Pub Date : 2025-12-01Epub Date: 2025-10-27DOI: 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 : 2025-12-01Epub Date: 2025-10-27DOI: 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}
In Friedreich ataxia (FRDA) the size of the smaller GAA expansion is a major determinant of disease severity; interruption motifs were identified after the discovery of the pathogenic expansions; however, their impact is only recently investigated.
Methods
164 patients with FRDA with biallelic expansions and 15 patients without FRDA were analyzed for interruption(s) number, position, and motif. Expansion size and age at onset of ataxia (AAO) were determined for patients with FRDA.
Results
Three groups of patients with FRDA were identified by the simultaneous analysis of the precise distance (“depth”) between the interruptions (mostly nontriplet) and the 3′ end of the expansion (P < .001), the smaller expansion size (P < .001), and AAO (P < .001). Classical FRDA corresponds to absence of interruption or interruption depth < 8 repeats, with AAO often <15 years (area under the curve [AUC] = 0.90; 95% CI, 0.84-0.96); LOFA to interruption depth of 8 to 18 repeats (AUC = 0.97; 95% CI, 0.94-1), with AAO 15 to 34 years (AUC = 1; 95% CI, 1-1); and vLOFA to interruption depth > 18 (AUC = 0.97; 95% CI, 0.92-1), with AAO > 34 years. Multiple (>5) triplet interruptions hamper further expansion.
Conclusion
This study provides the molecular basis for a novel classification of FRDA that should be recommended for correct diagnosis.
{"title":"Type and position of repeat interruptions as determinants of disease severity and expansion size in Friedreich ataxia","authors":"Mehdi Benkirane , Cecilia Marelli , Ariane Choumert , Cyril Goizet , Olivier Patat , Claire Ewenczyk , Mathieu Anheim , André Mégarbané , Lise Larrieu , Cyril Charlin , Fabienne Ory-Magne , Annabelle Chaussenot , Mélanie Fradin , Claire Guissart , Morgane Pointaux , Mireille Cossée , Marie-Claire Vincent , Anne Bergougnoux , Clément Hersent , Corinne Bareil , Michel Koenig","doi":"10.1016/j.gim.2025.101588","DOIUrl":"10.1016/j.gim.2025.101588","url":null,"abstract":"<div><h3>Purpose</h3><div>In Friedreich ataxia (FRDA) the size of the smaller GAA expansion is a major determinant of disease severity; interruption motifs were identified after the discovery of the pathogenic expansions; however, their impact is only recently investigated.</div></div><div><h3>Methods</h3><div>164 patients with FRDA with biallelic expansions and 15 patients without FRDA were analyzed for interruption(s) number, position, and motif. Expansion size and age at onset of ataxia (AAO) were determined for patients with FRDA.</div></div><div><h3>Results</h3><div>Three groups of patients with FRDA were identified by the simultaneous analysis of the precise distance (“depth”) between the interruptions (mostly nontriplet) and the 3′ end of the expansion (<em>P</em> < .001), the smaller expansion size (<em>P</em> < .001), and AAO (<em>P</em> < .001). Classical FRDA corresponds to absence of interruption or interruption depth < 8 repeats, with AAO often <15 years (area under the curve [AUC] = 0.90; 95% CI, 0.84-0.96); LOFA to interruption depth of 8 to 18 repeats (AUC = 0.97; 95% CI, 0.94-1), with AAO 15 to 34 years (AUC = 1; 95% CI, 1-1); and vLOFA to interruption depth > 18 (AUC = 0.97; 95% CI, 0.92-1), with AAO > 34 years. Multiple (>5) triplet interruptions hamper further expansion.</div></div><div><h3>Conclusion</h3><div>This study provides the molecular basis for a novel classification of FRDA that should be recommended for correct diagnosis.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101588"},"PeriodicalIF":6.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174673","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 : 2025-12-01Epub Date: 2025-11-28DOI: 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 : 2025-12-01Epub Date: 2025-09-18DOI: 10.1016/j.gim.2025.101586
Liselot van der Laan , Raissa Relator , Irene Valenzuela , Adri N. Mul , Mariëlle Alders , Michael A. Levy , Jennifer Kerkhof , Jessica Rzasa , Anna M. Cueto-González , Amaia Lasa-Aranzasti , Cristina Cea-Arestin , Marcel M.A.M. Mannens , Mieke M. van Haelst , Eduardo F. Tizzano , Bekim Sadikovic , Peter Henneman
Purpose
Fetal alcohol spectrum disorder (FASD) encompasses a range of clinical features and neurodevelopmental disorders in children exposed to alcohol in utero. Despite its global public health significance, FASD diagnosis remains challenging because of nonspecific clinical findings and the lack of an accurate molecular diagnostic biomarker. This study aimed to evaluate peripheral blood DNA methylation (DNAm) profiles as a potential diagnostic biomarker for fetal alcohol syndrome.
Methods
Genomic DNAm profiles from 93 individuals with suspected or confirmed FAS, including a clinically diagnosed FAS subgroup, were analyzed and compared with a large database of control and patient cohorts with previously reported DNAm episignatures. Functional analysis of these DNAm profiles was performed to identify episignatures and assess their potential diagnostic utility.
Results
A relatively sensitive and specific DNAm episignature for FAS was identified. Comparative epigenomic analysis revealed functional correlations between FAS and other rare genetic disorders, supporting the robustness of the identified DNAm profiles as a diagnostic tool.
Conclusion
This study demonstrates that unique DNAm profiles provide a robust episignature biomarker for FAS. These findings contribute to the molecular understanding of FAS and hold promise for improving diagnostic accuracy for this complex disorder.
{"title":"Discovery of a DNA methylation episignature as a molecular biomarker for fetal alcohol syndrome","authors":"Liselot van der Laan , Raissa Relator , Irene Valenzuela , Adri N. Mul , Mariëlle Alders , Michael A. Levy , Jennifer Kerkhof , Jessica Rzasa , Anna M. Cueto-González , Amaia Lasa-Aranzasti , Cristina Cea-Arestin , Marcel M.A.M. Mannens , Mieke M. van Haelst , Eduardo F. Tizzano , Bekim Sadikovic , Peter Henneman","doi":"10.1016/j.gim.2025.101586","DOIUrl":"10.1016/j.gim.2025.101586","url":null,"abstract":"<div><h3>Purpose</h3><div>Fetal alcohol spectrum disorder (FASD) encompasses a range of clinical features and neurodevelopmental disorders in children exposed to alcohol in utero. Despite its global public health significance, FASD diagnosis remains challenging because of nonspecific clinical findings and the lack of an accurate molecular diagnostic biomarker. This study aimed to evaluate peripheral blood DNA methylation (DNAm) profiles as a potential diagnostic biomarker for fetal alcohol syndrome.</div></div><div><h3>Methods</h3><div>Genomic DNAm profiles from 93 individuals with suspected or confirmed FAS, including a clinically diagnosed FAS subgroup, were analyzed and compared with a large database of control and patient cohorts with previously reported DNAm episignatures. Functional analysis of these DNAm profiles was performed to identify episignatures and assess their potential diagnostic utility.</div></div><div><h3>Results</h3><div>A relatively sensitive and specific DNAm episignature for FAS was identified. Comparative epigenomic analysis revealed functional correlations between FAS and other rare genetic disorders, supporting the robustness of the identified DNAm profiles as a diagnostic tool.</div></div><div><h3>Conclusion</h3><div>This study demonstrates that unique DNAm profiles provide a robust episignature biomarker for FAS. These findings contribute to the molecular understanding of FAS and hold promise for improving diagnostic accuracy for this complex disorder.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101586"},"PeriodicalIF":6.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112998","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 : 2025-12-01Epub Date: 2025-09-29DOI: 10.1016/j.gim.2025.101592
Annelieke R. Müller , Bibiche den Hollander , Agnies M. van Eeghen , Peter M. van de Ven , Martina Cornel , Mieke van Haelst , Jan J. Sprengers , Hilgo Bruining , Marion M. Brands , Clara D. van Karnebeek
Treatments often do not reach individuals affected with a rare disease because of several barriers. Legislation generally requires that therapies for rare diseases are tested and licensed according to the same rules as established for common diseases. However, conventional methods for evaluating treatment effectiveness are hampered by the small patient populations. Single-case experimental designs (SCEDs), including n-of-1 trials, may offer a solution. Advantages of SCEDs include the ability to study individualized treatment options, use of within-participant randomization to generate a high level of evidence, and guarantee that each individual receives treatment. Their individualized approach also has a positive impact on ensuring relevance of treatment approaches and outcomes for affected individuals. However, designing and performing SCEDs in rare diseases comes with specific challenges related to heterogeneity, selection of outcome measures, accessibility of therapy, development of study medication, treatment and trial adherence, regulation, reimbursement, and financial limitations. Here, the lessons learned from SCEDs in rare diseases are discussed, based on real-world experiences from the involved clinicians and researchers, and informal participants’ comments collected during and after participation in a SCED. Following these experiences and a thorough evaluation by an expert group, a manual for conducting SCEDs has been developed. This manual is presented as a steppingstone toward robust evidence generation and better access to treatments for individuals with rare diseases.
{"title":"Overcoming treatment implementation barriers for individuals with rare diseases using single-case experimental designs","authors":"Annelieke R. Müller , Bibiche den Hollander , Agnies M. van Eeghen , Peter M. van de Ven , Martina Cornel , Mieke van Haelst , Jan J. Sprengers , Hilgo Bruining , Marion M. Brands , Clara D. van Karnebeek","doi":"10.1016/j.gim.2025.101592","DOIUrl":"10.1016/j.gim.2025.101592","url":null,"abstract":"<div><div>Treatments often do not reach individuals affected with a rare disease because of several barriers. Legislation generally requires that therapies for rare diseases are tested and licensed according to the same rules as established for common diseases. However, conventional methods for evaluating treatment effectiveness are hampered by the small patient populations. Single-case experimental designs (SCEDs), including n-of-1 trials, may offer a solution. Advantages of SCEDs include the ability to study individualized treatment options, use of within-participant randomization to generate a high level of evidence, and guarantee that each individual receives treatment. Their individualized approach also has a positive impact on ensuring relevance of treatment approaches and outcomes for affected individuals. However, designing and performing SCEDs in rare diseases comes with specific challenges related to heterogeneity, selection of outcome measures, accessibility of therapy, development of study medication, treatment and trial adherence, regulation, reimbursement, and financial limitations. Here, the lessons learned from SCEDs in rare diseases are discussed, based on real-world experiences from the involved clinicians and researchers, and informal participants’ comments collected during and after participation in a SCED. Following these experiences and a thorough evaluation by an expert group, a manual for conducting SCEDs has been developed. This manual is presented as a steppingstone toward robust evidence generation and better access to treatments for individuals with rare diseases.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101592"},"PeriodicalIF":6.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206302","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 : 2025-12-01Epub Date: 2025-09-30DOI: 10.1016/j.gim.2025.101593
Runjun D. Kumar, Sarah A. Paolucci, Brittany Williams, Daniel W. Serber, Claire L. Wittowski, Ankita Jhuraney, Dru F. Leistritz, Jillian G. Buchan
Purpose
Clinical testing of rare genetic variants relies on population genomic data sets as a source of evidence. New data sets from the Genome Aggregation Database and All of Us Research Program are many-fold larger than previous data sets, and the latter includes highly detailed phenotype data. The effect of these data sets on variant classification and reporting for highly penetrant pediatric-onset disease is not well characterized; however, one likely effect is reduced reporting of variants of uncertain significance (VUS).
Methods
We retrospectively identified VUS previously reported by our clinically licensed laboratory and evaluated whether they are still reportable based on new reference data sets.
Results
By examining allele counts in new data sets, we identified 24 variants that are likely no longer reportable. Additionally, the All of Us phenotype data suggest that an additional 10 VUS are no longer reportable. Overall, we found that nearly one-fifth of VUS (34/173, 19.6%) are no longer reportable.
Conclusion
We conclude that the use of these new data sets is likely to reduce reported VUS for highly penetrant pediatric-onset disease. This may be further augmented through updated gene-specific thresholds and improved accessibility of All of Us phenotype data.
{"title":"Real-world effects of using gnomAD 4.1.0 and All of Us population reference data sets on reporting of variants of uncertain significance","authors":"Runjun D. Kumar, Sarah A. Paolucci, Brittany Williams, Daniel W. Serber, Claire L. Wittowski, Ankita Jhuraney, Dru F. Leistritz, Jillian G. Buchan","doi":"10.1016/j.gim.2025.101593","DOIUrl":"10.1016/j.gim.2025.101593","url":null,"abstract":"<div><h3>Purpose</h3><div>Clinical testing of rare genetic variants relies on population genomic data sets as a source of evidence. New data sets from the Genome Aggregation Database and All of Us Research Program are many-fold larger than previous data sets, and the latter includes highly detailed phenotype data. The effect of these data sets on variant classification and reporting for highly penetrant pediatric-onset disease is not well characterized; however, one likely effect is reduced reporting of variants of uncertain significance (VUS).</div></div><div><h3>Methods</h3><div>We retrospectively identified VUS previously reported by our clinically licensed laboratory and evaluated whether they are still reportable based on new reference data sets.</div></div><div><h3>Results</h3><div>By examining allele counts in new data sets, we identified 24 variants that are likely no longer reportable. Additionally, the All of Us phenotype data suggest that an additional 10 VUS are no longer reportable. Overall, we found that nearly one-fifth of VUS (34/173, 19.6%) are no longer reportable.</div></div><div><h3>Conclusion</h3><div>We conclude that the use of these new data sets is likely to reduce reported VUS for highly penetrant pediatric-onset disease. This may be further augmented through updated gene-specific thresholds and improved accessibility of All of Us phenotype data.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101593"},"PeriodicalIF":6.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212300","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 : 2025-12-01Epub Date: 2025-10-10DOI: 10.1016/j.gim.2025.101598
Anne B. Arnett , Ryan Koesterer , Paulina Gonzalez Tovar , Mia O’Connell , Soleha Patel , Han Zhang , Courtney E. French , Shira Rockowitz , Jason Flannick , Ryan Doan
Purpose
Pediatric attention deficit hyperactivity disorder (ADHD, OMIM 143465) is highly heritable, yet the genetic architecture of the condition remains poorly understood. This study tested the hypothesis that rare and common genetic variants reflect distinct genetic pathways to ADHD.
Methods
Genome sequencing was completed for 150 pediatric ADHD cases and 370 controls. ADHD polygenic scores were derived and compared across 5 methods, including 2 published genome-wide association studies and 2 publicly available catalogs. Likely pathogenic rare variants were identified with a previously published customized annotation and classification pipeline followed by manual curation using established American College of Medical Genetics and Genomics variant interpretation guidelines.
Results
ADHD cases had higher ADHD polygenic scores and lower IQ polygenic scores. Likely pathogenic variants for ADHD were identified in 13% of cases and 0.5% of controls. ADHD polygenic scores among cases without rare variants were higher than cases carrying rare variants. ADHD cases were predicted by ADHD and IQ polygenic scores, ancestry, and rare variant status with 70% area under the curve.
Conclusion
The genetic etiology of ADHD is likely multifactorial, with independent contributions from common and rare variants. Genome-wide association studies of ADHD may have increased power to detect common genetic loci if individuals with rare variants are excluded.
{"title":"Common and rare genetic variants explain distinct diagnostic variance in pediatric attention deficit hyperactivity disorder","authors":"Anne B. Arnett , Ryan Koesterer , Paulina Gonzalez Tovar , Mia O’Connell , Soleha Patel , Han Zhang , Courtney E. French , Shira Rockowitz , Jason Flannick , Ryan Doan","doi":"10.1016/j.gim.2025.101598","DOIUrl":"10.1016/j.gim.2025.101598","url":null,"abstract":"<div><h3>Purpose</h3><div>Pediatric attention deficit hyperactivity disorder (ADHD, OMIM <span><span>143465</span><svg><path></path></svg></span>) is highly heritable, yet the genetic architecture of the condition remains poorly understood. This study tested the hypothesis that rare and common genetic variants reflect distinct genetic pathways to ADHD.</div></div><div><h3>Methods</h3><div>Genome sequencing was completed for 150 pediatric ADHD cases and 370 controls. ADHD polygenic scores were derived and compared across 5 methods, including 2 published genome-wide association studies and 2 publicly available catalogs. Likely pathogenic rare variants were identified with a previously published customized annotation and classification pipeline followed by manual curation using established American College of Medical Genetics and Genomics variant interpretation guidelines.</div></div><div><h3>Results</h3><div>ADHD cases had higher ADHD polygenic scores and lower IQ polygenic scores. Likely pathogenic variants for ADHD were identified in 13% of cases and 0.5% of controls. ADHD polygenic scores among cases without rare variants were higher than cases carrying rare variants. ADHD cases were predicted by ADHD and IQ polygenic scores, ancestry, and rare variant status with 70% area under the curve.</div></div><div><h3>Conclusion</h3><div>The genetic etiology of ADHD is likely multifactorial, with independent contributions from common and rare variants. Genome-wide association studies of ADHD may have increased power to detect common genetic loci if individuals with rare variants are excluded.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101598"},"PeriodicalIF":6.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274466","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 : 2025-12-01Epub Date: 2025-09-23DOI: 10.1016/j.gim.2025.101589
Ruben J. Overduin , Andrea B. Haijer-Schreuder , Frederiec K. Withaar , Sarah C. Grünert , Jamas LaFreniere , Enrique L. Contreras , Gayle W. Temkin , Blair Stone-Schneider , Frédéric Vanneste , Hanka Dekker , Marieke J. Fokkert-Wilts , Melanie M. van der Klauw , David A. Weinstein , Alessandro Rossi , Terry G.J. Derks
Purpose
Health care and clinical trials for persons with liver glycogen storage diseases (GSD) can be improved by a consensus-based standard set of person-centered health outcomes, including patient-reported outcome measures.
Methods
Persons with GSD (n = 6), caregivers (n = 17), multidisciplinary health care providers (n = 38), industry representatives (n = 7), and value-based health care experts (n=4) from 25 countries participated in an international, iterative nominal consensus process to identify the most important health outcomes and case-mix variables for liver GSD.
Results
The following 14 health outcomes are recommended for measurement: (1) cure; (2) life-threatening GSD-related events; (3) glycemic control; (4) metabolic control; (5) acute metabolic decompensations; (6) GSD-related complications; (7) time to treatment of intercurrent complications; (8) time to return to functional status; (9) access and availability of GSD expertise care; (10) access and availability of GSD-related diagnostic, monitoring, and treatment products; (11) quality of life; (12) independence; (13) treatment adherence; and (14) food intake problems. A list of 29 case-mix variables was composed of demographic, diagnostic, clinical, and treatment factors. Recommendations were formulated on frequency of measurements.
Conclusion
An international consensus-based standard set of person-centered health outcomes for liver GSD was developed to apply in health care, registries, and clinical trials.
{"title":"Person-centered outcomes for liver glycogen storage diseases: Development of an international consensus-based standard outcome set","authors":"Ruben J. Overduin , Andrea B. Haijer-Schreuder , Frederiec K. Withaar , Sarah C. Grünert , Jamas LaFreniere , Enrique L. Contreras , Gayle W. Temkin , Blair Stone-Schneider , Frédéric Vanneste , Hanka Dekker , Marieke J. Fokkert-Wilts , Melanie M. van der Klauw , David A. Weinstein , Alessandro Rossi , Terry G.J. Derks","doi":"10.1016/j.gim.2025.101589","DOIUrl":"10.1016/j.gim.2025.101589","url":null,"abstract":"<div><h3>Purpose</h3><div>Health care and clinical trials for persons with liver glycogen storage diseases (GSD) can be improved by a consensus-based standard set of person-centered health outcomes, including patient-reported outcome measures.</div></div><div><h3>Methods</h3><div>Persons with GSD (<em>n</em> = 6), caregivers (<em>n</em> = 17), multidisciplinary health care providers (<em>n</em> = 38), industry representatives (<em>n</em> = 7), and value-based health care experts (n=4) from 25 countries participated in an international, iterative nominal consensus process to identify the most important health outcomes and case-mix variables for liver GSD.</div></div><div><h3>Results</h3><div>The following 14 health outcomes are recommended for measurement: (1) cure; (2) life-threatening GSD-related events; (3) glycemic control; (4) metabolic control; (5) acute metabolic decompensations; (6) GSD-related complications; (7) time to treatment of intercurrent complications; (8) time to return to functional status; (9) access and availability of GSD expertise care; (10) access and availability of GSD-related diagnostic, monitoring, and treatment products; (11) quality of life; (12) independence; (13) treatment adherence; and (14) food intake problems. A list of 29 case-mix variables was composed of demographic, diagnostic, clinical, and treatment factors. Recommendations were formulated on frequency of measurements.</div></div><div><h3>Conclusion</h3><div>An international consensus-based standard set of person-centered health outcomes for liver GSD was developed to apply in health care, registries, and clinical trials.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101589"},"PeriodicalIF":6.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174768","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 : 2025-12-01Epub Date: 2025-10-10DOI: 10.1016/j.gim.2025.101603
Jincong Q. Freeman , Yijia Sun , Wenji Guo , Briseis Aschebrook-Kilfoy , Cara Essling , Jan-Marie McEvilly , Ilona Siljander , Hatice Basdag , Olufunmilayo I. Olopade , Dezheng Huo
Purpose
To examine awareness, knowledge, and attitudes toward breast cancer (BC) polygenic risk scores (PRS) in women with high risk.
Methods
We surveyed women without BC enrolled in the Chicago Multiethnic Epidemiologic BC Cohort and Cancer Prone Registry between July and September 2024. PRS awareness was defined as having ever read/heard about PRS and discussed PRS with a provider. PRS knowledge scores range from 0 to 11. Higher scores indicate better knowledge. We also asked to what extent participants agreed that PRS testing should be offered to the general population or a routine part of BC risk assessment and how likely receiving PRS would influence their risk management behaviors.
Results
Of 828 women, 18.5% had read/heard about PRS, and 13.2% discussed PRS with a provider. Non-Hispanic White women scored slightly higher on PRS knowledge than Non-Hispanic Black and multiracial/other women. Higher education (P-trend < .001) and income (P-trend = .002) levels were associated with increased knowledge scores. More than 90.0% agreed/strongly agreed that PRS testing should be offered to the general population or a routine part of risk assessment. In total, 94.0% reported that PRS receipt would likely/very likely influence their risk management behaviors.
Conclusion
This study suggests an opportunity for tailored PRS education interventions and the need to improve patient-provider communication and knowledge gaps when implementing genetic testing to increase personalized BC screening.
{"title":"Awareness, knowledge, and attitudes toward polygenic risk scores for breast cancer in multiethnic high-risk cohorts of women","authors":"Jincong Q. Freeman , Yijia Sun , Wenji Guo , Briseis Aschebrook-Kilfoy , Cara Essling , Jan-Marie McEvilly , Ilona Siljander , Hatice Basdag , Olufunmilayo I. Olopade , Dezheng Huo","doi":"10.1016/j.gim.2025.101603","DOIUrl":"10.1016/j.gim.2025.101603","url":null,"abstract":"<div><h3>Purpose</h3><div>To examine awareness, knowledge, and attitudes toward breast cancer (BC) polygenic risk scores (PRS) in women with high risk.</div></div><div><h3>Methods</h3><div>We surveyed women without BC enrolled in the Chicago Multiethnic Epidemiologic BC Cohort and Cancer Prone Registry between July and September 2024. PRS awareness was defined as having ever read/heard about PRS and discussed PRS with a provider. PRS knowledge scores range from 0 to 11. Higher scores indicate better knowledge. We also asked to what extent participants agreed that PRS testing should be offered to the general population or a routine part of BC risk assessment and how likely receiving PRS would influence their risk management behaviors.</div></div><div><h3>Results</h3><div>Of 828 women, 18.5% had read/heard about PRS, and 13.2% discussed PRS with a provider. Non-Hispanic White women scored slightly higher on PRS knowledge than Non-Hispanic Black and multiracial/other women. Higher education (<em>P</em>-trend < .001) and income (<em>P</em>-trend = .002) levels were associated with increased knowledge scores. More than 90.0% agreed/strongly agreed that PRS testing should be offered to the general population or a routine part of risk assessment. In total, 94.0% reported that PRS receipt would likely/very likely influence their risk management behaviors.</div></div><div><h3>Conclusion</h3><div>This study suggests an opportunity for tailored PRS education interventions and the need to improve patient-provider communication and knowledge gaps when implementing genetic testing to increase personalized BC screening.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 12","pages":"Article 101603"},"PeriodicalIF":6.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286016","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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