Genetics in Medicine最新文献

{"title":"ClinGen recuration of hearing loss-associated genes demonstrates significant changes in gene-disease validity over time","authors":"Kezang C. Tshering, Marina T. DiStefano, Andrea M. Oza, Pamela Ajuyah, Ryan Webb, Enyonam Edoh, Ellie Broeren, Julie Ratliff, Vanessa Gitau, Kelley Paris, Amal Aburyyan, John Alexander, Victoria Albano, Donglin Bai, Kevin T.A. Booth, Paula I. Buonfiglio, Cherine Charfeddine, Viviana Dalamón, Ignacio del Castillo, Miguel Angel Moreno-Pelayo, Sami S. Amr","doi":"10.1016/j.gim.2025.101500","DOIUrl":"10.1016/j.gim.2025.101500","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 10","pages":"Article 101500"},"PeriodicalIF":6.2,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145007497","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":"“All doctors should be trained in that”: The co-production and mixed-methods evaluation of an educational toolkit to enable safe, high-quality genetic health care for people with intellectual disability","authors":"Iva Strnadová, Manjekah Dunn, Chloe Molnar, Julie Loblinzk Refalo, Jackie Leach Scully, Joanne Danker, Michelle Tso, Tiffany Qing Lim, Yasmin Cathcart-King, Karen-Maia Jackaman, Sarah Hayes, Sierra Angelina Willow, Jackie Boyle, Jennifer Hansen, Skie Sarfaraz, Caroline Basckin, Celia Halliburton, Thulasee Sri Ganeshan, Edwina K. Middleton, Bronwyn Terrill, Elizabeth Emma Palmer","doi":"10.1016/j.gim.2025.101499","DOIUrl":"10.1016/j.gim.2025.101499","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 10","pages":"Article 101499"},"PeriodicalIF":6.2,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145007362","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":"Newborn screening for common genetic variants associated with permanent hearing loss: Implementation in Ontario and a review of the first 3 years","authors":"Kristin D. Kernohan, Lauren Gallagher, Marie Pigeon, Ed Yeh, Melanie Lacaria, Michelle M. Axford, Johnna MacCormick, Vicky Papaioannou, Nada Quercia, Charles Rupar, Kim Zimmerman, Stacey Weber, Sharon L. Cushing, Pranesh Chakraborty","doi":"10.1016/j.gim.2025.101497","DOIUrl":"10.1016/j.gim.2025.101497","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 10","pages":"Article 101497"},"PeriodicalIF":6.2,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145007698","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":"Intersectionality in a sociogenomic world: How do race, disability, socioeconomic status, and polygenic prediction interact to affect perceptions of educational trajectories?","authors":"Lucas J. Matthews, Daphne O. Martschenko, Colby Lewis V, Maya Sabatello","doi":"10.1016/j.gim.2025.101498","DOIUrl":"10.1016/j.gim.2025.101498","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 10","pages":"Article 101498"},"PeriodicalIF":6.2,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145007699","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":"Genome sequencing reveals the impact of pseudoexons in rare genetic disease","authors":"Georgia Pitsava ,&nbsp;Megan Hawley ,&nbsp;Light Auriga ,&nbsp;Ivan de Dios ,&nbsp;Arthur Ko ,&nbsp;Sofia Marmolejos ,&nbsp;Miguel Almalvez ,&nbsp;Ingrid Chen ,&nbsp;Kaylee Scozzaro ,&nbsp;Jianhua Zhao ,&nbsp;Rebekah Barrick ,&nbsp;Nicholas Ah Mew ,&nbsp;Vincent A. Fusaro ,&nbsp;Jonathan LoTempio ,&nbsp;Matthew Taylor ,&nbsp;Luisa Mestroni ,&nbsp;Sharon Graw ,&nbsp;Dianna Milewicz ,&nbsp;Dongchuan Guo ,&nbsp;David R. Murdock ,&nbsp;Eric Vilain","doi":"10.1016/j.gim.2025.101574","DOIUrl":"10.1016/j.gim.2025.101574","url":null,"abstract":"<div><h3>Purpose</h3><div>Advancements in sequencing technologies have significantly improved clinical genetic testing; yet, the diagnostic yield remains around 30% to 40%. Emerging technologies are now being deployed to address the remaining diagnostic gap.</div></div><div><h3>Methods</h3><div>We tested whether short-read genome sequencing could increase the diagnostic yield in individuals enrolled into the UCI-GREGoR research study, who had suspected Mendelian conditions and prior inconclusive testing. Two other collaborative research cohorts, focused on aortopathy and dilated cardiomyopathy, consisted of individuals who were undiagnosed but had not undergone harmonized prior testing.</div></div><div><h3>Results</h3><div>We sequenced 353 families (754 participants) and found a molecular diagnosis in 54 (15.3%) of them. Of these diagnoses, 55.5% were previously missed because the causative variants were in regions not originally interrogated. In 5 cases, they were deep intronic variants, all of which led to abnormal splicing and pseudoexons, as directly shown by RNA sequencing. All 5 of these variants had inconclusive spliceAI scores. In 26% of newly diagnosed cases, the causal variant could have been detected by exome sequencing reanalysis.</div></div><div><h3>Conclusion</h3><div>Genome sequencing can overcome limitations of clinical genetic testing, such as the inability to call intronic variants. Our findings highlight pseudoexons as a common mechanism via which deep intronic variants cause Mendelian disease.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101574"},"PeriodicalIF":6.2,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029420","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":"Polygenic risk scores in the clinic: Health-system leaders and primary care providers weigh in","authors":"Susan Brown Trinidad ,&nbsp;Stephanie M. Fullerton ,&nbsp;Betty Cohn ,&nbsp;David R. Crosslin ,&nbsp;Gail P. Jarvik","doi":"10.1016/j.gim.2025.101575","DOIUrl":"10.1016/j.gim.2025.101575","url":null,"abstract":"<div><h3>Purpose</h3><div>The fourth phase of the Electronic Medical Records and Genome Network is testing the return of 10 polygenic risk scores (PRS) across multiple clinics. Understanding the perspectives of health-system leaders and frontline clinicians can inform plans for implementation of PRS.</div></div><div><h3>Methods</h3><div>A total of 15 health-system leaders and 20 primary care providers took part in semistructured interviews. A descriptive thematic analysis was performed.</div></div><div><h3>Results</h3><div>Interviewees generally perceived PRS to have limited clinical utility, although they saw value in the potential to identify and act upon risks that are not otherwise detectable. Perceived potential drawbacks included negative psycho-emotional effects on patients, unnecessary follow-up, distracting from population health priorities, opportunity costs, and medicolegal liability. Implementation considerations included increased encounter time and the need for clinical practice guidelines, provider training, care coordination, and point-of-care resources.</div></div><div><h3>Conclusion</h3><div>Participants generally expressed favorable views of precision medicine and also identified potential challenges to introducing PRS in clinical care. Implementation will require careful assessment of clinical utility vs usual care; ensuring that the benefit to be realized merits the time and resources required to interpret, return, and act on results and developing guidelines and other decision-making supports for providers and patients.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101575"},"PeriodicalIF":6.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015036","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":"Quantifying evidence for phenotypic specificity (PP4) for syndromic phenotypes: Large-scale integration of rare germline FH variants from diagnostic laboratory testing for HLRCC and renal cancer","authors":"Sophie Allen ,&nbsp;Charlie F. Rowlands ,&nbsp;Samantha Butler ,&nbsp;Miranda Durkie ,&nbsp;Carrie Horton ,&nbsp;Tina Pesaran ,&nbsp;Marcy Richardson ,&nbsp;Rachel Robinson ,&nbsp;Alice Garrett ,&nbsp;George J. Burghel ,&nbsp;Alison Callaway ,&nbsp;Joanne Field ,&nbsp;Bethan Frugtniet ,&nbsp;Sheila Palmer-Smith ,&nbsp;Jonathan Grant ,&nbsp;Judith Pagan ,&nbsp;Trudi McDevitt ,&nbsp;Katie Snape ,&nbsp;Avgi Andreou ,&nbsp;Eamonn R. Maher ,&nbsp;Z. Kemp","doi":"10.1016/j.gim.2025.101565","DOIUrl":"10.1016/j.gim.2025.101565","url":null,"abstract":"<div><h3>Purpose</h3><div>Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare cancer susceptibility syndrome exclusively attributable to pathogenic variants in <em>FH</em> (HGNC:3700). This article quantitatively weights the phenotypic context (PP4/PS4) of such very rare variants in <em>FH.</em></div></div><div><h3>Methods</h3><div>We collated clinical diagnostic testing data on germline <em>FH</em> variants from 387 individuals with HLRCC and 1780 individuals with renal cancer and compared the frequency of “very-rare” variants in each phenotypic cohort with 562,295 population controls. We generated pan-gene very rare variant likelihood ratios (PG-VRV-LRs), domain-specific likelihood ratios for missense variants (DS-VRMV-LR) using spatial clustering analysis, and log_2.08 likelihood ratios (LLRs) as applicable within the updated American College of Medical Genetics and Genomics/Association for Molecular Pathology variant classification framework.</div></div><div><h3>Results</h3><div>For HLRCC, the PG-VRV-LR was estimated to be 2669.4 (95% CI 1843.4-3881.2, LLR 10.77) for truncating variants and 214.7 (95% CI 185.0-246.9, LLR 7.33) for missense variants. For renal cancer, the PG-VRV-LR was 95.5 (95% CI 48.9-183.0, LLR 6.23) for truncating variants and 5.8 (95% CI 3.5-9.3, LLR 2.39) for missense variants. Clustering analysis in HLRCC cases revealed 3 “hotspot” regions wherein the DS-VRMV-LR increased to 1226.9.</div></div><div><h3>Conclusion</h3><div>These data provide quantitative measures for very rare missense and truncating variants in <em>FH</em>, which reflect the differing phenotypic specificity of HLRCC and renal cancer and may be applicable in clinical variant classification.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101565"},"PeriodicalIF":6.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145015074","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":"Two-tiered newborn screening for infantile Krabbe disease allows timely treatment initiation and avoids false-positive results.","authors":"Patricia L Hall, Amy L White, Dawn Peck, Gisele Pino, April Studinski, Dimitar Gavrilov, Devin Oglesbee, Matthew J Schultz, Silvia Tortorelli, Dietrich Matern","doi":"10.1016/j.gim.2025.101572","DOIUrl":"10.1016/j.gim.2025.101572","url":null,"abstract":"<p><strong>Purpose: </strong>Infantile Krabbe disease (IKD) is a severe, progressive neurological disorder that was recently added to the Recommended Uniform Screening Panel in the United States. IKD is a critical condition that requires a hematopoietic stem cell transplant, preferably by 30 days of age. This study examines whether the 2-tier newborn screening (NBS) strategy (psychosine [PSY] analysis when enzyme activity is low) causes clinically relevant delays compared with PSY measured at a first clinical follow-up visit.</p><p><strong>Methods: </strong>We reviewed the PSY analyses performed over a 6-year period on dried blood spots on infants < 28 days old. Results were sorted by the ordering site and final diagnosis.</p><p><strong>Results: </strong>On average, infants with a positive NBS for IKD that included abnormal PSY received their diagnosis 7 days sooner than whose PSY testing was initiated during follow-up. Hematopoietic stem cell transplant occurred by the 36th day of life, on average, for cases with IKD detected by 2-tiered NBS.</p><p><strong>Conclusion: </strong>Effective NBS for Krabbe disease requires the use of PSY as a second-tier test, allowing for timely initiation of treatment while virtually eliminating false-positive results. PSY should be included in NBS algorithms for Krabbe disease, and timeliness metrics need to be adjusted.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101572"},"PeriodicalIF":6.2,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951390","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 interventions to increase genetic testing for breast cancer among high-risk populations: A systematic review of implementation strategies, outcomes, and gaps","authors":"Subash Thapa ,&nbsp;Mette Just Bonde ,&nbsp;Anja Leppin","doi":"10.1016/j.gim.2025.101573","DOIUrl":"10.1016/j.gim.2025.101573","url":null,"abstract":"<div><h3>Purpose</h3><div>To systematically review the implementation strategies, outcomes, and quality of interventions aimed at increasing the uptake of breast cancer-related genetic testing services among women who are at high-risk.</div></div><div><h3>Methods</h3><div>A systematic search was conducted on PubMed, CINAHL, PsycINFO, EMBASE, Cochrane Library, and Campbell Coordinating Group databases from January 2005 to October 2024. Studies were included if they evaluated interventions to increase genetic testing uptake or facilitate decision making about genetic testing.</div></div><div><h3>Results</h3><div>A total of 27 articles were identified, including 18 interventions aimed at supporting the uptake of genetic testing for breast cancer. Half of the interventions evaluated face-to-face counseling, whereas the other half used alternative counseling modalities, such as standardized DVD counseling, tailored written materials, and remote video or telephone counseling. Participant satisfaction was consistently high (≥80%) among most interventions; however, cost analyses suggested time savings with alternative delivery strategies. Nevertheless, feasibility varied according to the delivery mode. Remote video counseling faced some technical challenges, decision aids/patient education materials were partly less engaging, and alternative counseling modalities might provide more limited opportunities to discuss emotional and social concerns. None of the interventions progressed beyond early adoption.</div></div><div><h3>Conclusion</h3><div>Alternative approaches to genetic counseling, such as video- and telephone-based delivery and tailored written materials, show promise in terms of feasibility and acceptability. Future research should adopt more rigorous, framework-guided implementation methods with attention to long-term sustainability, while also promoting greater consistency in terminology to improve transparency and comparability.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101573"},"PeriodicalIF":6.2,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951114","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":"A founder variant in TBCB is associated with global developmental delay, autism spectrum, and spastic paraparesis","authors":"Sharon Bratman Morag ,&nbsp;Chen Itzkovich ,&nbsp;Alina Kurolap ,&nbsp;Mordechai Shohat ,&nbsp;Alexandra Durr ,&nbsp;Jean-Madeleine de Sainte Agathe ,&nbsp;Jeremy Bertrand ,&nbsp;Arie Koifman ,&nbsp;Anna Alkelai ,&nbsp;Alan R. Shuldiner ,&nbsp;Adi Mory ,&nbsp;Tamar Harel ,&nbsp;Hagar Mor-Shaked ,&nbsp;Adel Shalata ,&nbsp;Tamar Paperna ,&nbsp;Hagit Baris Feldman ,&nbsp;Reli R. Kakun ,&nbsp;Daniel Kornitzer ,&nbsp;Adi Salzberg ,&nbsp;Karin Weiss","doi":"10.1016/j.gim.2025.101569","DOIUrl":"10.1016/j.gim.2025.101569","url":null,"abstract":"<div><h3>Purpose</h3><div>Hereditary spastic paraparesis (HSP) is a genetically diverse group of Mendelian disorders characterized by length-dependent axonal degeneration. Microtubule dysfunction is a known mechanism in HSP that impairs axonal dynamics. TBCB encodes tubulin-folding cofactor B (TBCB), which, along with TBCE, regulates αβ-heterodimer dynamics and neuronal axonal growth. Here, we describe a new form of complicated HSP caused by a founder variant in TBCB.</div></div><div><h3>Methods</h3><div>Exome sequencing revealed a homozygous c.589T&gt;A p.(Tyr197Asn) variant in <em>TBCB</em> in a cohort of 10 individuals assembled through genematching tools. Protein function was assessed using Saccharomyces cerevisiae ortholog ALF1, and a CRISPR-Cas9-generated homologous mutant in <em>Drosophila melanogaster</em>. TBCB expression and localization were examined in fibroblasts using western blot and immunofluorescence.</div></div><div><h3>Results</h3><div>Participants displayed late-childhood-onset spastic paraparesis, global developmental delay, and autism spectrum. TBCB protein levels were reduced in affected fibroblasts. The ALF1 mutant in yeast increased benomyl sensitivity, resembling a loss-of-function phenotype. In <em>Drosophila melanogaster</em>, the homologous mutant led to reduced survival and impaired climbing ability.</div></div><div><h3>Conclusion</h3><div>We describe a novel neurodevelopmental disorder with spastic paraparesis and a high carrier rate in the Ashkenazi Jewish population. Our results indicate that <em>TBCB</em> has a vital role in the development of central nervous system and potentially in axonal function in humans.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101569"},"PeriodicalIF":6.2,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951663","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}