Genetics in Medicine最新文献

{"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":"https://doi.org/10.1016/j.gim.2025.101592","url":null,"abstract":"<p><p>Treatments often do not reach individuals affected with a rare disease due to 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 guaranteeing 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 towards robust evidence generation and better access to treatments for individuals with rare diseases.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101592"},"PeriodicalIF":6.2,"publicationDate":"2025-09-29","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}

{"title":"HCSeeker: A Classification Tool for Human Genetic Variant Hot and Cold Spots Designed for PM1 and Benign Criteria in the ACMG-AMP Guideline.","authors":"Xinpan Yuan, Xingquan Xia, Jinchen Li, Guihu Zhao","doi":"10.1016/j.gim.2025.101591","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101591","url":null,"abstract":"<p><strong>Purpose: </strong>The PM1 criterion, which states that a variant is located in a mutational hot spot and/or critical and well-established functional domain without benign variation (such as the active site of an enzyme), is considered moderate evidence for assessing its pathogenicity. Although guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) are widely adopted, the PM1 criterion remains limited from lacking a reliable database of variant hot spots. Compared to hot spots, cold spots are neglected by the guidelines. To improve variant classification, we suggest including cold spots for supporting benign classifications. Consequently , we have developed the HCSeeker to provide data support for PM1 and the 'Benign' criteria.</p><p><strong>Methods: </strong>HCSeeker employs the Kernel Density Estimation (KDE) and the Expectation-Maximization (EM) algorithm to identify hot and cold spot regions.</p><p><strong>Results: </strong>Through HCSeeker, we identified 988 hot spots and 682 cold spots across 889 genes and provided a public database (http://www.genemed.tech/hcseeker/) for researchers and clinicians to query variant locations, facilitating the application of ACMG/AMP PM1 or 'Benign' criteria.</p><p><strong>Conclusion: </strong>We developed the HCSeeker tool, which can effectively identify variant hot and cold spots within genes to enhancing the interpretability of gene variants.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101591"},"PeriodicalIF":6.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Infantile-onset Pompe disease entering adulthood: insights from two decades of enzyme replacement therapy experience.","authors":"Neha Regmi, Daniel Kenney-Jung, Grace Stafford, Michael Malinzak, Gail A Spiridigliozzi, Tracy Boggs, Rebecca L Koch, Phillip Brian Smith, Laura E Case, Sarah P Young, Harrison N Jones, Priya S Kishnani","doi":"10.1016/j.gim.2025.101590","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101590","url":null,"abstract":"<p><strong>Purpose: </strong>This study details the long-term clinical outcomes in adult participants with CRIM-positive infantile-onset Pompe disease (IOPD) treated with enzyme replacement therapy (ERT), initially reported in 2012 (n=11).</p><p><strong>Methods: </strong>Medical records were reviewed for multisystem involvement and biomarker trends. Central nervous system (CNS) involvement was evaluated using a Modified Fazekas Score (MFS) to grade white matter hyperintensities (WMHI) on brain MRI.</p><p><strong>Results: </strong>Of the initial 11 participants, 8 survived to adulthood (median age 19.6 years); 3 died (2 of arrhythmia, 1 of status epilepticus). All survivors began ERT between 0.2-6 months of age (seven at 20 mg/kg biweekly; one at 40 mg/kg biweekly), with subsequent escalation to 40 mg/kg/week of alglucosidase alfa between ages 8-15 years. None received immune modulation. Cardiac hypertrophy resolved in all; two developed arrhythmias requiring intervention. None required invasive ventilation. Two participants were ambulatory, six used wheelchairs. Flaccid dysarthria (8/8), ptosis (4/8), and sensorineural hearing loss (6/8) were common. WMHI were present in all but remained mild to moderate on MFS. Cognitive function remained stable.</p><p><strong>Conclusions: </strong>Long-term ERT preserves cardiac and respiratory function in adult IOPD survivors, but multisystem morbidity persists, highlighting the need for earlier diagnosis and better therapies targeting muscle and other tissues including the CNS.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101590"},"PeriodicalIF":6.2,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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, Agathe Roubertie, Frédérique Fluchère, Mathilde Renaud, Laurent Kremer, Christine Tranchant, Shahram Attarian, Sylvie Odent, Vincent Laugel, Ulrike Walther-Louvier, Beatrice Desnous, Eric Bieth, Isabelle Husson, Jean Phillipe Azulay, François Rivier, Bérénice Doray, Alexandra Durr, Safa Aouinti, Nicolas Molinari, Michel Koenig","doi":"10.1016/j.gim.2025.101588","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101588","url":null,"abstract":"<p><strong>Purpose: </strong>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, but their impact only recently investigated.</p><p><strong>Methods: </strong>164 FRDA patients with biallelic expansions, and 15 non-FRDA patients were analyzed for interruption(s) number, position, and motif. Expansion size and age at onset of ataxia (AAO) were determined for FRDA patients.</p><p><strong>Results: </strong>Three groups of FRDA patients were identified by the simultaneous analysis of the precise distance (\"depth\") between the interruptions (mostly non-triplet) and the 3' end of the expansion (P < 0.001), the smaller expansion size (P < 0.001), and AAO (P < 0.001). Classical FRDA corresponds to absence of interruption or interruption depth <8 repeats, with AAO often < 15 years (AUC = 0.90; 95% CI, 0.84-0.96); LOFA to interruption depth of 8-18 repeats (AUC = 0.97; 95% CI, 0.94-1), with AAO 15-34 years (AUC = 1; 95% CI, 1-1); vLOFA to interruption depth > 18 (AUC = 0.97; 95% CI, 0.92-1) and AAO >34 years. Multiple (>5) triplet interruptions hamper further expansion.</p><p><strong>Conclusion: </strong>This study provides the molecular basis for a novel classification of FRDA that should be recommended for correct diagnosis.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101588"},"PeriodicalIF":6.2,"publicationDate":"2025-09-23","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}

{"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":"https://doi.org/10.1016/j.gim.2025.101589","url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101589"},"PeriodicalIF":6.2,"publicationDate":"2025-09-23","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}

{"title":"Comprehensive Genotypic, Phenotypic, and Biochemical Characterization of GOT2 Deficiency: A Progressive Neurodevelopmental Disorder with Epilepsy and Abnormal Movements.","authors":"Hannah M German, Maha S Zaki, Muhammad A Usmani, Irem Karagoz, Stephanie Efthymiou, Mohamed S Abdel-Hamid, Haya Abdelhafez Arabiyat, Amama Ghaffar, Mohsin Shahzad, Hans van Bokhoven, Zubair M Ahmed, Omid Yaghini, Neda Hosseini, Maede Majidinezhad, Shahryar Alavi, Marjolein Bosma, Melissa H Broeks, Dilşad Türdoğan, Mohnish Suri, Laiz Laura de Godoy, Nanda M Verhoeven-Duif, Sheikh Riazuddin, Joseph G Gleeson, Cesar Alves, Judith J M Jans, Saima Riazuddin, Henry Houlden, Reza Maroofian","doi":"10.1016/j.gim.2025.101587","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101587","url":null,"abstract":"<p><strong>Purpose: </strong>Glutamic-oxaloacetic transaminase (GOT), also known as aspartate aminotransferase, catalyzes the reversible transamination of oxaloacetate and glutamate to aspartate and α-ketoglutarate. Two isoforms, cytosolic (GOT1) and mitochondrial (GOT2), are integral to the malate-aspartate shuttle (MAS), a key regulator of intracellular redox homeostasis. Recently, five patients with biallelic variants in GOT2 were described, presenting with developmental and epileptic encephalopathy.</p><p><strong>Methods: </strong>We report 11 additional patients with homozygous GOT2 variants, along with additional data from 4 previously reported patients. Through genetic, clinical and biochemical analyses, we further characterize the phenotypic spectrum of GOT2 deficiency.</p><p><strong>Results: </strong>Most patients exhibited progressive neurodevelopmental delay, severe to profound intellectual disability, infantile epilepsy, progressive microcephaly, and hypotonia evolving into spasticity with axial hypotonia. Dysmorphic features included narrow foreheads, broad nasal tips, and tall or pointed chins. Neuroimaging revealed two severity groups based on cerebral volume loss and myelination defects. Thinning of the corpus callosum and white matter abnormalities were common. Biochemical profiling identified low aspartate and high glycerol-3-phosphate in dried blood spots as potential screening markers. Patient fibroblast cells showed reduced serine and glycine biosynthesis, rescuable by pyruvate supplementation.</p><p><strong>Conclusion: </strong>These findings expand the phenotypic spectrum of GOT2 deficiency, establish it as a cause of DEE, and propose novel biomarkers for diagnosis and treatment.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101587"},"PeriodicalIF":6.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correspondence on “Digital technologies in genetic counseling: Recommendations for a morally sound integration” by van Lingen et al","authors":"Erma Pratiwi Nufi","doi":"10.1016/j.gim.2025.101541","DOIUrl":"10.1016/j.gim.2025.101541","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 10","pages":"Article 101541"},"PeriodicalIF":6.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to Nufi","authors":"Marlies N. van Lingen ,&nbsp;Noor A.A. Giesbertz ,&nbsp;Karin R. Jongsma","doi":"10.1016/j.gim.2025.101542","DOIUrl":"10.1016/j.gim.2025.101542","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 10","pages":"Article 101542"},"PeriodicalIF":6.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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":"https://doi.org/10.1016/j.gim.2025.101586","url":null,"abstract":"<p><strong>Purpose: </strong>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 due to non-specific 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.</p><p><strong>Methods: </strong>Genomic DNAm profiles from 93 individuals with suspected or confirmed FAS, including a clinically diagnosed FAS subgroup, were analyzed and compared to 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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101586"},"PeriodicalIF":6.2,"publicationDate":"2025-09-18","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}

{"title":"Addendum: Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: A technical standard of the American College of Medical Genetics and Genomics (ACMG)","authors":"Lina Shao,&nbsp;Vimla Aggarwal,&nbsp;Nan Jiang,&nbsp;Sung-Hae L. Kang,&nbsp;Joie Olayiwola,&nbsp;John M. O’Shea,&nbsp;Gordana Raca,&nbsp;Jennifer Sanmann,&nbsp;Elizabeth Spiteri,&nbsp;Fady M. Mikhail,&nbsp;ACMG Laboratory Quality Assurance Committee","doi":"10.1016/j.gim.2025.101531","DOIUrl":"10.1016/j.gim.2025.101531","url":null,"abstract":"<div><div>This document was reaffirmed by the ACMG Board of Directors as of 23 June 2025 with the following addendum.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 11","pages":"Article 101531"},"PeriodicalIF":6.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145020723","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}