Pub Date : 2026-02-12DOI: 10.1016/j.gim.2026.102537
Ilana B Solomon, Patrick Boyd, Yi Xiao, Kathryn Reyes, Ashley Mochizuki, Madeline Currey, Michael Garcia, Marilan Luong, Frances Cheung, Stephen B Gruber, Heather Hampel, Sarah Labib, Angela Mak, Ran Qiao, Sarah Tang, Sandra Davey, Stacy W Gray
Purpose: New care models promise to increase access to germline genetic testing. To decrease testing gaps, we offered universal germline testing without pre-test genetic counseling to unselected patients at a comprehensive cancer center. To address safety concerns over the elimination of pre-test counseling, we examined detrimental psychological impact (DPI) after participants underwent testing in this novel model.
Methods: We assessed participants' genomic testing specific DPI using the FACToR instrument (2-weeks/6-months post disclosure). Overall DPI, negativity, uncertainty, positivity, and privacy concerns were assessed. We used chi-square, ANCOVA multivariable regression, and mediation analysis to examine relationships between variables.
Results: 846 participants completed the survey. Most participants (96.0%) exhibited low DPI, negativity (95.6%), uncertainty (94.0%), and concerns about privacy (95.6%), and high positivity (55.6%). Participants with cancer had higher negativity and uncertainty than those without. DPI significantly diminished over time in participants with positive tests.
Conclusion: Overall DPI was low, demonstrating that most participants are at minimal psychological risk when receiving germline results without pre-test counseling. However, a small subset of participants exhibit high distress and uncertainty. Additional efforts are needed to identify at risk participants receiving universal testing who would benefit from interventions aimed at mitigating DPI.
{"title":"A Scalable New Model of Germline Cancer Genomic Care Delivery: Assessing Psychological Outcomes.","authors":"Ilana B Solomon, Patrick Boyd, Yi Xiao, Kathryn Reyes, Ashley Mochizuki, Madeline Currey, Michael Garcia, Marilan Luong, Frances Cheung, Stephen B Gruber, Heather Hampel, Sarah Labib, Angela Mak, Ran Qiao, Sarah Tang, Sandra Davey, Stacy W Gray","doi":"10.1016/j.gim.2026.102537","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102537","url":null,"abstract":"<p><strong>Purpose: </strong>New care models promise to increase access to germline genetic testing. To decrease testing gaps, we offered universal germline testing without pre-test genetic counseling to unselected patients at a comprehensive cancer center. To address safety concerns over the elimination of pre-test counseling, we examined detrimental psychological impact (DPI) after participants underwent testing in this novel model.</p><p><strong>Methods: </strong>We assessed participants' genomic testing specific DPI using the FACToR instrument (2-weeks/6-months post disclosure). Overall DPI, negativity, uncertainty, positivity, and privacy concerns were assessed. We used chi-square, ANCOVA multivariable regression, and mediation analysis to examine relationships between variables.</p><p><strong>Results: </strong>846 participants completed the survey. Most participants (96.0%) exhibited low DPI, negativity (95.6%), uncertainty (94.0%), and concerns about privacy (95.6%), and high positivity (55.6%). Participants with cancer had higher negativity and uncertainty than those without. DPI significantly diminished over time in participants with positive tests.</p><p><strong>Conclusion: </strong>Overall DPI was low, demonstrating that most participants are at minimal psychological risk when receiving germline results without pre-test counseling. However, a small subset of participants exhibit high distress and uncertainty. Additional efforts are needed to identify at risk participants receiving universal testing who would benefit from interventions aimed at mitigating DPI.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102537"},"PeriodicalIF":6.2,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197651","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}
Pub Date : 2026-02-03DOI: 10.1016/j.gim.2026.102532
Petros Giannikopoulos, Marlen C Lauffer, Christian R Marshall, Gregory Costain, Zhiyv Niu, David Bick, Wei Shen, Matthew C Hiemenz, Sucheta Bhatt, Wayne Grody, Vaidehi Jobanputra
Recent advances in personalized therapies for germline genetic disorders are expanding the clinical utility of genome sequencing beyond diagnosis and risk assessment. In this perspective, we introduce interventional genomics as a clinical paradigm in which germline genomic testing serves as the starting point for personalized treatment planning that integrates established and emerging therapeutic options. Drawing lessons and parallels from oncology, we propose embedding structured treatment insights into germline genomic reports, supported by a standardized lexicon of pathogenic mechanisms, therapeutic feasibility frameworks, and dedicated informatics tools. To translate this vision into clinical practice, we also propose the establishment of multidisciplinary Interventional Genomics Boards and explore the infrastructure needed to support such diagnosis-to-treatment workflows in the clinic. We also highlight the need to train a new class of clinicians with expertise in genomic interpretation and therapeutic design. Such clinicians must be able to interface with preclinical development efforts, clinical trial execution, and the rapidly evolving regulatory frameworks that govern genomic therapies. Finally, regulatory complexities and access-related challenges that will affect equitable implementation across diverse clinical settings are also discussed.
{"title":"Interventional Genomics: Bridging Germline Diagnosis and Therapeutic Action.","authors":"Petros Giannikopoulos, Marlen C Lauffer, Christian R Marshall, Gregory Costain, Zhiyv Niu, David Bick, Wei Shen, Matthew C Hiemenz, Sucheta Bhatt, Wayne Grody, Vaidehi Jobanputra","doi":"10.1016/j.gim.2026.102532","DOIUrl":"https://doi.org/10.1016/j.gim.2026.102532","url":null,"abstract":"<p><p>Recent advances in personalized therapies for germline genetic disorders are expanding the clinical utility of genome sequencing beyond diagnosis and risk assessment. In this perspective, we introduce interventional genomics as a clinical paradigm in which germline genomic testing serves as the starting point for personalized treatment planning that integrates established and emerging therapeutic options. Drawing lessons and parallels from oncology, we propose embedding structured treatment insights into germline genomic reports, supported by a standardized lexicon of pathogenic mechanisms, therapeutic feasibility frameworks, and dedicated informatics tools. To translate this vision into clinical practice, we also propose the establishment of multidisciplinary Interventional Genomics Boards and explore the infrastructure needed to support such diagnosis-to-treatment workflows in the clinic. We also highlight the need to train a new class of clinicians with expertise in genomic interpretation and therapeutic design. Such clinicians must be able to interface with preclinical development efforts, clinical trial execution, and the rapidly evolving regulatory frameworks that govern genomic therapies. Finally, regulatory complexities and access-related challenges that will affect equitable implementation across diverse clinical settings are also discussed.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102532"},"PeriodicalIF":6.2,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131567","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}
Pub Date : 2026-02-01Epub Date: 2025-11-20DOI: 10.1016/j.gim.2025.101650
Stephanie A. Felker , Bruce R. Korf , Gregory S. Barsh
Purpose
Phenotype-based ascertainment of probands in studies of Mendelian disorders may exclude individuals with mild phenotypes or that lack health care access. We explore this premise in All of Us Research Program participants with pathogenic variation causal for 3 Mendelian conditions: autosomal dominant polycystic kidney disease (ADPKD), Marfan syndrome, and neurofibromatosis type 1 (NF1).
Methods
We identified All of Us Research Program participants with putatively pathogenic variation in NF1, FBN1, PKD1, and PKD2. Concept terms were extracted from electronic health records to assess participant diagnosis and phenotype. Variant annotation and participant surveys were evaluated to identify biological and social factors differentiating diagnosed and undiagnosed individuals.
Results
Large proportions of individuals with pathogenic variation in NF1, FBN1, or PKD1/PKD2 lack the associated diagnosis of NF1 (47%), Marfan syndrome (58%), or ADPKD (52%), respectively. Pathogenic variants in diagnosed individuals have greater inferred deleteriousness for NF1 and ADPKD, and undiagnosed individuals had less severe phenotypes compared with diagnosed individuals for all 3 conditions.
Conclusion
A genotype-first ascertainment of individuals in genomic research allows for a more comprehensive assessment of Mendelian disease and removes biases that confound our understanding of the penetrance and presentation of these conditions.
{"title":"Genotype-first assessment of presentation and penetrance of neurofibromatosis type 1, autosomal dominant polycystic kidney disease, and Marfan syndrome within the All of Us research program cohort","authors":"Stephanie A. Felker , Bruce R. Korf , Gregory S. Barsh","doi":"10.1016/j.gim.2025.101650","DOIUrl":"10.1016/j.gim.2025.101650","url":null,"abstract":"<div><h3>Purpose</h3><div>Phenotype-based ascertainment of probands in studies of Mendelian disorders may exclude individuals with mild phenotypes or that lack health care access. We explore this premise in All of Us Research Program participants with pathogenic variation causal for 3 Mendelian conditions: autosomal dominant polycystic kidney disease (ADPKD), Marfan syndrome, and neurofibromatosis type 1 (NF1).</div></div><div><h3>Methods</h3><div>We identified All of Us Research Program participants with putatively pathogenic variation in <em>NF1</em>, <em>FBN1</em>, <em>PKD1</em>, and <em>PKD2</em>. Concept terms were extracted from electronic health records to assess participant diagnosis and phenotype. Variant annotation and participant surveys were evaluated to identify biological and social factors differentiating diagnosed and undiagnosed individuals.</div></div><div><h3>Results</h3><div>Large proportions of individuals with pathogenic variation in <em>NF1</em>, <em>FBN1</em>, or <em>PKD1/PKD2</em> lack the associated diagnosis of NF1 (47%), Marfan syndrome (58%), or ADPKD (52%), respectively. Pathogenic variants in diagnosed individuals have greater inferred deleteriousness for NF1 and ADPKD, and undiagnosed individuals had less severe phenotypes compared with diagnosed individuals for all 3 conditions.</div></div><div><h3>Conclusion</h3><div>A genotype-first ascertainment of individuals in genomic research allows for a more comprehensive assessment of Mendelian disease and removes biases that confound our understanding of the penetrance and presentation of these conditions.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 2","pages":"Article 101650"},"PeriodicalIF":6.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145587144","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}
Pub Date : 2026-02-01Epub Date: 2025-12-08DOI: 10.1016/j.gim.2025.101662
Diana Martínez-Minguet , René Noel , Alberto G. Simón , Óscar Pastor
Purpose
The translation of polygenic risk score (PRS) analyses into clinical practice is gaining momentum; yet, it remains limited by multiple implementation barriers studied across fragmented research lines. This study aims to systematically identify, classify, and synthesize these challenges and the proposed solutions in the literature.
Methods
A systematic literature review is conducted following PRISMA guidelines across PubMed, Scopus, and Web of Science, from 2020 to 2025. Included studies are classified by scientific formalism and by pertinence to PRS clinical translation topic. Data extraction is focused on challenge identification, proposed solutions and validations, with challenges aggregated into cluster categories.
Results
From 1245 initial records, 54 studies were included. We identified 8 challenge categories: heterogeneity in the reporting of PRS models, complexity in model selection, technological barriers, lack of best practices for results reporting, limited clinical guidelines and educational material, lack of clinical implementation workflows, and limitations for general applicability of PRS results. We observed varying levels of conceptual clarity and uneven research efforts in proposing solutions for the identified challenges.
Conclusion
This review offers a structured catalog of implementation challenges and representative solutions. Findings highlight the need for covering less-addressed gaps and coordinated efforts across research domains to support the effective and responsible integration of PRS analyses into clinical care.
目的：将多基因风险评分（PRS）分析转化为临床实践正在获得动力，但仍然受到多个实施障碍的限制，这些障碍是在分散的研究领域研究的。本研究旨在系统地识别、分类和综合这些挑战和文献中提出的解决方案。方法：在2020-2025年期间，按照PRISMA指南对PubMed、Scopus和Web of Science进行系统文献综述。纳入的研究按科学形式主义和与PRS临床翻译主题的相关性进行分类。数据提取的重点是挑战识别、提出的解决方案和验证，并将挑战聚合到集群类别中。结果：从1245份初始记录中，纳入54项研究。我们确定了8个挑战类别：PRS模型报告的异质性、模型选择的复杂性、技术障碍、缺乏结果报告的最佳实践、有限的临床指南和教育材料、缺乏临床实施工作流程以及PRS结果普遍适用性的限制。我们观察到，在为确定的挑战提出解决方案时，概念清晰度和研究努力程度各不相同。结论：本综述提供了一个结构化的实施挑战和代表性解决方案的目录。研究结果强调，需要覆盖较少解决的差距，并协调跨研究领域的努力，以支持有效和负责任的PRS分析整合到临床护理中。
{"title":"Challenges in clinical translation of polygenic risk score analyses: A systematic review","authors":"Diana Martínez-Minguet , René Noel , Alberto G. Simón , Óscar Pastor","doi":"10.1016/j.gim.2025.101662","DOIUrl":"10.1016/j.gim.2025.101662","url":null,"abstract":"<div><h3>Purpose</h3><div>The translation of polygenic risk score (PRS) analyses into clinical practice is gaining momentum; yet, it remains limited by multiple implementation barriers studied across fragmented research lines. This study aims to systematically identify, classify, and synthesize these challenges and the proposed solutions in the literature.</div></div><div><h3>Methods</h3><div>A systematic literature review is conducted following PRISMA guidelines across PubMed, Scopus, and Web of Science, from 2020 to 2025. Included studies are classified by scientific formalism and by pertinence to PRS clinical translation topic. Data extraction is focused on challenge identification, proposed solutions and validations, with challenges aggregated into cluster categories.</div></div><div><h3>Results</h3><div>From 1245 initial records, 54 studies were included. We identified 8 challenge categories: heterogeneity in the reporting of PRS models, complexity in model selection, technological barriers, lack of best practices for results reporting, limited clinical guidelines and educational material, lack of clinical implementation workflows, and limitations for general applicability of PRS results. We observed varying levels of conceptual clarity and uneven research efforts in proposing solutions for the identified challenges.</div></div><div><h3>Conclusion</h3><div>This review offers a structured catalog of implementation challenges and representative solutions. Findings highlight the need for covering less-addressed gaps and coordinated efforts across research domains to support the effective and responsible integration of PRS analyses into clinical care.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 2","pages":"Article 101662"},"PeriodicalIF":6.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145742175","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}
Innovation in rare disease research is constrained by limited access to reliable and accessible patient data. Accurate characterization of many conditions requires infrastructure that captures population diversity. Existing efforts are often disease specific, investigators led, with limited data sharing. The RARE-X platform was developed to address these limitations by enabling patient-reported data collection and supporting broader data access.
Methods
RARE-X is a disease-agnostic platform designed to capture symptoms and patient-reported outcomes using a shared survey structure. Participants across conditions complete a core set of surveys, enabling standardized data collection and cross-disease comparisons. The platform supports global participation, enables longitudinal data capture, and provides data access to researchers through an established request process.
Results
Since its launch, and at the time of this report, RARE-X has enrolled 7493 participants from 93 countries, including 3857 patients and 3636 caregivers or siblings, across 74 rare disease communities supported by more than 120 Patient Advocacy Groups. Sixty-three percent are US-based and 37% international. Data are used in research applications, community reporting, and computational analyses.
Conclusion
RARE-X addresses limitations of traditional registries by enabling standardized, cross-disease data collection, stakeholder input and data sharing, with the potential to inform therapeutic development and advance rare disease research.
{"title":"RARE-X: A patient-driven approach for collecting symptom and patient-reported outcome data in rare diseases","authors":"Vanessa Vogel-Farley , Karmen Trzupek , Jade Gosar , Katelyn Hobbs , Kelly Wentworth , Bridget Michaels , Geoffrey Beek , Tina Dang , Mackenzie Abramson , Megan O’Boyle , Nicole Boice , Charlene Son Rigby , Zohreh Talebizadeh","doi":"10.1016/j.gim.2025.101634","DOIUrl":"10.1016/j.gim.2025.101634","url":null,"abstract":"<div><h3>Purpose</h3><div>Innovation in rare disease research is constrained by limited access to reliable and accessible patient data. Accurate characterization of many conditions requires infrastructure that captures population diversity. Existing efforts are often disease specific, investigators led, with limited data sharing. The RARE-X platform was developed to address these limitations by enabling patient-reported data collection and supporting broader data access.</div></div><div><h3>Methods</h3><div>RARE-X is a disease-agnostic platform designed to capture symptoms and patient-reported outcomes using a shared survey structure. Participants across conditions complete a core set of surveys, enabling standardized data collection and cross-disease comparisons. The platform supports global participation, enables longitudinal data capture, and provides data access to researchers through an established request process.</div></div><div><h3>Results</h3><div>Since its launch, and at the time of this report, RARE-X has enrolled 7493 participants from 93 countries, including 3857 patients and 3636 caregivers or siblings, across 74 rare disease communities supported by more than 120 Patient Advocacy Groups. Sixty-three percent are US-based and 37% international. Data are used in research applications, community reporting, and computational analyses.</div></div><div><h3>Conclusion</h3><div>RARE-X addresses limitations of traditional registries by enabling standardized, cross-disease data collection, stakeholder input and data sharing, with the potential to inform therapeutic development and advance rare disease research.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 2","pages":"Article 101634"},"PeriodicalIF":6.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523296","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}
Pub Date : 2026-02-01Epub Date: 2025-12-02DOI: 10.1016/j.gim.2025.101655
Marianna De Stefano , Rudolf van Olden , Elnaz Arjmand , Julian Nam , Lasse de Fries Jensen , Birgit Schäfer , Janbernd Kirschner , Alessandra Ferlini , Carl Rudolf Blankart , Rachel Cassidy
Purpose
Next-generation sequencing (NGS) can accelerate the diagnosis of rare diseases (RDs). Economic evaluations assess the costs and benefits of new technologies and can help inform policy decisions on upscaled adoption into clinical practice. This review synthesizes current evidence on the economic evaluation of NGS for diagnosing RDs in pediatrics.
Methods
Seven databases were consulted to identify full economic evaluations of NGS technologies used in the RD screening pathway for pediatric populations. Eligible studies were conducted in Organization for Economic Co-operation and Development or European Union member countries published between January 2015 and May 2024.
Results
Of the 25 studies, most found NGS to be cost-effective compared with standard diagnostic methods, especially when used early in the diagnostic pathway. There remains significant variability in study methodology (including study perspective and lack of long-term cost considerations), which limits comparability of evidence. There has also been limited evaluation of NGS screening in healthy or asymptomatic populations (eg, newborn screening).
Conclusion
Although evidence shows that NGS technologies are generally cost-effective when used to screen for RD in pediatrics, there is a need for standardized approaches to contribute robust evidence that can be used to effectively support health care policy in this area.
{"title":"Economic evaluation of next-generation sequencing technologies in pediatric patient groups with confirmed or possible rare diseases: A systematic literature review","authors":"Marianna De Stefano , Rudolf van Olden , Elnaz Arjmand , Julian Nam , Lasse de Fries Jensen , Birgit Schäfer , Janbernd Kirschner , Alessandra Ferlini , Carl Rudolf Blankart , Rachel Cassidy","doi":"10.1016/j.gim.2025.101655","DOIUrl":"10.1016/j.gim.2025.101655","url":null,"abstract":"<div><h3>Purpose</h3><div>Next-generation sequencing (NGS) can accelerate the diagnosis of rare diseases (RDs). Economic evaluations assess the costs and benefits of new technologies and can help inform policy decisions on upscaled adoption into clinical practice. This review synthesizes current evidence on the economic evaluation of NGS for diagnosing RDs in pediatrics.</div></div><div><h3>Methods</h3><div>Seven databases were consulted to identify full economic evaluations of NGS technologies used in the RD screening pathway for pediatric populations. Eligible studies were conducted in Organization for Economic Co-operation and Development or European Union member countries published between January 2015 and May 2024.</div></div><div><h3>Results</h3><div>Of the 25 studies, most found NGS to be cost-effective compared with standard diagnostic methods, especially when used early in the diagnostic pathway. There remains significant variability in study methodology (including study perspective and lack of long-term cost considerations), which limits comparability of evidence. There has also been limited evaluation of NGS screening in healthy or asymptomatic populations (eg, newborn screening).</div></div><div><h3>Conclusion</h3><div>Although evidence shows that NGS technologies are generally cost-effective when used to screen for RD in pediatrics, there is a need for standardized approaches to contribute robust evidence that can be used to effectively support health care policy in this area.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 2","pages":"Article 101655"},"PeriodicalIF":6.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145677296","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}
Pub Date : 2026-02-01Epub Date: 2025-11-13DOI: 10.1016/j.gim.2025.101640
Jessica Le Gall , Catherine Dehainault , Ambre Petitalot , Elsa Amouyal , Jeanne Petitou , Sandrine M. Caputo , François Radvanyi , Alexandre Matet , Nathalie Cassoux , Livia Lumbroso-Le Rouic , Isabelle Aerts , François Doz , Marion Gauthier-Villars , Dominique Stoppa-Lyonnet , Claude Houdayer , Lisa Golmard , François Lallemand
Purpose
The RB1 gene encodes the retinoblastoma protein (pRB) playing a major role in cell cycle control, particularly by its interaction with E2F transcription factors. Familial forms of retinoblastoma are caused by germline pathogenic variants in the RB1 gene predisposing to retinoblastoma and other tumors. By analyzing the RB1 gene in patients with retinoblastoma, we found that missense variants often remain variants of uncertain significance (VUS).
Methods
To classify RB1 VUS, we developed a functional assay evaluating their impact on the ability of pRB to inhibit the activity of the E2F1 promoter, with a luciferase reporter gene. A set of 14 pathogenic/likely pathogenic and benign/likely benign RB1 variants was used for validation.
Results
We tested 16 VUS detected in patients with retinoblastoma and found that 9 VUS reduced the ability of pRB to inhibit E2F1 promoter. Among them, the (RB1) c.2263T>G p.(Phe755Val) variant showed a reduced level of pRB on Western blot, suggesting a defect in pRB stability. By applying the criterion PS3_moderate of the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification to this functional assay, 5 of the 9 VUS with functional impact could be classified as likely pathogenic.
Conclusion
This functional assay can improve the molecular diagnosis of retinoblastoma predisposition by a better determination of pathogenic/likely pathogenic RB1 variants.
目的：RB1基因编码视网膜母细胞瘤蛋白（pRB），在细胞周期控制中发挥重要作用，特别是通过其与E2F转录因子的相互作用。家族性视网膜母细胞瘤是由RB1基因的种系致病性变异引起的，易导致视网膜母细胞瘤和其他肿瘤。通过分析视网膜母细胞瘤患者的RB1基因，错义变异通常仍然是不确定意义的变异（VUS）。方法：为了对RB1 VUS进行分类，我们开发了一种功能分析方法，评估它们对pRB抑制E2F1启动子活性的能力的影响，该能力具有荧光素酶报告基因。一组14个致病性/可能致病性和良性/可能良性的RB1变异被用于验证。结果：我们检测了视网膜母细胞瘤患者中检测到的16个VUS，发现9个VUS降低了pRB抑制E2F1启动子的能力。其中，（RB1） c. 2263T>G . p.（Phe755Val）变异在Western Blot上显示pRB水平降低，提示pRB稳定性存在缺陷。通过将ACMG/AMP分类的PS3_moderate标准应用于该功能分析，9个具有功能影响的VUS中有5个可归类为可能致病。结论：该功能检测可以通过更好地确定致病性/可能致病性RB1变异来提高视网膜母细胞瘤易感性的分子诊断。
{"title":"A functional assay to classify RB1 variants of uncertain significance","authors":"Jessica Le Gall , Catherine Dehainault , Ambre Petitalot , Elsa Amouyal , Jeanne Petitou , Sandrine M. Caputo , François Radvanyi , Alexandre Matet , Nathalie Cassoux , Livia Lumbroso-Le Rouic , Isabelle Aerts , François Doz , Marion Gauthier-Villars , Dominique Stoppa-Lyonnet , Claude Houdayer , Lisa Golmard , François Lallemand","doi":"10.1016/j.gim.2025.101640","DOIUrl":"10.1016/j.gim.2025.101640","url":null,"abstract":"<div><h3>Purpose</h3><div>The <em>RB1</em> gene encodes the retinoblastoma protein (pRB) playing a major role in cell cycle control, particularly by its interaction with E2F transcription factors. Familial forms of retinoblastoma are caused by germline pathogenic variants in the <em>RB1</em> gene predisposing to retinoblastoma and other tumors. By analyzing the <em>RB1</em> gene in patients with retinoblastoma, we found that missense variants often remain variants of uncertain significance (VUS).</div></div><div><h3>Methods</h3><div>To classify <em>RB1</em> VUS, we developed a functional assay evaluating their impact on the ability of pRB to inhibit the activity of the <em>E2F1</em> promoter, with a luciferase reporter gene. A set of 14 pathogenic/likely pathogenic and benign/likely benign <em>RB1</em> variants was used for validation.</div></div><div><h3>Results</h3><div>We tested 16 VUS detected in patients with retinoblastoma and found that 9 VUS reduced the ability of pRB to inhibit <em>E2F1</em> promoter. Among them, the (<em>RB1</em>) c.2263T>G p.(Phe755Val) variant showed a reduced level of pRB on Western blot, suggesting a defect in pRB stability. By applying the criterion PS3_moderate of the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification to this functional assay, 5 of the 9 VUS with functional impact could be classified as likely pathogenic.</div></div><div><h3>Conclusion</h3><div>This functional assay can improve the molecular diagnosis of retinoblastoma predisposition by a better determination of pathogenic/likely pathogenic <em>RB1</em> variants.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 2","pages":"Article 101640"},"PeriodicalIF":6.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530624","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}
Pub Date : 2026-02-01Epub Date: 2026-01-15DOI: 10.1016/j.gim.2025.101632
Sarah L. Malecki , David DArienzo , Erica Wennberg , Emily Ana Butler , Nimit Vediya , Manav V. Vyas , Vanda McNiven , Jessie Cunningham , Therese A. Stukel , Amol A. Verma , Eyal Cohen , Anne S. Bassett
Purpose
Genomic disorders comprise a major source of human disease with survival into adulthood for most individuals, but data on adult outcomes are limited.
Methods
We conducted a formal search to identify studies of 14 clinically relevant, molecularly confirmed deletion syndromes with ≥5 adults reporting on prevalence of cardiovascular risk and other outcomes. Outcomes were pooled across deletion syndromes and by syndrome, using random-effects models.
Results
Of 1352 studies screened, 53 reported on nonoverlapping samples of 13 deletion syndromes. Estimated pooled prevalences, at age <30-40 for most, included 47% (95% CI 33-57%; n = 2076) for obesity, and for 10 deletion syndromes: diabetes 24% (95% CI 17-33%; n = 1739), hypertension 36% (95% CI 28-33%; n = 1314), and dyslipidemia 29% (95% CI 22-36%; n = 1127). High heterogeneity for each outcome was partly explained by a significant subgroup effect of individual syndrome. The few available mortality studies indicated premature mortality.
Conclusion
Pooled results suggest that, although there may be elevated prevalence of adult cardiovascular risk conditions, high heterogeneity indicates caution when considering rare deletion syndromes collectively. The paucity of data extending into later adulthood and using age-matched control comparisons supports the need for prospective studies of large, well-phenotyped cohorts to inform adult penetrance of treatable medical diseases in this emerging group of young adults.
{"title":"Adult outcomes of clinically relevant genomic disorders: A systematic review and meta-analysis","authors":"Sarah L. Malecki , David DArienzo , Erica Wennberg , Emily Ana Butler , Nimit Vediya , Manav V. Vyas , Vanda McNiven , Jessie Cunningham , Therese A. Stukel , Amol A. Verma , Eyal Cohen , Anne S. Bassett","doi":"10.1016/j.gim.2025.101632","DOIUrl":"10.1016/j.gim.2025.101632","url":null,"abstract":"<div><h3>Purpose</h3><div>Genomic disorders comprise a major source of human disease with survival into adulthood for most individuals, but data on adult outcomes are limited.</div></div><div><h3>Methods</h3><div>We conducted a formal search to identify studies of 14 clinically relevant, molecularly confirmed deletion syndromes with ≥5 adults reporting on prevalence of cardiovascular risk and other outcomes. Outcomes were pooled across deletion syndromes and by syndrome, using random-effects models.</div></div><div><h3>Results</h3><div>Of 1352 studies screened, 53 reported on nonoverlapping samples of 13 deletion syndromes. Estimated pooled prevalences, at age <30-40 for most, included 47% (95% CI 33-57%; <em>n</em> = 2076) for obesity, and for 10 deletion syndromes: diabetes 24% (95% CI 17-33%; <em>n</em> = 1739), hypertension 36% (95% CI 28-33%; <em>n</em> = 1314), and dyslipidemia 29% (95% CI 22-36%; <em>n</em> = 1127). High heterogeneity for each outcome was partly explained by a significant subgroup effect of individual syndrome. The few available mortality studies indicated premature mortality.</div></div><div><h3>Conclusion</h3><div>Pooled results suggest that, although there may be elevated prevalence of adult cardiovascular risk conditions, high heterogeneity indicates caution when considering rare deletion syndromes collectively. The paucity of data extending into later adulthood and using age-matched control comparisons supports the need for prospective studies of large, well-phenotyped cohorts to inform adult penetrance of treatable medical diseases in this emerging group of young adults.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 2","pages":"Article 101632"},"PeriodicalIF":6.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989123","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}
Pub Date : 2026-02-01Epub Date: 2025-11-12DOI: 10.1016/j.gim.2025.101635
Annie D. Niehaus , David A. Stevenson , Miriam G. Blitzer
Purpose
This report analyzes Medical Genetics and Genomics (MGG) training trends from 2015 to 2024. Understanding such trends is vital for developing targeted recruitment and workforce development initiatives.
Methods
Matriculation data from the American Board of Medical Genetics and Genomics (ABMGG) and publicly available data from the National Resident Matching Program (NRMP) Main Residency and Specialty Matches were reviewed. Descriptive statistics and linear regression analysis were used to compare growth among MGG training pathways and to analyze trends.
Results
From 2015 to 2024, there has been a small, but not statistically significant, increase in the total number of individuals who have matched into categorical MGG, combined Pediatrics (Peds)-MGG, and combined Internal Medicine (IM)-MGG residency programs as a whole. This has been driven by an increase in the number of matches to combined Peds-MGG programs. Matriculation into training programs has exceeded the number of matches in categorical MGG as some positions have been filled outside of the NRMP Match. The average match rate for all applicants in categorical MGG (87%) has been higher than that for Peds-MGG (52%).
Conclusion
Growth in applicants to combined programs and matriculation into residency programs after the NRMP Match has been promising; however, these increases are not enough to fulfill growing workforce demands.
{"title":"Medical genetics and genomics residency programs: Trends in applications, match rates, and matriculation from 2015 to 2024","authors":"Annie D. Niehaus , David A. Stevenson , Miriam G. Blitzer","doi":"10.1016/j.gim.2025.101635","DOIUrl":"10.1016/j.gim.2025.101635","url":null,"abstract":"<div><h3>Purpose</h3><div>This report analyzes Medical Genetics and Genomics (MGG) training trends from 2015 to 2024. Understanding such trends is vital for developing targeted recruitment and workforce development initiatives.</div></div><div><h3>Methods</h3><div>Matriculation data from the American Board of Medical Genetics and Genomics (ABMGG) and publicly available data from the National Resident Matching Program (NRMP) Main Residency and Specialty Matches were reviewed. Descriptive statistics and linear regression analysis were used to compare growth among MGG training pathways and to analyze trends.</div></div><div><h3>Results</h3><div>From 2015 to 2024, there has been a small, but not statistically significant, increase in the total number of individuals who have matched into categorical MGG, combined Pediatrics (Peds)-MGG, and combined Internal Medicine (IM)-MGG residency programs as a whole. This has been driven by an increase in the number of matches to combined Peds-MGG programs. Matriculation into training programs has exceeded the number of matches in categorical MGG as some positions have been filled outside of the NRMP Match. The average match rate for all applicants in categorical MGG (87%) has been higher than that for Peds-MGG (52%).</div></div><div><h3>Conclusion</h3><div>Growth in applicants to combined programs and matriculation into residency programs after the NRMP Match has been promising; however, these increases are not enough to fulfill growing workforce demands.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 2","pages":"Article 101635"},"PeriodicalIF":6.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523317","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}
Pub Date : 2026-02-01Epub Date: 2025-08-21DOI: 10.1016/j.gim.2025.101561
Wendy J. Ungar , Vercancy Wu , Christian R. Marshall , Jackie Hwang , Robin Z. Hayeems , Kate Tsiplova , Meredith K. Gillespie , Anna Szuto , Caitlin Chisholm , Dimitri J. Stavropoulos , Viji Venkataramanan , Bowen Xiao , Gregory Costain , Mélanie Beaulieu Bergeron , Sarah Sawyer , Lynette Lau , Lijia Huang , Roberto Mendoza-Londono , Martin J. Somerville , Kym M. Boycott , Syed Hassan Zaidi
Purpose
Diagnosing rare diseases is costly. The objectives were to microcost exome (ES) and genome sequencing (GS) trios and estimate the incremental costs of GS per additional diagnosis from an institutional payer perspective.
Methods
Trios (proband plus biological parents) that are referred for sequencing were randomly assigned to ES or GS. Laboratory workflow and sequencing were microcosted. Total and category cost per trio were estimated probabilistically. Effectiveness was expressed as diagnostic yield (rates of diagnostic or partially diagnostic variants detected). Incremental costs and effectiveness were calculated.
Results
The mean total cost per trio was CAD 2888.79 (95% CI 2567.72, 3492.72) for ES (n = 329) and 4364.02 (95% CI 3984.94, 5013.67) for GS (n = 324). Reagents accounted for 34% and 61% of total costs for ES and GS, respectively. The incremental cost of GS was 1475.23. The diagnostic yield was 35.9% for ES and 32.7% for GS with a difference of 0.032 (95% CI: −0.041, 0.104, P value .397).
Conclusion
GS demonstrated higher costs and a similar diagnostic yield to ES but was limited by technical capabilities at the time of the study. The study provides comprehensive costs for the economic evaluation comparing alternative diagnostic pathways and impetus for further evaluating variants uniquely detectable by GS.
目的：诊断罕见病是昂贵的。目的是对外显子组（ES）和基因组测序（GS）三人组进行微成本分析，并从机构付款人的角度估计每增加一次诊断的GS增量成本。方法：参照测序的三人组（先证者加亲生父母）随机分为ES组或GS组。对实验室工作流程和测序进行了微成本计算。对每三人组的总成本和类别成本进行了概率估计。有效性表示为诊断率（诊断性或部分诊断性变异检出率）。计算增量成本和效果。结果：ES组（n=329）的平均总成本为2888.79加元（95% CI 2567.72, 3492.72）， GS组（n=324）的平均总成本为4364.02加元（95% CI 3984.94, 5013.67）。试剂分别占ES和GS总成本的34%和61%。GS的增量成本为1475.23。ES和GS的诊断率分别为35.9%和32.7%，差异为0.032 （95% CI: -0.041, 0.104， p值0.397）。结论：与ES相比，GS显示出更高的成本和相似的诊断率，但在研究时受到技术能力的限制。该研究为经济评估提供了综合成本，比较了替代诊断途径，并推动了进一步评估GS唯一可检测的变异。
{"title":"A microcosting and cost consequence analysis from a randomized controlled trial comparing genome sequencing with exome sequencing for genetic diagnosis","authors":"Wendy J. Ungar , Vercancy Wu , Christian R. Marshall , Jackie Hwang , Robin Z. Hayeems , Kate Tsiplova , Meredith K. Gillespie , Anna Szuto , Caitlin Chisholm , Dimitri J. Stavropoulos , Viji Venkataramanan , Bowen Xiao , Gregory Costain , Mélanie Beaulieu Bergeron , Sarah Sawyer , Lynette Lau , Lijia Huang , Roberto Mendoza-Londono , Martin J. Somerville , Kym M. Boycott , Syed Hassan Zaidi","doi":"10.1016/j.gim.2025.101561","DOIUrl":"10.1016/j.gim.2025.101561","url":null,"abstract":"<div><h3>Purpose</h3><div>Diagnosing rare diseases is costly. The objectives were to microcost exome (ES) and genome sequencing (GS) trios and estimate the incremental costs of GS per additional diagnosis from an institutional payer perspective.</div></div><div><h3>Methods</h3><div>Trios (proband plus biological parents) that are referred for sequencing were randomly assigned to ES or GS. Laboratory workflow and sequencing were microcosted. Total and category cost per trio were estimated probabilistically. Effectiveness was expressed as diagnostic yield (rates of diagnostic or partially diagnostic variants detected). Incremental costs and effectiveness were calculated.</div></div><div><h3>Results</h3><div>The mean total cost per trio was CAD 2888.79 (95% CI 2567.72, 3492.72) for ES (<em>n</em> = 329) and 4364.02 (95% CI 3984.94, 5013.67) for GS (<em>n</em> = 324). Reagents accounted for 34% and 61% of total costs for ES and GS, respectively. The incremental cost of GS was 1475.23. The diagnostic yield was 35.9% for ES and 32.7% for GS with a difference of 0.032 (95% CI: −0.041, 0.104, <em>P</em> value .397).</div></div><div><h3>Conclusion</h3><div>GS demonstrated higher costs and a similar diagnostic yield to ES but was limited by technical capabilities at the time of the study. The study provides comprehensive costs for the economic evaluation comparing alternative diagnostic pathways and impetus for further evaluating variants uniquely detectable by GS.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 2","pages":"Article 101561"},"PeriodicalIF":6.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951629","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}
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