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}
Pub Date : 2025-11-20DOI: 10.1016/j.gim.2025.101649
Maria Francesca Di Feo, Ida Paramonov, Leslie Matalonga Borrel, Ana Töpf, Alexander Hoischen, Sergi Beltran, Holm Graessner, Lisenka Vissers, Richarda de Voer, Marielle van Gijn, Simona Balestrini, Holger Lerche, Gaëtan Lesca, Swethaa Natraj Gayathri, Kornelia Ellwanger, Mireille Cossee, Aurelien Perrin, Anna Sarkozy, Gisele Bonne, Job A J Verdonschot, German Demidov, Steven Laurie, Mridul Johari, Peter Hackman, Marco Savarese, Bjarne Udd
Purpose: Titin, the largest protein in the human body, has been associated with several disease phenotypes caused by variants in the TTN gene. With around 20% of the population carrying a rare TTN variant and over 60 million genomes expected to have been sequenced worldwide by 2025, interpreting these findings presents major challenges. This study analyzed TTN variants in the Solve-RD cohort, the European network for unsolved rare disease cases.
Methods: We collected data from 11,072 individuals with suspected rare diseases and 7,390 healthy relatives from the Solve-RD consortium, checking and manually reviewing TTN variants. We then used a filtering approach focused on clinical relevance, and we provided updated recommendations based on recent literature.
Results: Among the cohort, 240 individuals (1.3%) carried at least one heterozygous TTN truncating variant (TTNtv), with a 3.8% prevalence in the neuromuscular subgroup, primarily composed of unsolved cases. Four individuals received a titinopathy diagnosis. Additionally, 99 participants (0.5%) had a TTNtv in a high-cardiac-PSI exon (>80%), and four had an overt cardiomyopathy.
Conclusion: This study highlights the need for standardized approach to TTN variants, and investigation of missing heritability in myopathic individuals with het TTNtv. Establishing consensus on PSI-based thresholds will be essential for assessing cardiac risk and guiding the management of asymptomatic individuals.
{"title":"The burden of TTN variants in the genomic era: analysis of 18,462 individuals from the Solve-RD consortium and general recommendations.","authors":"Maria Francesca Di Feo, Ida Paramonov, Leslie Matalonga Borrel, Ana Töpf, Alexander Hoischen, Sergi Beltran, Holm Graessner, Lisenka Vissers, Richarda de Voer, Marielle van Gijn, Simona Balestrini, Holger Lerche, Gaëtan Lesca, Swethaa Natraj Gayathri, Kornelia Ellwanger, Mireille Cossee, Aurelien Perrin, Anna Sarkozy, Gisele Bonne, Job A J Verdonschot, German Demidov, Steven Laurie, Mridul Johari, Peter Hackman, Marco Savarese, Bjarne Udd","doi":"10.1016/j.gim.2025.101649","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101649","url":null,"abstract":"<p><strong>Purpose: </strong>Titin, the largest protein in the human body, has been associated with several disease phenotypes caused by variants in the TTN gene. With around 20% of the population carrying a rare TTN variant and over 60 million genomes expected to have been sequenced worldwide by 2025, interpreting these findings presents major challenges. This study analyzed TTN variants in the Solve-RD cohort, the European network for unsolved rare disease cases.</p><p><strong>Methods: </strong>We collected data from 11,072 individuals with suspected rare diseases and 7,390 healthy relatives from the Solve-RD consortium, checking and manually reviewing TTN variants. We then used a filtering approach focused on clinical relevance, and we provided updated recommendations based on recent literature.</p><p><strong>Results: </strong>Among the cohort, 240 individuals (1.3%) carried at least one heterozygous TTN truncating variant (TTNtv), with a 3.8% prevalence in the neuromuscular subgroup, primarily composed of unsolved cases. Four individuals received a titinopathy diagnosis. Additionally, 99 participants (0.5%) had a TTNtv in a high-cardiac-PSI exon (>80%), and four had an overt cardiomyopathy.</p><p><strong>Conclusion: </strong>This study highlights the need for standardized approach to TTN variants, and investigation of missing heritability in myopathic individuals with het TTNtv. Establishing consensus on PSI-based thresholds will be essential for assessing cardiac risk and guiding the management of asymptomatic individuals.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101649"},"PeriodicalIF":6.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145587150","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 : 2025-11-13DOI: 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":"2025-11-13","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}
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":"2025-11-12","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}
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