HGG AdvancesPub Date : 2024-04-01DOI: 10.1016/j.xhgg.2024.100288
Benjamin T. Cocanougher, Samuel W. Liu, Ludmila Francescatto, Alexander Behura, Mariele Anneling, David G. Jackson, Kristen L. Deak, Chi D. Hornik, Mai K. ElMallah, Carolyn E Pizoli, Edward C. Smith, Khoon Ghee Queenie Tan, Marie T. McDonald
{"title":"The severity of MUSK pathogenic variants is predicted by the protein domain they disrupt.","authors":"Benjamin T. Cocanougher, Samuel W. Liu, Ludmila Francescatto, Alexander Behura, Mariele Anneling, David G. Jackson, Kristen L. Deak, Chi D. Hornik, Mai K. ElMallah, Carolyn E Pizoli, Edward C. Smith, Khoon Ghee Queenie Tan, Marie T. McDonald","doi":"10.1016/j.xhgg.2024.100288","DOIUrl":"https://doi.org/10.1016/j.xhgg.2024.100288","url":null,"abstract":"","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140795831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2024-04-01DOI: 10.1016/j.xhgg.2024.100298
Evanjalina J. Matoy, Jocelyn N. Plowman, Cynthia J. Watson, Michael A. Belshan, Elizabeth E. Blue, Chad D. Huff, Holly A F Stessman
{"title":"In vitro data suggest a role for PMS2 Kozak sequence mutations in Lynch Syndrome risk.","authors":"Evanjalina J. Matoy, Jocelyn N. Plowman, Cynthia J. Watson, Michael A. Belshan, Elizabeth E. Blue, Chad D. Huff, Holly A F Stessman","doi":"10.1016/j.xhgg.2024.100298","DOIUrl":"https://doi.org/10.1016/j.xhgg.2024.100298","url":null,"abstract":"","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140794186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2024-04-01DOI: 10.1016/j.xhgg.2024.100289
Liselot van der Laan, Peter Lauffer, Kathleen Rooney, Ananília Silva, Sadegheh Haghshenas, R. Relator, M. Levy, S. Trajkova, Sylvia A Huisman, E. Bijlsma, T. Kleefstra, B. V. van Bon, Özlem Baysal, Christiane Zweier, M. Palomares-Bralo, Jan Fischer, K. Szakszon, Laurence Faivre, Amélie Piton, S. Mesman, Ron Hochstenbach, M. Elting, J. M. van Hagen, Astrid S Plomp, M. Mannens, Marielle Alders, M. M. van Haelst, G. B. Ferrero, Alfredo Brusco, P. Henneman, D. Sweetser, B. Sadikovic, A. Vitobello, L. Menke
{"title":"DNA methylation episignature and comparative epigenomic profiling for Pitt-Hopkins syndrome caused by TCF4 variants.","authors":"Liselot van der Laan, Peter Lauffer, Kathleen Rooney, Ananília Silva, Sadegheh Haghshenas, R. Relator, M. Levy, S. Trajkova, Sylvia A Huisman, E. Bijlsma, T. Kleefstra, B. V. van Bon, Özlem Baysal, Christiane Zweier, M. Palomares-Bralo, Jan Fischer, K. Szakszon, Laurence Faivre, Amélie Piton, S. Mesman, Ron Hochstenbach, M. Elting, J. M. van Hagen, Astrid S Plomp, M. Mannens, Marielle Alders, M. M. van Haelst, G. B. Ferrero, Alfredo Brusco, P. Henneman, D. Sweetser, B. Sadikovic, A. Vitobello, L. Menke","doi":"10.1016/j.xhgg.2024.100289","DOIUrl":"https://doi.org/10.1016/j.xhgg.2024.100289","url":null,"abstract":"","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140765462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2024-01-11Epub Date: 2023-09-27DOI: 10.1016/j.xhgg.2023.100243
Michael Bentz, Aliya Saperstein, Stephanie M Fullerton, Janet K Shim, Sandra Soo-Jin Lee
{"title":"Conflating race and ancestry: Tracing decision points about population descriptors over the precision medicine research life course.","authors":"Michael Bentz, Aliya Saperstein, Stephanie M Fullerton, Janet K Shim, Sandra Soo-Jin Lee","doi":"10.1016/j.xhgg.2023.100243","DOIUrl":"10.1016/j.xhgg.2023.100243","url":null,"abstract":"<p><p>Responding to calls for human genomics to shift away from the use of race, genomic investigators are coalescing around the possibility of using genetic ancestry. This shift has renewed questions about the use of social and genetic concepts of difference in precision medicine research (PMR). Drawing from qualitative data on five PMR projects, we illustrate negotiations within and between research teams as genomic investigators deliberate on the relevance of race and genetic ancestry for different analyses and contexts. We highlight how concepts of both social and genetic difference are embedded within and travel through research practices, and identify multiple points across the research life course at which conceptual slippage and conflation between race and genetic ancestry occur. We argue that moving beyond race will require PMR investigators to confront the entrenched ways in which race is built into research practices and biomedical infrastructures.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3b/97/main.PMC10585473.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41142594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2024-01-11Epub Date: 2023-10-28DOI: 10.1016/j.xhgg.2023.100245
Yilun Li, Kin Yau Wong, Annie Green Howard, Penny Gordon-Larsen, Heather M Highland, Mariaelisa Graff, Kari E North, Carolina G Downie, Christy L Avery, Bing Yu, Kristin L Young, Victoria L Buchanan, Robert Kaplan, Lifang Hou, Brian Thomas Joyce, Qibin Qi, Tamar Sofer, Jee-Young Moon, Dan-Yu Lin
{"title":"Mendelian randomization with incomplete measurements on the exposure in the Hispanic Community Health Study/Study of Latinos.","authors":"Yilun Li, Kin Yau Wong, Annie Green Howard, Penny Gordon-Larsen, Heather M Highland, Mariaelisa Graff, Kari E North, Carolina G Downie, Christy L Avery, Bing Yu, Kristin L Young, Victoria L Buchanan, Robert Kaplan, Lifang Hou, Brian Thomas Joyce, Qibin Qi, Tamar Sofer, Jee-Young Moon, Dan-Yu Lin","doi":"10.1016/j.xhgg.2023.100245","DOIUrl":"10.1016/j.xhgg.2023.100245","url":null,"abstract":"<p><p>Mendelian randomization has been widely used to assess the causal effect of a heritable exposure variable on an outcome of interest, using genetic variants as instrumental variables. In practice, data on the exposure variable can be incomplete due to high cost of measurement and technical limits of detection. In this paper, we propose a valid and efficient method to handle both unmeasured and undetectable values of the exposure variable in one-sample Mendelian randomization analysis with individual-level data. We estimate the causal effect of the exposure variable on the outcome using maximum likelihood estimation and develop an expectation maximization algorithm for the computation of the estimator. Simulation studies show that the proposed method performs well in making inference on the causal effect. We apply our method to the Hispanic Community Health Study/Study of Latinos, a community-based prospective cohort study, and estimate the causal effect of several metabolites on phenotypes of interest.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10628889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41214769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2024-01-11Epub Date: 2023-11-24DOI: 10.1016/j.xhgg.2023.100257
Kathryn O Farley, Catherine A Forbes, Nicole C Shaw, Emma Kuzminski, Michelle Ward, Gareth Baynam, Timo Lassmann, Vanessa S Fear
{"title":"CRISPR-Cas9-generated PTCHD1 2489T>G stem cells recapitulate patient phenotype when undergoing neural induction.","authors":"Kathryn O Farley, Catherine A Forbes, Nicole C Shaw, Emma Kuzminski, Michelle Ward, Gareth Baynam, Timo Lassmann, Vanessa S Fear","doi":"10.1016/j.xhgg.2023.100257","DOIUrl":"10.1016/j.xhgg.2023.100257","url":null,"abstract":"<p><p>An estimated 3.5%-5.9% of the global population live with rare diseases, and approximately 80% of these diseases have a genetic cause. Rare genetic diseases are difficult to diagnose, with some affected individuals experiencing diagnostic delays of 5-30 years. Next-generation sequencing has improved clinical diagnostic rates to 33%-48%. In a majority of cases, novel variants potentially causing the disease are discovered. These variants require functional validation in specialist laboratories, resulting in a diagnostic delay. In the interim, the finding is classified as a genetic variant of uncertain significance (VUS) and the affected individual remains undiagnosed. A VUS (PTCHD1 c. 2489T>G) was identified in a child with autistic behavior, global developmental delay, and hypotonia. Loss of function mutations in PTCHD1 are associated with autism spectrum disorder and intellectual disability; however, the molecular function of PTCHD1 and its role in neurodevelopmental disease is unknown. Here, we apply CRISPR gene editing and induced pluripotent stem cell (iPSC) neural disease modeling to assess the variant. During differentiation from iPSCs to neural progenitors, we detect subtle but significant gene signatures in synaptic transmission and muscle contraction pathways. Our work supports the causal link between the genetic variant and the child's phenotype, providing evidence for the variant to be considered a pathogenic variant according to the American College of Medical Genetics and Genomics guidelines. In addition, our study provides molecular data on the role of PTCHD1 in the context of other neurodevelopmental disorders.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10787298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138441382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2024-01-11Epub Date: 2023-10-04DOI: 10.1016/j.xhgg.2023.100244
Emilia M Pinto, Cintia Fridman, Bonald C Figueiredo, Hector Salvador, Manuel R Teixeira, Carla Pinto, Manuela Pinheiro, Christian P Kratz, Cinzia Lavarino, Edith A M F Legal, Anh Le, Gregory Kelly, Erika Koeppe, Elena M Stoffel, Kelsey Breen, Stefanie Hahner, Britta Heinze, Piti Techavichit, Amanda Krause, Tsutomu Ogata, Yasuko Fujisawa, Michael F Walsh, Huma Q Rana, Kara N Maxwell, Judy E Garber, Carlos Rodriguez-Galindo, Raul C Ribeiro, Gerard P Zambetti
{"title":"Multiple TP53 p.R337H haplotypes and implications for tumor susceptibility.","authors":"Emilia M Pinto, Cintia Fridman, Bonald C Figueiredo, Hector Salvador, Manuel R Teixeira, Carla Pinto, Manuela Pinheiro, Christian P Kratz, Cinzia Lavarino, Edith A M F Legal, Anh Le, Gregory Kelly, Erika Koeppe, Elena M Stoffel, Kelsey Breen, Stefanie Hahner, Britta Heinze, Piti Techavichit, Amanda Krause, Tsutomu Ogata, Yasuko Fujisawa, Michael F Walsh, Huma Q Rana, Kara N Maxwell, Judy E Garber, Carlos Rodriguez-Galindo, Raul C Ribeiro, Gerard P Zambetti","doi":"10.1016/j.xhgg.2023.100244","DOIUrl":"10.1016/j.xhgg.2023.100244","url":null,"abstract":"<p><p>The germline TP53 p.R337H mutation is reported as the most common germline TP53 variant. It exists at a remarkably high frequency in the population of southeast Brazil as founder mutation in two distinct haplotypes with the most frequent co-segregating with the p.E134∗ variant of the XAF1 tumor suppressor and an increased cancer risk. Founder mutations demonstrate linkage disequilibrium with neighboring genetic polymorphic markers that can be used to identify the founder variant in different geographic regions and diverse populations. We report here a shared haplotype among Brazilian, Portuguese, and Spanish families and the existence of three additional distinct TP53 p.R337H alleles. Mitochondrial DNA sequencing and Y-STR profiling of Brazilian carriers of the founder TP53 p.R337H allele reveal an excess of Native American haplogroups in maternal lineages and exclusively European haplogroups in paternal lineages, consistent with communities established through male European settlers with extensive intermarriage with Indigenous women. The identification of founder and independent TP53 p.R337H alleles underlines the importance for considering the haplotype as a functional unit and the additive effects of constitutive polymorphisms and associated variants in modifier genes that can influence the cancer phenotype.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10597792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41150718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
HGG AdvancesPub Date : 2024-01-11Epub Date: 2023-11-02DOI: 10.1016/j.xhgg.2023.100253
Dominique L Brooks, Madelynn N Whittaker, Hooda Said, Garima Dwivedi, Ping Qu, Kiran Musunuru, Rebecca C Ahrens-Nicklas, Mohamad-Gabriel Alameh, Xiao Wang
{"title":"A base editing strategy using mRNA-LNPs for in vivo correction of the most frequent phenylketonuria variant.","authors":"Dominique L Brooks, Madelynn N Whittaker, Hooda Said, Garima Dwivedi, Ping Qu, Kiran Musunuru, Rebecca C Ahrens-Nicklas, Mohamad-Gabriel Alameh, Xiao Wang","doi":"10.1016/j.xhgg.2023.100253","DOIUrl":"10.1016/j.xhgg.2023.100253","url":null,"abstract":"<p><p>The c.1222C>T (p.Arg408Trp) phenylalanine hydroxylase (PAH) variant is the most frequent cause of phenylketonuria (PKU), an autosomal recessive disorder characterized by accumulation of blood phenylalanine (Phe) to neurotoxic levels. Here we devised a therapeutic base editing strategy to correct the variant, using prime-edited hepatocyte cell lines engineered with the c.1222C>T variant to screen a variety of adenine base editors and guide RNAs in vitro, followed by assessment in c.1222C>T humanized mice in vivo. We found that upon delivery of a selected adenine base editor mRNA/guide RNA combination into mice via lipid nanoparticles (LNPs), there was sufficient PAH editing in the liver to fully normalize blood Phe levels within 48 h. This work establishes the viability of a base editing strategy to correct the most common pathogenic variant found in individuals with the most common inborn error of metabolism, albeit with potential limitations compared with other genome editing approaches.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10800763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71486824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Evaluating polygenic risk scores for predicting cardiometabolic traits and disease risks in the Taiwan Biobank.","authors":"Ren-Hua Chung, Shao-Yuan Chuang, Yong-Sheng Zhuang, Yi-Syuan Jhang, Tsung-Hsien Huang, Guo-Hung Li, I-Shou Chang, Chao A Hsiung, Hung-Yi Chiou","doi":"10.1016/j.xhgg.2023.100260","DOIUrl":"10.1016/j.xhgg.2023.100260","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) and hypertension are common comorbidities and, along with hyperlipidemia, serve as risk factors for cardiovascular diseases. This study aimed to evaluate the predictive value of polygenic risk scores (PRSs) on cardiometabolic traits related to T2D, hypertension, and hyperlipidemia and the incidence of these three diseases in Taiwan Biobank samples. Using publicly available, large-scale genome-wide association studies summary statistics, we constructed cross-ethnic PRSs for T2D, hypertension, body mass index, and nine quantitative traits typically used to define the three diseases. A composite PRS (cPRS) for each of the nine traits was constructed by aggregating the significant PRSs of its genetically correlated traits. The associations of each of the nine traits at baseline as well as the change of trait values during a 3- to 6-year follow-up period with its cPRS were evaluated. The predictive performances of cPRSs in predicting future incidences of T2D, hypertension, and hyperlipidemia were assessed. The cPRSs had significant associations with baseline and changes of trait values in 3-6 years and explained a higher proportion of variance for all traits than individual PRSs. Furthermore, models incorporating disease-related cPRSs, along with clinical features and relevant trait measurements achieved area under the curve values of 87.8%, 83.7%, and 75.9% for predicting future T2D, hypertension, and hyperlipidemia in 3-6 years, respectively.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10777116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138488561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
