American Journal of Medical Genetics Part C: Seminars in Medical Genetics最新文献

{"title":"Commentary: Interventional Genetics.","authors":"Tara L Wenger, Margaret P Adam","doi":"10.1002/ajmg.c.32152","DOIUrl":"10.1002/ajmg.c.32152","url":null,"abstract":"","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"151-153"},"PeriodicalIF":4.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted Therapies for Genetic Conditions: Guest Editor Remarks.","authors":"Margaret P Adam","doi":"10.1002/ajmgc.70001","DOIUrl":"10.1002/ajmgc.70001","url":null,"abstract":"","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"141-142"},"PeriodicalIF":2.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted Therapies in Neurofibromatosis Type 1.","authors":"Aimee A Sato, Dawn Earl, Stephanie E Wallace","doi":"10.1002/ajmg.c.32151","DOIUrl":"10.1002/ajmg.c.32151","url":null,"abstract":"<p><p>Neurofibromatosis type 1 (NF1) is a progressive multisystem condition that is characterized by a wide range of clinical manifestations and clinical variability. Individuals with NF1 can be significantly impacted by NF1-related complications, and targeted therapies are emerging. Currently, MEK inhibitors selumetinib and mirdametinib are the only FDA-approved targeted therapies for NF1-related symptomatic or progressive, inoperable plexiform neurofibromas. Several additional MEK inhibitors are being investigated in clinical trials for the treatment of plexiform neurofibromas. Additional therapies are currently under investigation for the treatment of malignant peripheral nerve sheath tumors, low-grade gliomas, skeletal manifestations, cutaneous neurofibromas, and other NF1-related complications.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"154-160"},"PeriodicalIF":4.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Utero Therapies, the Next Frontier.","authors":"Teodora R Kolarova, Edith Cheng","doi":"10.1002/ajmg.c.32135","DOIUrl":"10.1002/ajmg.c.32135","url":null,"abstract":"<p><p>Advancements in molecular diagnostics and the expanded understanding of pathophysiologic processes underlying a variety of genetic conditions have led to the design and implementation of many targeted therapies in the past decade. In the prenatal space, these advancements have rapidly changed the field of prenatal diagnosis and have garnered enthusiasm toward interventions aimed at correcting specific disease mechanisms in utero to prevent irreversible injury and/or leverage fetal physiology to increase the effectiveness of these treatments. Although many promising trials are underway, continued efforts to fully elucidate the intricacies of fetal immunology, the fetal blood-brain barrier and precise molecular processes during different stages of development will be paramount to continued refinement of in utero therapies. The social and ethical implications of fetal therapy are also of utmost importance, especially in an era of increasing restrictions on reproductive autonomy. This review aims to summarize current efforts toward in utero targeted fetal therapies as well as the history and ethical implications of such endeavors.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"194-202"},"PeriodicalIF":4.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CURE ID: A Platform to Collect Real-World Treatment Data for Drug Repurposing in Rare Genetic Disorders.","authors":"Tahsin Farid, Maura R Z Ruzhnikov, Mili Duggal, Keyla C Tumas, Shira Strongin, Eric Sid, Sarah R Fuchs, Leonard Sacks, Dominique C Pichard, Catherine Pilgrim-Grayson, Ewy A Mathé, Heather A Stone","doi":"10.1002/ajmg.c.32153","DOIUrl":"10.1002/ajmg.c.32153","url":null,"abstract":"<p><p>Rare diseases collectively affect millions of Americans, but less than 5% have approved treatments, and new drug development remains limited. For such diseases, drug repurposing may be an effective strategy to find new treatment options. In the rare genetic disorder community, drugs are frequently prescribed off-label. This information is rarely available for research, but if captured, could be leveraged to accelerate the identification of candidate drugs to be evaluated for safety and efficacy of the treatment of rare diseases. CURE ID is a publicly available treatment registry that collects real-world treatment data directly from healthcare providers, patients, and care partners in a consistent format. By aggregating this information, CURE ID can generate hypotheses for follow-up targeted research of repurposed drugs, potentially leading to the approval of these drugs for new indications. The success of the platform is predicated on its adoption in the rare disease community and routinely reporting treatment experiences to CURE ID.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"189-193"},"PeriodicalIF":2.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12822485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Genomic Analysis of Usher Syndrome: Population-Scale Prevalence and Therapeutic Targets.","authors":"Shelby E Redfield, Stephanie A Mauriac, Gwenaëlle S Géléoc, A Eliot Shearer","doi":"10.1002/ajmg.c.32142","DOIUrl":"10.1002/ajmg.c.32142","url":null,"abstract":"<p><p>Usher syndrome, the most common form of deaf-blindness, displays extensive genetic, allelic, and phenotypic heterogeneity. The dual sensory impairment associated with this autosomal recessive disorder makes Usher syndrome an important target for gene therapy, with dozens of published preclinical studies targeting multiple Usher syndrome genes and using multiple gene therapy strategies. Nine genes have been conclusively linked to Usher syndrome; however, data on the prevalence and contribution of specific genetic variants is lacking. Such information is essential to choosing a favorable target gene or therapeutic approach during clinical trial design. Here, we used large genomic databases to systematically evaluate the genomics of Usher syndrome. We ascertained pathogenic Usher syndrome variants from three clinical databases and determined the occurrence of these pathogenic Usher syndrome variants within: (1) a publicly available dataset including worldwide populations (GnomAD), (2) a cohort of 3888 children without hearing loss, and (3) 637 children with hearing loss. Results show significant variability in the frequency of Usher syndrome variants by gene and genetic ancestry. 1% of control subjects carry a pathogenic USH variant. Pathogenic variants in USH2A are the most prevalent, at 1 in 150 individuals (0.0062). Calculated general population prevalence for all Usher syndrome subtypes is 1 in ~29,000, indicating that 30,405 individuals in the United States and 721,769 individuals worldwide are affected. We estimate that 324 babies in the United States and 12,090 worldwide are born with Usher syndrome each year. We identify key targets for genetic therapy based on population-level prevalence including a focus on alternatives to gene replacement therapies, specifically for USH2A.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"218-227"},"PeriodicalIF":2.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12353266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposing With Purpose: Treatment of Bachmann-Bupp Syndrome With Eflornithine and Implications for Other Polyaminopathies.","authors":"Caleb P Bupp, Elizabeth A VanSickle, Julianne Michael, Chad R Schultz, Kelly Nguyen, Melissa Hoefer, Surender Rajasekaran, André S Bachmann","doi":"10.1002/ajmg.c.32138","DOIUrl":"10.1002/ajmg.c.32138","url":null,"abstract":"<p><p>Rare diseases impact approximately 1 in 10 people worldwide, and yet, less than 5% of all rare diseases currently have an approved treatment option available. This is due to many challenges unique to rare diseases, including small, diverse patient populations, the cost of drug development that is not proportionate to the number of patients who could potentially benefit from treatment, and difficulty with clinical trial design to validate new therapeutics. As a result, drug repurposing has become an increasingly promising option for finding treatment options for rare diseases. First described in 2018, Bachmann-Bupp Syndrome (BABS) is a rare neurodevelopmental disorder that is caused by gain-of-function variants in the ornithine decarboxylase (ODC1) gene and is characterized by developmental delay, hypotonia, and alopecia. Through collaboration and the use of a unique drug repurposing strategy, the first patient identified with BABS was treated with the repurposed drug eflornithine, also known as α-difluoromethylornithine (DFMO), in just 16 months. Currently, five additional patients with BABS are being treated with DFMO. This model of drug repurposing of an FDA-approved drug for use in another indication can serve as an example of what is possible in the scope of other rare diseases, specifically in other polyaminopathies.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"183-188"},"PeriodicalIF":4.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12353620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Impact of Karyotype on Congenital Heart Diseases in Turner Syndrome: A Systematic Review and Meta-Analysis","authors":"Francisco Álvarez-Nava,&nbsp;Melissa L. Crenshaw,&nbsp;Ivonne Bedei,&nbsp;Marisol Soto,&nbsp;Andréa T. Maciel-Guerra,&nbsp;Anne Skakkebæk","doi":"10.1002/ajmg.c.32146","DOIUrl":"10.1002/ajmg.c.32146","url":null,"abstract":"<p>It is evident that Turner syndrome (TS) impacts almost all developmental stages of the fetal heart with congenital heart disease (CHD) being seen in 23%–50% of individuals. Although the spectrum of CHDs in TS is well-established, with left-sided lesions predominating, the influence of specific karyotypes on the prevalence and types of CHDs remains incompletely understood. The primary objective of this systematic review/meta-analysis was to quantitatively synthesize the existing evidence on the association between specific karyotypes in TS and the risk of various CHDs. A systematic literature search was conducted through December 2023 to identify studies reporting the prevalence of CHDs in relation to TS karyotype. The quality of the individual studies was assessed using the Joanna Briggs Institute critical appraisal tools for systematic reviews. The overall estimates were pooled using both fixed- and random-effects models. Sensitivity and subgroup analysis were performed. Twenty-five studies were included in the analysis. TS individuals with a 45,X karyotype showed a significantly higher likelihood of bicuspid aortic valve (BAV) (pooled OR, 3.14 [95% CI: 2.49–3.94]), aortic coarctation (CoA) (pooled OR, 4.16 [95% CI: 2.74–6.31]), and partial anomalous pulmonary venous return (PAPVR) (pooled OR, 4.86 [2.31–10.2]) compared with TS individuals with a non-45,X karyotype. In addition, TS individuals with a 45,X karyotype also showed a significantly higher likelihood of BAV (pooled OR, 2.72 [95% CI: 1.62–4.56]) when compared with TS individuals with 45,X/46,XX mosaicism. TS individuals with a 45,X karyotype showed a significantly higher risk of BAV (pooled OR, 2.13 [95% CI: 1.42–3.21]) and CoA (pooled OR, 4.52 [95% CI: 1.58–13.0]) when compared with TS individuals with an isochromosome Xq. A significantly higher likelihood of BAV was also found in 45,X compared to other karyotypes (e.g., 45,X/46,XY and TS karyotypes with ring X chromosome). Some heterogeneity was evident, but publication was low. This meta-analysis confirms a strong association between the 45,X karyotype and increased prevalence of BAV, CoA, and PAPVR in TS. While 45,X/46,XX mosaicism and karyotypes with an isochromosome Xq mitigate risk, the findings emphasize the need for large-scale studies to refine risk assessment and management strategies.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"199 2","pages":"93-106"},"PeriodicalIF":4.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32146","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Visualizing Turner Syndrome","authors":"Kirstine Stochholm,&nbsp;Astrid Bruun Rasmussen,&nbsp;Anne Skakkebæk","doi":"10.1002/ajmg.c.32144","DOIUrl":"10.1002/ajmg.c.32144","url":null,"abstract":"<p>Turner syndrome (TS) continues to present a diagnostic challenge to healthcare professionals. The diagnostic challenges associated with TS result in delayed treatment and clinical care. Here we provide an update of the physical appearance of girls and women with TS by presenting clinical photographs and detailed clinical descriptions of 25 Danish girls and women with TS. Our data highlight the wide variation in physical appearance and clinical phenotype seen in girls and women with TS.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"199 2","pages":"134-138"},"PeriodicalIF":4.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32144","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144197992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Table of Contents, Volume 199, Number 1, March 2025","authors":"","doi":"10.1002/ajmg.c.32091","DOIUrl":"https://doi.org/10.1002/ajmg.c.32091","url":null,"abstract":"","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"199 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144108978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}