinVar.</div></div><div><h3>Results</h3><div>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 in which the testing lab updated ClinVar, but the reclassification was never communicated to the patient.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 9","pages":"Article 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 ,&nbsp;Simon A. Jones ,&nbsp;Derralynn A. Hughes ,&nbsp;Heather J. Church ,&nbsp;Timothy M. Cox","doi":"10.1016/j.gim.2025.101502","DOIUrl":"10.1016/j.gim.2025.101502","url":null,"abstract":"<div><h3>Purpose</h3><div>Type 3 Gaucher disease (GD), the chronic neuronopathic form caused by biallelic pathogenic variants in <em>GBA1,</em> is clinically heterogeneous, and there have been few comprehensive studies of its natural history and phenotypic diversity. The greatest unmet clinical need is for a disease-modifying treatment for the neurological manifestations; however, 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.</div></div><div><h3>Methods</h3><div>A multicenter cohort study in England, GAUCHERITE, undertook retrospective and prospective clinical evaluation of patients with GD; this substudy is focused on patients with neuronopathic GD. The research cohort is registered with <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span>, NCT03240653.</div></div><div><h3>Results</h3><div>A total of 42 patients with neuronopathic GD were recruited: 16 males and 26 females. Nine patients had died (age of death 4-28 years); living patients aged 6 to 61 years. We categorized them clinically (“attenuated,” “intermediate,” and “severe”) and on the basis of defined pathogenic variants in <em>GBA1</em>. Childhood disease manifestations provide prognostic utility, especially in context of genotype.</div></div><div><h3>Conclusion</h3><div>This work captures the full phenotypic spectrum and striking clinical diversity of neuronopathic GD that is not encompassed by the existing nomenclature. We propose a novel descriptive system of phenotypic categorization: although this requires refinement and validation across the global population, it seeks to stimulate further exploration of disease behaviors that can be clearly stratified. By these means, we contend that identification of disease manifestations that are 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.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 9","pages":"Article 101502"},"PeriodicalIF":6.6,"publicationDate":"2025-06-18","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}