Pub Date : 2025-12-17DOI: 10.1016/j.gim.2025.101667
Eva Martinez , Jillian Serrano , Siwaar Abouhala , Ashana Neale , Grace VanNoy , Heidi L. Rehm , Melanie O’Leary , Anne O’Donnell-Luria , Monica H. Wojcik
Purpose
Rare disease genomic research suffers from a lack of diverse participation. We therefore implemented and evaluated a multi-faceted intervention to support recruitment of populations previously underrepresented by race, ethnicity, primary language, household income, education level, or rural residence to the Rare Genomes Project.
Methods
For a prospective cohort, we tracked completion of our enrollment processes supported by interventions including clinician engagement, language support, proactive and flexible participant contact, and use of mobile phlebotomy. Participants were offered a survey upon enrollment to assess values and priorities.
Results
In total, 161 of 195 (83%) participants completed enrollment. High-yield interventions included clinician referral forms and increased staff assistance. Genome sequencing data have been generated for 133 participants, with a diagnosis found for 17 (13%) and candidate for 23 (17%) thus far. Most diagnosed participants (13/17, 76%) benefited from clinician rather than self-referral. Perceived importance of a genetic diagnosis was ranked very/extremely high for 81 of 96 (84%) of participants. Spanish primary language was associated with higher perceived importance and high income with lower perceived importance, although only income remained significant in a multivariable model.
Conclusion
Overall, our equity-focused initiative enabled enrollment of participants from populations previously underrepresented in rare disease genomic research and offers insight into potential motivators.
{"title":"Equity-focused implementation to enhance access to rare disease genomic research and understand diverse perspectives","authors":"Eva Martinez , Jillian Serrano , Siwaar Abouhala , Ashana Neale , Grace VanNoy , Heidi L. Rehm , Melanie O’Leary , Anne O’Donnell-Luria , Monica H. Wojcik","doi":"10.1016/j.gim.2025.101667","DOIUrl":"10.1016/j.gim.2025.101667","url":null,"abstract":"<div><h3>Purpose</h3><div>Rare disease genomic research suffers from a lack of diverse participation. We therefore implemented and evaluated a multi-faceted intervention to support recruitment of populations previously underrepresented by race, ethnicity, primary language, household income, education level, or rural residence to the Rare Genomes Project.</div></div><div><h3>Methods</h3><div>For a prospective cohort, we tracked completion of our enrollment processes supported by interventions including clinician engagement, language support, proactive and flexible participant contact, and use of mobile phlebotomy. Participants were offered a survey upon enrollment to assess values and priorities.</div></div><div><h3>Results</h3><div>In total, 161 of 195 (83%) participants completed enrollment. High-yield interventions included clinician referral forms and increased staff assistance. Genome sequencing data have been generated for 133 participants, with a diagnosis found for 17 (13%) and candidate for 23 (17%) thus far. Most diagnosed participants (13/17, 76%) benefited from clinician rather than self-referral. Perceived importance of a genetic diagnosis was ranked very/extremely high for 81 of 96 (84%) of participants. Spanish primary language was associated with higher perceived importance and high income with lower perceived importance, although only income remained significant in a multivariable model.</div></div><div><h3>Conclusion</h3><div>Overall, our equity-focused initiative enabled enrollment of participants from populations previously underrepresented in rare disease genomic research and offers insight into potential motivators.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"28 3","pages":"Article 101667"},"PeriodicalIF":6.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794014","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 : 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":"2025-12-08","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}
Pub Date : 2025-12-08DOI: 10.1016/j.gim.2025.101661
Maria Cerminara, Giovanni Spirito, Luca Pandolfini, Silvia Boeri, Giulia Rosti, Margherita Mancardi, Livia Pisciotta, Marco Fontana, Alessandra Bianchi, Iris Chen, Loretta Ferrera, Francesco Caroli, Marco Di Duca, Andrea Cavalli, Maria Teresa Divizia, Elisa De Grandis, Silvia Casabona, Sara Trova, Diego Vozzi, Antonio Amoroso, Laure Obino, Remo Sanges, Manuela Vecchi, Lino Nobili, Federico Zara, Stefano Gustincich, Aldamaria Puliti
Purpose: Developmental regression, characterized by the loss of acquired milestones, occurs in some individuals with neurdevelopmental disorders (NDDs), yet its molecular basis remains unclear. Studies suggest that DNA damage repair (DDR) genes, such as FAN1, may protect against neurological dysfunction by modulating the somatic stability of short tandem repeats (STRs). This study explores the contribution of DDR gene variants in NDD cases presenting with regression.
Methods: We analyzed 1,087 NDD patients, focusing on those carrying variants in DDR genes and presenting regression. We assessed the sensitivity to DNA damage using mitomycin C on lymphoblastoid cells. Somatic variants and STR expansions were evaluated through high-depth short-read genome sequencing. To further investigate the pathogenetic role of STR expansions, we performed long-read genome sequencing on the most severely affected proband.
Results: Probands with regression carried multiple DDR gene variants, several within the Fanconi anemia pathway. Their lymphoblastoid cells showed increased sensitivity to mitomycin C-induced cytotoxicity compared to parental and control samples. Probands with severe phenotypes and regression exhibited an accumulation of somatic variants and STR instability, enriched in neurodevelopmental genes.
Conclusions: Our findings suggest that polygenic DDR gene variants may contribute to developmental regression in NDDs by promoting the accumulation of somatic variants and STR expansions.
{"title":"Polygenic variants in DNA repair genes are associated with neurodevelopmental disorders, regression and increased burdens of somatic variants and short tandem repeat expansions.","authors":"Maria Cerminara, Giovanni Spirito, Luca Pandolfini, Silvia Boeri, Giulia Rosti, Margherita Mancardi, Livia Pisciotta, Marco Fontana, Alessandra Bianchi, Iris Chen, Loretta Ferrera, Francesco Caroli, Marco Di Duca, Andrea Cavalli, Maria Teresa Divizia, Elisa De Grandis, Silvia Casabona, Sara Trova, Diego Vozzi, Antonio Amoroso, Laure Obino, Remo Sanges, Manuela Vecchi, Lino Nobili, Federico Zara, Stefano Gustincich, Aldamaria Puliti","doi":"10.1016/j.gim.2025.101661","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101661","url":null,"abstract":"<p><strong>Purpose: </strong>Developmental regression, characterized by the loss of acquired milestones, occurs in some individuals with neurdevelopmental disorders (NDDs), yet its molecular basis remains unclear. Studies suggest that DNA damage repair (DDR) genes, such as FAN1, may protect against neurological dysfunction by modulating the somatic stability of short tandem repeats (STRs). This study explores the contribution of DDR gene variants in NDD cases presenting with regression.</p><p><strong>Methods: </strong>We analyzed 1,087 NDD patients, focusing on those carrying variants in DDR genes and presenting regression. We assessed the sensitivity to DNA damage using mitomycin C on lymphoblastoid cells. Somatic variants and STR expansions were evaluated through high-depth short-read genome sequencing. To further investigate the pathogenetic role of STR expansions, we performed long-read genome sequencing on the most severely affected proband.</p><p><strong>Results: </strong>Probands with regression carried multiple DDR gene variants, several within the Fanconi anemia pathway. Their lymphoblastoid cells showed increased sensitivity to mitomycin C-induced cytotoxicity compared to parental and control samples. Probands with severe phenotypes and regression exhibited an accumulation of somatic variants and STR instability, enriched in neurodevelopmental genes.</p><p><strong>Conclusions: </strong>Our findings suggest that polygenic DDR gene variants may contribute to developmental regression in NDDs by promoting the accumulation of somatic variants and STR expansions.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101661"},"PeriodicalIF":6.2,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145722532","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 : 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":"2025-12-02","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 : 2025-12-01DOI: 10.1016/j.gim.2025.101566
Angela Krutish , Rebekah Kukurudz-Gorowski , Elizabeth Spriggs , Aizeddin A. Mhanni , Cheryl Rockman-Greenberg
{"title":"Correspondence on “Mainstreaming of clinical genetic testing: a conceptual framework” by Mackley et al","authors":"Angela Krutish , Rebekah Kukurudz-Gorowski , Elizabeth Spriggs , Aizeddin A. Mhanni , Cheryl Rockman-Greenberg","doi":"10.1016/j.gim.2025.101566","DOIUrl":"10.1016/j.gim.2025.101566","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101566"},"PeriodicalIF":6.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145377123","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 : 2025-12-01DOI: 10.1016/j.gim.2025.101567
Michael P. Mackley , Julie Richer , Kym M. Boycott
{"title":"Response to Krutish et al","authors":"Michael P. Mackley , Julie Richer , Kym M. Boycott","doi":"10.1016/j.gim.2025.101567","DOIUrl":"10.1016/j.gim.2025.101567","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101567"},"PeriodicalIF":6.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145372583","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 : 2025-12-01DOI: 10.1016/j.gim.2025.101559
Mia J. Gruzin , Swaroop Aradhya , Leslie Burnett
{"title":"Correspondence on “Estimation of carrier frequencies of autosomal and X-linked recessive genetic conditions based on gnomAD v4.0 data in different ancestries” by Hotakainen et al","authors":"Mia J. Gruzin , Swaroop Aradhya , Leslie Burnett","doi":"10.1016/j.gim.2025.101559","DOIUrl":"10.1016/j.gim.2025.101559","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101559"},"PeriodicalIF":6.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620117","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 : 2025-11-25DOI: 10.1016/j.gim.2025.101654
Mia Aagaard Doherty, Kathrine Grell, Hanne Hove, Mette M Handrup, John R Østergaard, Anja Krøyer, Thomas T Nielsen, Henrik Hjalgrim, John J Mulvihill, Henrik Hasle, Cecilie Ejerskov, Jan Wohlfahrt, Line Kenborg
Purpose: Neurofibromatosis 1 (NF1) is associated with reduced life expectancy due to malignancies; however, the risk of non-neoplastic causes of death is less well characterised.
Methods: A total of 1622 persons with NF1, identified through either the Danish National Patient Registry or a clinical database, and 15856 matched comparators born 1951-2002 were followed from either age 20 or NF1 diagnosis. Death causes were from the Danish Cause of Death Register. Cumulative risks of different causes of death were compared between persons with and without NF1, and years of life lost (YLL) were calculated.
Results: Overall, 259 persons with NF1 (16.0%) and 578 comparators (3.6%) died during follow-up. The most frequent non-neoplastic causes of death in NF1 were diseases in the circulatory and nervous systems, with the latter showing a statistically significant higher 70-year cumulative risk in NF1. An excess of 6.1 (4.7-7.5) YLL within age 20-60 was seen in NF1 including 2.5 (1.5-3.5) years from non-neoplastic causes, and 3.6 (2.5-4.7) years from neoplasms.
Conclusion: Persons with NF1 showed an increased risk of death from nervous system diseases and neoplasms and a reduced life expectancy, with non-neoplastic causes accounting for almost half of the YLL.
{"title":"Non-neoplastic causes of death in neurofibromatosis 1: A cohort study with long-term follow-up.","authors":"Mia Aagaard Doherty, Kathrine Grell, Hanne Hove, Mette M Handrup, John R Østergaard, Anja Krøyer, Thomas T Nielsen, Henrik Hjalgrim, John J Mulvihill, Henrik Hasle, Cecilie Ejerskov, Jan Wohlfahrt, Line Kenborg","doi":"10.1016/j.gim.2025.101654","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101654","url":null,"abstract":"<p><strong>Purpose: </strong>Neurofibromatosis 1 (NF1) is associated with reduced life expectancy due to malignancies; however, the risk of non-neoplastic causes of death is less well characterised.</p><p><strong>Methods: </strong>A total of 1622 persons with NF1, identified through either the Danish National Patient Registry or a clinical database, and 15856 matched comparators born 1951-2002 were followed from either age 20 or NF1 diagnosis. Death causes were from the Danish Cause of Death Register. Cumulative risks of different causes of death were compared between persons with and without NF1, and years of life lost (YLL) were calculated.</p><p><strong>Results: </strong>Overall, 259 persons with NF1 (16.0%) and 578 comparators (3.6%) died during follow-up. The most frequent non-neoplastic causes of death in NF1 were diseases in the circulatory and nervous systems, with the latter showing a statistically significant higher 70-year cumulative risk in NF1. An excess of 6.1 (4.7-7.5) YLL within age 20-60 was seen in NF1 including 2.5 (1.5-3.5) years from non-neoplastic causes, and 3.6 (2.5-4.7) years from neoplasms.</p><p><strong>Conclusion: </strong>Persons with NF1 showed an increased risk of death from nervous system diseases and neoplasms and a reduced life expectancy, with non-neoplastic causes accounting for almost half of the YLL.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101654"},"PeriodicalIF":6.2,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145632463","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 : 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":"2025-11-20","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}
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