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

{"title":"Note from the editors","authors":"Tiina K. Urv, Melissa A. Parisi","doi":"10.1002/ajmg.c.32039","DOIUrl":"10.1002/ajmg.c.32039","url":null,"abstract":"This special issue, Gene-Targeted Therapies: Early Diagnosis and Equitable Delivery, is the result of a workshop held in June 2021 by the National Institutes of Health (NIH), led by the National Center for Advancing Translational Sciences (NCATS), in conjunction with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Neurological Disorders and Stroke (NINDS), entitled, “Gene-Targeted Therapies: Early Diagnosis and Equitable Delivery” (GTT-EDED; National Institutes of Health, 2021). The workshop was stimulated by the development of genomic technologies that are offering the hope of new therapies for individuals with rare disease, while simultaneously challenging the existing infrastructure for efficient, effective, and equitable delivery of treatments. The intent of the meeting and the resulting papers was to call attention to the challenges we face in moving gene-targeted therapies from the research environment to a public health environment. The preparation for the meeting began with convening working groups consisting of members from academia, industry, government, public health, and patient advocacy groups. We are grateful for the commitment and efforts of all the workgroup members without whom none of this would have been possible. Each of five groups met regularly during the course of several months to discuss one of the following topics: (a) Who are the individuals that could benefit from genetargeted therapies, now and in the future? (b) What novel approaches are needed to enable the development of gene-targeted therapies? (c) When is the optimal time to identify individuals who could benefit from gene-targeted therapies? (d) Identifying existing systems that can be leveraged or adapted to bring treatments to individuals who can benefit from them; and (e) identifying gaps that need to be addressed to facilitate the effective dissemination of treatments in equitable manner. The discussions resulted in 3 days of presentations that led to the nine papers in this issue. The first paper, Are we prepared to deliver gene-targeted therapies for rare diseases? (Yu et al., 2023), provides an overview of the current landscape of gene-targeted therapies and their potential, presenting a rationale for the use of such therapies in a more systematic manner, while recognizing some of the serious ethical, financial, and infrastructure considerations of widespread adoption of such therapies. Gene-targeted therapies: Overview and implications (Brooks, Urv, & Parisi, 2023) is a primer for readers that provides a general overview of the three main categories of genetargeted therapies, including gene therapy, gene editing, and oligonucleotide therapies. The other accompanying papers take a deeper dive into issues that were identified during the course of the meeting as crucial to the field, including the importance of whole genome sequencing in establishing an effective infrastructure for fu","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"193 1","pages":"5-6"},"PeriodicalIF":3.1,"publicationDate":"2023-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9526918","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":"Table of Contents, Volume 193, Number 1, March 2023","authors":"","doi":"10.1002/ajmg.c.31974","DOIUrl":"https://doi.org/10.1002/ajmg.c.31974","url":null,"abstract":"","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"193 1","pages":"1-2"},"PeriodicalIF":3.1,"publicationDate":"2023-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.31974","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50141976","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":"COL1A1 and COL1A2 variants in Ehlers-Danlos syndrome phenotypes and COL1-related overlap disorder","authors":"Elise Venable,&nbsp;Dacre R. T. Knight,&nbsp;Emily K. Thoreson,&nbsp;Linnea M. Baudhuin","doi":"10.1002/ajmg.c.32038","DOIUrl":"10.1002/ajmg.c.32038","url":null,"abstract":"<p>Pathogenic variants in <i>COL1A1</i> and <i>COL1A2</i> are involved in osteogenesis imperfecta (OI) and, rarely, Ehlers-Danlos syndrome (EDS) subtypes and OI-EDS overlap syndromes (OIEDS1 and OIEDS2, respectively). Here we describe a cohort of 34 individuals with likely pathogenic and pathogenic variants in <i>COL1A1</i> and <i>COL1A2</i>, 15 of whom have potential OIEDS1 (<i>n</i> = 5) or OIEDS2 (<i>n</i> = 10). A predominant OI phenotype and <i>COL1A1</i> frameshift variants are present in 4/5 cases with potential OIEDS1. On the other hand, 9/10 potential OIEDS2 cases have a predominant EDS phenotype, including four with an initial diagnosis of hypermobile EDS (hEDS). An additional case with a predominant EDS phenotype had a <i>COL1A1</i> arginine-to-cysteine variant that was originally misclassified as a variant of uncertain significance despite this type of variant being associated with classical EDS with vascular fragility. Vascular/arterial fragility was observed in 4/15 individuals (including one individual with an original diagnosis of hEDS), which underscores the unique clinical surveillance and management needs in these patients. In comparison to previously described OIEDS1/2, we observed differentiating features that should be considered to refine currently proposed criteria for genetic testing in OIEDS, which will be beneficial for diagnosis and management. Additionally, these results highlight the importance of gene-specific knowledge for informed variant classification and point to a potential genetic resolution (<i>COL1A2</i>) for some cases of clinically diagnosed hEDS.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"193 2","pages":"147-159"},"PeriodicalIF":3.1,"publicationDate":"2023-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9674077","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":"When is the best time to screen and evaluate for treatable genetic disorders?: A lifespan perspective","authors":"Melissa A. Parisi,&nbsp;Michele Caggana,&nbsp;Jennifer L. Cohen,&nbsp;Nina B. Gold,&nbsp;Jill A. Morris,&nbsp;Joseph J. Orsini,&nbsp;Tiina K. Urv,&nbsp;Melissa P. Wasserstein","doi":"10.1002/ajmg.c.32036","DOIUrl":"10.1002/ajmg.c.32036","url":null,"abstract":"<p>This paper focuses on the question of, “When is the best time to identify an individual at risk for a treatable genetic condition?” In this review, we describe a framework for considering the optimal timing for pursuing genetic and genomic screening for treatable genetic conditions incorporating a lifespan approach. Utilizing the concept of a carousel that represents the four broad time periods when critical decisions might be made around genetic diagnoses during a person's lifetime, we describe genetic testing during the prenatal period, the newborn period, childhood, and adulthood. For each of these periods, we describe the objectives of genetic testing, the current status of screening or testing, the near-term vision for the future of genomic testing, the advantages and disadvantages of each approach, and the feasibility and ethical considerations of testing and treating. The notion of a “Genomics Passbook” is one where an early genomic screening evaluation could be performed on each individual through a public health program, with that data ultimately serving as a “living document” that could be queried and/or reanalyzed at prescribed times during the lifetime of that person, or in response to concerns about symptoms of a genetic disorder in that individual.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"193 1","pages":"44-55"},"PeriodicalIF":3.1,"publicationDate":"2023-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10139052","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":"Gene-targeted therapies: Overview and implications","authors":"P J Brooks,&nbsp;Tiina K. Urv,&nbsp;Melissa A. Parisi","doi":"10.1002/ajmg.c.32033","DOIUrl":"10.1002/ajmg.c.32033","url":null,"abstract":"<p>Gene-targeted therapies (GTTs) are therapeutic platforms that are in principle applicable to large numbers of monogenic diseases. The rapid development and implementation of GTTs have profound implications for rare monogenic disease therapy development. This article provides a brief summary of the primary types of GTTs and a brief overview of the current state of the science. It also serves as a primer for the articles in this special issue.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"193 1","pages":"13-18"},"PeriodicalIF":3.1,"publicationDate":"2023-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9342782","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 review of economic issues for gene-targeted therapies: Value, affordability, and access","authors":"Louis P. Garrison Jr,&nbsp;Andrew W. Lo,&nbsp;Richard S. Finkel,&nbsp;Patricia A. Deverka","doi":"10.1002/ajmg.c.32037","DOIUrl":"10.1002/ajmg.c.32037","url":null,"abstract":"<p>The National Center for Advancing Translational Sciences' virtual 2021 conference on gene-targeted therapies (GTTs) encouraged multidisciplinary dialogue on a wide range of GTT topic areas. Each of three parallel working groups included social scientists and clinical scientists, and the three major sessions included a presentation on economic issues related to their focus area. These experts also coordinated their efforts across the three groups. The economics-related presentations covered three areas with some overlap: (1) value assessment, uncertainty, and dynamic efficiency; (2) affordability, pricing, and financing; and (3) evidence generation, coverage, and access. This article provides a synopsis of three presentations, some of their key recommendations, and an update on related developments in the past year. The key high-level findings are that GTTs present unique data and policy challenges, and that existing regulatory, health technology assessment, as well as payment and financing systems will need to adapt. But these adjustments can build on our existing foundation of regulatory and incentive systems for innovation, and much can be done to accelerate progress in GTTs. Given the substantial unmet medical need that exists for these oft-neglected patients suffering from rare diseases, it would be a tragedy to not leverage these exciting scientific advances in GTTs.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"193 1","pages":"64-76"},"PeriodicalIF":3.1,"publicationDate":"2023-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9342777","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":"Privacy, bias and the clinical use of facial recognition technology: A survey of genetics professionals","authors":"Elias Aboujaoude,&nbsp;Janice Light,&nbsp;Julia E. H. Brown,&nbsp;W. John Boscardin,&nbsp;Benedikt Hallgrímsson,&nbsp;Ophir D. Klein","doi":"10.1002/ajmg.c.32035","DOIUrl":"10.1002/ajmg.c.32035","url":null,"abstract":"<p>Facial recognition technology (FRT) has been adopted as a precision medicine tool. The medical genetics field highlights both the clinical potential and privacy risks of this technology, putting the discipline at the forefront of a new digital privacy debate. Investigating how geneticists perceive the privacy concerns surrounding FRT can help shape the evolution and regulation of the field, and provide lessons for medicine and research more broadly. Five hundred and sixty-two genetics clinicians and researchers were approached to fill out a survey, 105 responded, and 80% of these completed. The survey consisted of 48 questions covering demographics, relationship to new technologies, views on privacy, views on FRT, and views on regulation. Genetics professionals generally placed a high value on privacy, although specific views differed, were context-specific, and covaried with demographic factors. Most respondents (88%) agreed that privacy is a basic human right, but only 37% placed greater weight on it than other values such as freedom of speech. Most respondents (80%) supported FRT use in genetics, but not necessarily for broader clinical use. A sizeable percentage (39%) were unaware of FRT's lower accuracy rates in marginalized communities and of the mental health effects of privacy violations (62%), but most (76% and 75%, respectively) expressed concern when informed. Overall, women and those who self-identified as politically progressive were more concerned about the lower accuracy rates in marginalized groups (88% vs. 64% and 83% vs. 63%, respectively). Younger geneticists were more wary than older geneticists about using FRT in genetics (28% compared to 56% “strongly” supported such use). There was an overall preference for more regulation, but respondents had low confidence in governments' or technology companies' ability to accomplish this. Privacy views are nuanced and context-dependent. Support for privacy was high but not absolute, and clear deficits existed in awareness of crucial FRT-related discrimination potential and mental health impacts. Education and professional guidelines may help to evolve views and practices within the field.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"193 3","pages":""},"PeriodicalIF":3.1,"publicationDate":"2023-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10563129","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":"Moving away from one disease at a time: Screening, trial design, and regulatory implications of novel platform technologies","authors":"Julie Lekstrom-Himes,&nbsp;P J Brooks,&nbsp;Dwight D. Koeberl,&nbsp;Amy Brower,&nbsp;Aaron Goldenberg,&nbsp;Robert C. Green,&nbsp;Jill A. Morris,&nbsp;Joseph J. Orsini,&nbsp;Timothy W. Yu,&nbsp;Erika F. Augustine","doi":"10.1002/ajmg.c.32031","DOIUrl":"10.1002/ajmg.c.32031","url":null,"abstract":"<p>Most rare diseases are caused by single-gene mutations, and as such, lend themselves to a host of new gene-targeted therapies and technologies including antisense oligonucleotides, phosphomorpholinos, small interfering RNAs, and a variety of gene delivery and gene editing systems. Early successes are encouraging, however, given the substantial number of distinct rare diseases, the ability to scale these successes will be unsustainable without new development efficiencies. Herein, we discuss the need for genomic newborn screening to match pace with the growing development of targeted therapeutics and ability to rapidly develop individualized therapies for rare variants. We offer approaches to move beyond conventional “one disease at a time” preclinical and clinical drug development and discuss planned regulatory innovations that are necessary to speed therapy delivery to individuals in need. These proposals leverage the shared properties of platform classes of therapeutics and innovative trial designs including master and platform protocols to better serve patients and accelerate drug development. Ultimately, there are risks to these novel approaches; however, we believe that close partnership and transparency between health authorities, patients, researchers, and drug developers present the path forward to overcome these challenges and deliver on the promise of gene-targeted therapies for rare diseases.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"193 1","pages":"30-43"},"PeriodicalIF":3.1,"publicationDate":"2023-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32031","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9342287","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":"Natural history of MRAS-related Noonan syndrome: Evidence of mild adult-onset left ventricular hypertrophy and neuropsychiatric features","authors":"Manuela Priolo,&nbsp;Cecilia Mancini,&nbsp;Francesca Clementina Radio,&nbsp;Luigi Chiriatti,&nbsp;Andrea Ciolfi,&nbsp;Camilla Cappelletti,&nbsp;Viviana Cordeddu,&nbsp;Letizia Pintomalli,&nbsp;Alfredo Brusco,&nbsp;Corrado Mammi,&nbsp;Marco Tartaglia","doi":"10.1002/ajmg.c.32034","DOIUrl":"10.1002/ajmg.c.32034","url":null,"abstract":"<p>Gain of function pathogenic variants in <i>MRAS</i> have been found in a small subset of pediatric subjects presenting with Noonan syndrome (NS) associated with hypertrophic cardiomyopathy (HCM) and moderate to severe intellectual disability. These variants are considered to confer a high-risk for the development of severe HCM with poor prognosis and fatal outcome. We report on the natural history of the first adult subject with NS carrying the recurrent pathogenic p.Thr68Ile amino acid substitution. Different from what had previously been observed, he presented with a mild, late-onset left ventricular hypertrophy, and a constellation of additional symptoms rarely seen in NS. The present case provides evidence that HCM does not represent an obligatory, early-onset and severe complication in subjects with <i>MRAS</i> variants. It also adds new data about late-onset features suggesting that other unexpected complications might be observed in adult subjects providing anticipatory guidance for individuals of all age.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"193 2","pages":"160-166"},"PeriodicalIF":3.1,"publicationDate":"2023-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32034","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9669772","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":"Are we prepared to deliver gene-targeted therapies for rare diseases?","authors":"Timothy W. Yu,&nbsp;Stephen F. Kingsmore,&nbsp;Robert C. Green,&nbsp;Tippi MacKenzie,&nbsp;Melissa Wasserstein,&nbsp;Michele Caggana,&nbsp;Nina B. Gold,&nbsp;Annie Kennedy,&nbsp;Priya S. Kishnani,&nbsp;Matthew Might,&nbsp;Phillip J. Brooks,&nbsp;Jill A. Morris,&nbsp;Melissa A. Parisi,&nbsp;Tiina K. Urv","doi":"10.1002/ajmg.c.32029","DOIUrl":"10.1002/ajmg.c.32029","url":null,"abstract":"<p>The cost and time needed to conduct whole-genome sequencing (WGS) have decreased significantly in the last 20 years. At the same time, the number of conditions with a known molecular basis has steadily increased, as has the number of investigational new drug applications for novel gene-based therapeutics. The prospect of precision gene-targeted therapy for all seems in reach… or is it? Here we consider practical and strategic considerations that need to be addressed to establish a foundation for the early, effective, and equitable delivery of these treatments.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"193 1","pages":"7-12"},"PeriodicalIF":3.1,"publicationDate":"2023-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9341459","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}