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

{"title":"Cover Image, Volume 190, Number 1, March 2022","authors":"","doi":"10.1002/ajmg.c.31929","DOIUrl":"https://doi.org/10.1002/ajmg.c.31929","url":null,"abstract":"<p>Cover image: RASopathy genes and the role of their encoded proteins in the RAS-MAPK signaling cascades. Cartoon lists the genes implicated in RASopathies and their year of discovery. Genes requiring further clinical delineation and/or functional validation in the context of the RASopathies are shown in red. Milestones linked to these discoveries are also reported. D and R indicate dominant and recessive, respectively. Below the figure of gene discovery timeline, the RAS-MAPK signaling cascade showing the signal flow through the pathway (black arrows), together with the proteins positively (blue) and negatively (red) controlling the cascade, is presented. P and Ub indicate phosphorylation and ubiquitination, respectively. For further explanations see Figure 1 legend from paper by Tartaglia et al. (present issue). Image also shows pictures of some individuals affected by RASopathies.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.31929","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137647457","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 190, Number 4, December 2022","authors":"","doi":"10.1002/ajmg.c.31927","DOIUrl":"10.1002/ajmg.c.31927","url":null,"abstract":"","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.31927","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72471365","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":"Data sharing to advance gene-targeted therapies in rare diseases","authors":"Julie Lekstrom-Himes,&nbsp;Erika F. Augustine,&nbsp;Amy Brower,&nbsp;Thomas Defay,&nbsp;Richard S. Finkel,&nbsp;Amy L. McGuire,&nbsp;Mark W. Skinner,&nbsp;Timothy W. Yu","doi":"10.1002/ajmg.c.32028","DOIUrl":"10.1002/ajmg.c.32028","url":null,"abstract":"<p>Recent advancements in gene-targeted therapies have highlighted the critical role data sharing plays in successful translational drug development for people with rare diseases. To scale these efforts, we need to systematize these sharing principles, creating opportunities for more rapid, efficient, and scalable drug discovery/testing including long-term and transparent assessment of clinical safety and efficacy. A number of challenges will need to be addressed, including the logistical difficulties of studying rare diseases affecting individuals who may be scattered across the globe, scientific, technical, regulatory, and ethical complexities of data collection, and harmonization and integration across multiple platforms and contexts. The NCATS/NIH Gene-Targeted Therapies: Early Diagnosis and Equitable Delivery meeting series held during June 2021 included data sharing models that address these issues and framed discussions of areas that require improvement. This article describes these discussions and provides a series of considerations for future data sharing.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9696657","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":"Dermatological manifestations, management, and care in RASopathies","authors":"Maria Ines Kavamura,&nbsp;Chiara Leoni,&nbsp;Giovanni Neri","doi":"10.1002/ajmg.c.32027","DOIUrl":"10.1002/ajmg.c.32027","url":null,"abstract":"<p>RASopathies are rare genetic disorders caused by germline pathogenic variants in genes belonging to the RAS/MAPK pathway, which signals cell proliferation, differentiation, survival and death. The dysfunction of such signaling pathway causes syndromes with overlapping clinical manifestations. Skin and adnexal lesions are the cardinal clinical signs of RASopathies, such as cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, formerly known as LEOPARD syndrome, Costello syndrome, neurofibromatosis (NF1), Legius syndrome, Noonan-like syndrome with loose anagen hair (NSLH) and Noonan syndrome. As NF1, one of the most common RASopathies, described in 1882, has its clinical features well delineated, we will focus on the dermatological diagnosis, management and care of non-NF1 RASopathies, which are less known and more recently described. Dermatological manifestations are important clinical diagnostic elements that can aid differential diagnosis among RASopathies. They can affect dermis and epidermis, causing pigmented lesions (melanocytic nevi, café-au-lait spots, and lentigines), hyperkeratosis (keratosis pilaris, ulerythema ophryogenes, and palmoplantar keratosis) or hyperplasia. To date there are rare known links to malignancy, but oftentimes skin lesions require close attention because they can highly affect quality of life.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10626241","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":"Molecular advances, clinical management, and treatment opportunities in RASopathies","authors":"Chiara Leoni,&nbsp;Giovanni Neri","doi":"10.1002/ajmg.c.32026","DOIUrl":"10.1002/ajmg.c.32026","url":null,"abstract":"RASopathies are the quintessential paradigm of the complex relationship between genetic heterogeneity and clinical variability: lumping multiple genes as cause of one and the same syndrome versus splitting multiple phenotypes caused by one and the same gene. RASopathies are a group of syndromes involving development and growth, caused by pathogenic germline variants in a group of genes, mostly enhancing signaling through the RAS-MAPK cascade, a master regulator of cell proliferation, differentiation and death (Aoki & Matsubara, 2013; Aoki, Niihori, Inoue, & Matsubara, 2016). Of note, somatic mutations of these genes also cause cancer (Dunnett-Kane et al., 2020). In a balanced situation, where the status of genes and the conformation of the respective protein products vary inside acceptable limits, the resulting phenotype is normal. Strong variations at the germinal level will cause the demise of the developmental project (spontaneous abortion); mild variations will cause one or other of the RASopathies; strong somatic variations will cause cancer. The present issue of Seminars in Medical Genetics deals with RASopathies, a family of syndromes that over the years accrued around the prototype of the family, the Noonan syndrome (NS), the mildest of all, running in some families as an autosomal dominant trait (Aoki, Niihori, Narumi, Kure, & Matsubara, 2008). The others that followed, such as cardiofaciocutaneous syndrome (CFCS) (Roberts et al., 2006; Narumi et al., 2007) and Costello syndrome (CS) (Aoki et al., 2005; Niihori et al., 2011), have generally a more severe phenotype and present as sporadic cases, assumed to be caused by new heterozygous variants of genes yet to be discovered (Tartaglia, Cotter, Zampino, Gelb, & Rauen, 2003). In the early days, lack of knowledge of these genes led to a controversy among authors on whether newly reported syndromes were authentically distinct conditions or simply phenotypic variants of NS. Typical in this respect was the much debated distinction between NS and CFCS (Fryer, Holt, & Hughes, 1991; Neri, Zollino, & Reynolds, 1991; Verloes et al., 1988; Ward, Moss, & McKeown, 1994; Wieczorek, Majewski, & Gillessen-Kaesbach, 1997), not devoid of practical implications. In the perspective of genetic counseling, while the estimation of the recurrence risk was not an issue, given that both syndromes were firmly thought to be of autosomal dominant heritability, the prediction of clinical manifestations was a problem since mild (NS) and severe (CFCS) phenotypic features could coexist in the same family if the two syndromes were etiologically one and the same (Leichtman, 1996). The dilemma was eventually solved by the discovery, in succession: (a) that NS is caused by mutation of the PTPN11 gene (Tartaglia et al., 2001); (b) that none of selected cases of CFCS tested positive for this mutation (Ion et al., 2002); (c) that cases of CFCS are caused by mutations of either BRAF, MEK1, or MEK2 genes (Niihori et al., 2006; Now","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10626239","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":"Cancer incidence and surveillance strategies in individuals with RASopathies","authors":"Gina Ney,&nbsp;Andrea Gross,&nbsp;Alicia Livinski,&nbsp;Christian P. Kratz,&nbsp;Douglas R. Stewart","doi":"10.1002/ajmg.c.32018","DOIUrl":"10.1002/ajmg.c.32018","url":null,"abstract":"<p>RASopathies are a set of clinical syndromes that have molecular and clinical overlap. Genetically, these syndromes are defined by germline pathogenic variants in RAS/MAPK pathway genes resulting in activation of this pathway. Clinically, their common molecular signature leads to comparable phenotypes, including cardiac anomalies, neurologic disorders and notably, elevated cancer risk. Cancer risk in individuals with RASopathies has been estimated from retrospective reviews and cohort studies. For example, in Costello syndrome, cancer incidence is significantly elevated over the general population, largely due to solid tumors. In some forms of Noonan syndrome, cancer risk is also elevated over the general population and is enriched for hematologic malignancies. Thus, cancer surveillance guidelines have been developed to monitor for the occurrence of such cancers in individuals with some RASopathies. These include abdominal ultrasound and urinalyses for individuals with Costello syndrome, while complete blood counts and splenic examination are recommended in Noonan syndrome. Improved cancer risk estimates and refinement of surveillance recommendations will improve the care of individuals with RASopathies.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2022-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9193415","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":"New prospectives on treatment opportunities in RASopathies","authors":"Bruce D. Gelb,&nbsp;Marielle E. Yohe,&nbsp;Cordula Wolf,&nbsp;Gregor Andelfinger","doi":"10.1002/ajmg.c.32024","DOIUrl":"10.1002/ajmg.c.32024","url":null,"abstract":"<p>The RASopathies are a group of clinically defined developmental syndromes caused by germline variants of the RAS/mitogen-activated protein (MAPK) cascade. The prototypic RASopathy is Noonan syndrome, which has phenotypic overlap with related disorders such as cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome with multiple lentigines, and others. In this state-of-the-art review, we summarize current knowledge on unmet therapeutic needs in these diseases and novel treatment approaches informed by insights from RAS/MAPK-associated cancer therapies, in particular through inhibition of MEK1/2 and mTOR in patients with severe disease manifestations. We explore the possibilities of integrating a larger arsenal of molecules currently under development into future care plans. Lastly, we describe both medical and ethical challenges and opportunities for future clinical trials in the field.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2022-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9380773","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":"Management of nutritional and gastrointestinal issues in RASopathies: A narrative review","authors":"Roberta Onesimo,&nbsp;Valentina Giorgio,&nbsp;Germana Viscogliosi,&nbsp;Elisabetta Sforza,&nbsp;Eliza Kuczynska,&nbsp;Gaia Margiotta,&nbsp;Mariella Iademarco,&nbsp;Francesco Proli,&nbsp;Donato Rigante,&nbsp;Giuseppe Zampino,&nbsp;Chiara Leoni","doi":"10.1002/ajmg.c.32019","DOIUrl":"10.1002/ajmg.c.32019","url":null,"abstract":"<p>Noonan, Costello, and cardio-facio-cutaneous syndrome are neurodevelopmental disorders belonging to the RASopathies, a group of syndromes caused by alterations in the RAS/MAPK pathway. They are characterized by similar clinical features, among which feeding difficulties, growth delay, and gastro-intestinal disorders are frequent, causing pain and discomfort in patients. Hereby, we describe the main nutritional and gastrointestinal issues reported in individuals with RASopathies, specifically in Noonan syndrome, Noonan syndrome-related disorders, Costello, and cardio-facio-cutaneous syndromes. Fifty percent of children with Noonan syndrome may experience feeding difficulties that usually have a spontaneous resolution by the second year of life, especially associated to genes different than <i>PTPN11</i> and <i>SOS1</i>. More severe manifestations often require artificial enteral nutrition in infancy are observed in Costello syndrome, mostly associated to c.34G&gt;A substitution in the <i>HRAS</i> gene. In cardio-facio-cutaneous syndrome feeding issues are usually present (90–100% of cases), especially in individuals carrying variants in <i>BRAF</i>, <i>MAP2K1</i>, and <i>MAP2K2</i> genes, and artificial enteral intervention, even after scholar age, may be required. Moreover, disorders associated with gastrointestinal dysmotility as gastro-esophageal reflux and constipation are commonly reported in all the above-mentioned syndromes. Given the impact on growth and on the quality of life of these patients, early evaluation and prompt personalized management plans are fundamental.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2022-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9193403","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":"Neuropsychological features in RASopathies: A pilot study on parent training program involving families of children with Noonan syndrome","authors":"Federica Alice Maria Montanaro,&nbsp;Paolo Alfieri,&nbsp;Cristina Caciolo,&nbsp;Francesca Cumbo,&nbsp;Simone Piga,&nbsp;Marco Tartaglia,&nbsp;Serena Licchelli,&nbsp;Maria Cristina Digilio,&nbsp;Stefano Vicari","doi":"10.1002/ajmg.c.32025","DOIUrl":"10.1002/ajmg.c.32025","url":null,"abstract":"<p>Noonan syndrome (NS) is a clinical variable multisystem disorder caused by mutations in genes encoding proteins involved in the RAS/mitogen-activated protein kinase signaling pathway. NS is characterized by a distinctive facies, short stature, and congenital heart defects. Psychomotor delay, learning difficulties, and social deficits are also common. Furthermore, behavioral and attention problems can be reckoned as a key symptom in NS, with functioning resembling the patterns observed in attention deficit hyperactivity disorder (ADHD). The complex behavioral phenotype has great impact on the quality of life and raises demanding management issues also for patients' families. Parent management training (PMT) is recommended as first-line treatment for ADHD; however, no study has been performed to test the efficacy of PMT in NS, thus far. The aim of this pilot study is the implementation and evaluation of a PMT dedicated to NS families. Parents of seven children with NS were recruited and underwent to a 10-session PMT. Three different questionnaires were administered to both parents: Conners Parent Rating Scales, Parenting Stress Index Short Form (PSI-SF), and Alabama Parenting Questionnaire (APQ). Our findings on this first small cohort of families indicate that positive perception and satisfaction about the child and the interaction with him increased in mothers after the intervention, as measured respectively by PSI-SF difficult child (DC) and PSI-SF parent–child dysfunctional interaction (PCDI), while mothers' level of stress decreased after the PMT, as indicated by PSI-SF total scores. Furthermore, APQ positive parenting, which measures behaviors of positive relationship with the child, increased in mothers after the intervention. Statistical analysis on fathers' questionnaires did not show significant differences after the PMT sessions. This pilot study suggests that PMT is a promising intervention for parents of NS children with behavioral and ADHD symptoms. Changes in mothers' attitudes and distress indicate that behaviorally oriented programs may help parents to manage with NS phenotype.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2022-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f0/5d/AJMG-190-510.PMC10107825.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9319727","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":"Mosaic RASopathies: A review of disorders caused by somatic pathogenic variants in the genes of the RAS/MAPK pathway","authors":"Diana Carli,&nbsp;Nicoletta Resta,&nbsp;Giovanni Battista Ferrero,&nbsp;Martino Ruggieri,&nbsp;Alessandro Mussa","doi":"10.1002/ajmg.c.32021","DOIUrl":"10.1002/ajmg.c.32021","url":null,"abstract":"<p>Mosaic RASopathies are a heterogeneous group of diseases characterized by the presence at birth or early onset of congenital anomalies, cutaneous and vascular anomalies, segmental overgrowth, and increased cancer risk. They are caused by somatic pathogenic variants of the genes belonging the RAt Sarcoma Mitogen-activated protein kinase (RAS/MAPK) pathway causing its hyperactivation. Here, we review the clinical and molecular characteristics of this heterogeneous group of diseases, including the possibilities of molecular diagnosis and new therapeutic perspectives.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2022-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10631326","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}