HGG Advances最新文献_第3页

Polygenic risk scores for prostate cancer: Comparative evaluations in UK and Australian cohorts. 前列腺癌的多基因风险评分：英国和澳大利亚队列的比较评估。

IF 3.6

HGG Advances Pub Date : 2025-10-09 Epub Date: 2025-07-07 DOI: 10.1016/j.xhgg.2025.100477

Hamzeh M Tanha, Matthew H Law, Nathan Ingold, Philip Ly, Catherine M Olsen, Nirmala Pandeya, David P Smith, Robert J MacInnis, David C Whiteman, Anne E Cust, Julia Steinberg

{"title":"Polygenic risk scores for prostate cancer: Comparative evaluations in UK and Australian cohorts.","authors":"Hamzeh M Tanha, Matthew H Law, Nathan Ingold, Philip Ly, Catherine M Olsen, Nirmala Pandeya, David P Smith, Robert J MacInnis, David C Whiteman, Anne E Cust, Julia Steinberg","doi":"10.1016/j.xhgg.2025.100477","DOIUrl":"10.1016/j.xhgg.2025.100477","url":null,"abstract":"Risk-based approaches offer promise for enhancing early detection of prostate cancer. Polygenic risk scores (PGSs) have emerged as a potential approach for risk stratification, though their performance varies by population. We evaluated nine PGSs (four existing, five new) for predicting 5-year prostate cancer risk across three international population-based prospective cohorts: UK Biobank (UKB), the Australian QSkin Sun and Health Study (QSkin), and Melbourne Collaborative Cohort Study (MCCS). We analyzed UKB European-ancestry (n = 184,010), South-Asian-ancestry (n = 5,097), and African-ancestry (n = 3,193), QSkin European-ancestry (n = 6,791), and MCCS European-ancestry (n = 1,809) male participants. We estimated age-specific 5-year prostate cancer risks (from population data) and PGS-adjusted risks (age-specific risks multiplied by PGS-based relative risks). Predictive performance was assessed using discrimination (AUC) and calibration. PGS significantly enhanced 5-year risk prediction over age alone, particularly for European ancestry (AUC increase 0.05-0.12, p < 10-6). PGS performance was consistent across European-ancestry men in Australian and UK cohorts, and by pre-baseline prostate-specific antigen tests and family history in UKB. No single PGS outperformed others across all cohorts and ancestry groups. As an illustrative example for potential risk stratification, for a leading PGS in both Australian cohorts, we estimated the population-average 5-year risk at age 50 was reached 5 years earlier by individuals with 20% highest PGS451 and 5 years later by those with 20% lowest PGS451. In conclusion, rigorous analyses with consistent results from international cohorts support the potential of PGS to improve 5-year prostate cancer risk prediction. In the future, PGS may be improved further to enhance performance in diverse populations.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100477"},"PeriodicalIF":3.6,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12304678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592482","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}

引用次数: 0

Evaluation of SLC6A8 species conservation and the effect of pathogenic variants on creatine transport. SLC6A8物种保护评价及致病变异对肌酸运输的影响。

IF 3.6

HGG Advances Pub Date : 2025-10-09 Epub Date: 2025-08-07 DOI: 10.1016/j.xhgg.2025.100489

Taryn Diep, Gerald S Lipshutz

{"title":"Evaluation of SLC6A8 species conservation and the effect of pathogenic variants on creatine transport.","authors":"Taryn Diep, Gerald S Lipshutz","doi":"10.1016/j.xhgg.2025.100489","DOIUrl":"10.1016/j.xhgg.2025.100489","url":null,"abstract":"Creatine phosphate is a high-energy molecule essential for the normal functioning of highly metabolically active organs and tissues. SLC6A8 encodes the only known creatine transporter in humans (CRT1); pathogenic variants result in a neurophenotype that includes intellectual disability, seizures, and autistic-like behaviors. Due to the importance of creatine phosphate in normal brain function, we compared the amino acid sequence among a group of terrestrial mammals and zebrafish. Finding high interspecies invariance, we (1) sought to quantitatively assess the effect of a number of existing disease-causing SLC6A8 variants on in vitro creatine uptake, comparing variant type/location, along with (2) the reported effect of missense variants on severity classification. Creatine uptake in the pathogenic variants studied demonstrated that the vast majority had a profound effect on uptake; only 1, in a peripheral extracellular loop, had a moderately reduced effect. Of the missense variant analysis, those occurring in C and N termini were tolerated more, while variants in transmembrane domains tended to more likely affect function. While the high degree of amino acid conservation across terrestrial mammals underscores its evolutionary importance, together with the variant analysis, these findings provide a framework for understanding genotype-phenotype correlations in variants of CRT1 and highlight the critical functional constraints.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100489"},"PeriodicalIF":3.6,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805010","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}

引用次数: 0

Admixture Mapping Analysis Reveals Genetic Determinants of the Human Plasma Proteome. 混合定位分析揭示了人类血浆蛋白质组的遗传决定因素。

IF 3.6

HGG Advances Pub Date : 2025-10-08 DOI: 10.1016/j.xhgg.2025.100529

Daniel E Cruz, Shuliang Deng, Usman A Tahir, Zsu-Zsu Chen, Mark D Benson, Bjoernar Tuftin, Jiawen Chen, Laurie Farrell, Dongxiao Shen, Mariah Meyer, Ethan Lange, Yan Gao, Michael E Hall, Russell P Tracy, Stephen S Rich, Kent Taylor, Ani Manichaikul, Jerome I Rotter, Tamar Sofer, James G Wilson, Robert E Gerszten, Laura M Raffield

{"title":"Admixture Mapping Analysis Reveals Genetic Determinants of the Human Plasma Proteome.","authors":"Daniel E Cruz, Shuliang Deng, Usman A Tahir, Zsu-Zsu Chen, Mark D Benson, Bjoernar Tuftin, Jiawen Chen, Laurie Farrell, Dongxiao Shen, Mariah Meyer, Ethan Lange, Yan Gao, Michael E Hall, Russell P Tracy, Stephen S Rich, Kent Taylor, Ani Manichaikul, Jerome I Rotter, Tamar Sofer, James G Wilson, Robert E Gerszten, Laura M Raffield","doi":"10.1016/j.xhgg.2025.100529","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100529","url":null,"abstract":"Protein profiling and genetic findings can be integrated to define the genetic architecture of the circulating proteome in chronic diseases. Most self-identified African American (AA) individuals have both African and European genetic ancestry. Admixture mapping can detect genomic association regions in which causal variants exist with substantial differences in allele frequency or effect sizes between genetic ancestries. We performed admixture mapping of the circulating proteome in 1,989 participants from the Jackson Heart Study (JHS), investigating the relation of local African ancestry within genomic regions with levels of circulating proteins. We conditioned protein-local ancestry association models on variants previously found to be associated with those proteins in genome-wide association studies (GWAS). We replicated findings in 196 AA participants from the Multi-Ethnic Study of Atherosclerosis (MESA). 62 proteins were associated with local African ancestry. 21 of 62 remained statistically significant after conditioning on protein-associated variants observed in previous GWAS. 48 of 54 available protein-local ancestry associations replicated in MESA. Proteins associated with local African ancestry included chemokines, factors associated with vascular biology and inflammation, and other biologically interesting proteins. Admixture associations unexplained by previously reported protein-associated variants in conditional analysis suggest the existence of causal variants missed by standard GWAS techniques.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100529"},"PeriodicalIF":3.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259564","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}

引用次数: 0

Colon Cancer in Appalachian Kentucky: Unique Genetic, Microbiome and Obesity Findings in a Cohort Comparison. 肯塔基州阿巴拉契亚地区的结肠癌：队列比较中独特的遗传、微生物组和肥胖发现。

IF 3.6

HGG Advances Pub Date : 2025-10-07 DOI: 10.1016/j.xhgg.2025.100527

Zeta Chow, Jinpeng Liu, Daheng He, Chi Wang, Tong Gan, Akila Mansour, Nuha Shaker, Caroline Dravillas, Rebecca Hoyd, Eric Durbin, Dana Napier, Tianyan Gao, Kurt Schaberg, Lyen Huang, Neli Ulrich, Erin Siegel, Stephen Edge, Linda Cook, Bodour Salhia, Michelle Churchman, Jill Kolesar, Daniel Spakowicz, B Mark Evers, Therese Bocklage

{"title":"Colon Cancer in Appalachian Kentucky: Unique Genetic, Microbiome and Obesity Findings in a Cohort Comparison.","authors":"Zeta Chow, Jinpeng Liu, Daheng He, Chi Wang, Tong Gan, Akila Mansour, Nuha Shaker, Caroline Dravillas, Rebecca Hoyd, Eric Durbin, Dana Napier, Tianyan Gao, Kurt Schaberg, Lyen Huang, Neli Ulrich, Erin Siegel, Stephen Edge, Linda Cook, Bodour Salhia, Michelle Churchman, Jill Kolesar, Daniel Spakowicz, B Mark Evers, Therese Bocklage","doi":"10.1016/j.xhgg.2025.100527","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100527","url":null,"abstract":"We investigated colon cancer genomics and microenvironmental features in the Appalachian Kentucky population, a group with the highest incidence of colon cancer in the United States. We assessed two inter-related risk factors for colon cancer (obesity and abnormal gut bacterial microbiome) and their genetic associations within this population. To evaluate potential unique characteristics of the high-incidence cohort, we compared 99 propensity-matched colon cancer tumors from Appalachian Kentucky patients to 95 non-Appalachian patient tumors to evaluate driver mutations, differentially expressed genes (DEGs), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures, immune cell populations and microbiomes in an obesity context. Our comparison identified significant population-specific DEGs and differences in COSMIC signature frequencies, KEGG pathway regulation, pro-carcinogenic immune cell features, microbiome species, and obesity-associated inflammatory and metabolic responses between the cohorts. The findings offer generalizable implications deriving from Appalachian Kentuckians while highlighting the critical importance of population-based studies in colon cancer research.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100527"},"PeriodicalIF":3.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253085","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}

引用次数: 0

A de novo frameshift variant in the candidate RBM15 in a proband with congenital mirror movements. 先天性镜像运动先证者候选RBM15的新移码变异。

IF 3.6

HGG Advances Pub Date : 2025-10-06 DOI: 10.1016/j.xhgg.2025.100528

Frederike L Harms, Fanny Kortüm, Malik Alawi, Martin Staudt, Kerstin Kutsche

{"title":"A de novo frameshift variant in the candidate RBM15 in a proband with congenital mirror movements.","authors":"Frederike L Harms, Fanny Kortüm, Malik Alawi, Martin Staudt, Kerstin Kutsche","doi":"10.1016/j.xhgg.2025.100528","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100528","url":null,"abstract":"Congenital mirror movements (CMM) are involuntary movements of one body side that mirror intentional movements of the opposite side. DCC, NTN1, RAD51, ARHGEF7, and DNAL4 have been associated with CMM. Two thirds of CMM-affected individuals remain without a genetic diagnosis, indicating that variants in additional genes need to be discovered. We report on a 27-year-old female with CMM of the hands. Trio exome sequencing in the proband and healthy parents did not reveal a likely pathogenic variant in one of the CMM-associated genes, but a de novo heterozygous frameshift variant c.523dup; p.(Ser175Lysfs*8) in the candidate RBM15. The variant results in only partial nonsense-mediated mRNA decay of RBM15 transcripts in the proband's lymphoblastoid cells. RBM15 encodes an RNA binding protein involved in alternative splicing besides other processes. Dcc alternative splicing generates Dcclong and Dccshort isoforms which are important for commissural axon midline crossing. We tested if Rbm15 regulates Dcc alternative splicing by using an in vitro minigene assay. Ectopic expression of Rbm15, similar to the splicing factors Nova1 and Nova2, promotes the production of Dcclong transcripts. The possible link between Rbm15 and Dcc supports a role for Rbm15 in CMM.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100528"},"PeriodicalIF":3.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245500","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}

引用次数: 0

Phasing millions of samples achieves near perfect accuracy, enabling parent-of-origin analyses. 分阶段数以百万计的样品实现了近乎完美的准确性，使母体起源分析成为可能。

IF 3.6

HGG Advances Pub Date : 2025-10-03 DOI: 10.1016/j.xhgg.2025.100526

Cole M Williams, Jared O'Connell, Ethan Jewett, William A Freyman, Christopher R Gignoux, Sohini Ramachandran, Amy L Williams

引用次数: 0

Accurate DNA Methylation Predictor for C9orf72 Repeat Expansion Alleles in the Pathogenic Range. 致病范围内C9orf72重复扩增等位基因的精确DNA甲基化预测因子

IF 3.6

HGG Advances Pub Date : 2025-09-29 DOI: 10.1016/j.xhgg.2025.100522

Naren Ramesh, Alexandria Evans, Kevin Wojta, Zhongan Yang, Marco P Boks, René S Kahn, Sterre C M de Boer, Sven J van der Lee, Yolande A L Pijnenburg, Lianne M Reus, Roel A Ophoff

{"title":"Accurate DNA Methylation Predictor for C9orf72 Repeat Expansion Alleles in the Pathogenic Range.","authors":"Naren Ramesh, Alexandria Evans, Kevin Wojta, Zhongan Yang, Marco P Boks, René S Kahn, Sterre C M de Boer, Sven J van der Lee, Yolande A L Pijnenburg, Lianne M Reus, Roel A Ophoff","doi":"10.1016/j.xhgg.2025.100522","DOIUrl":"10.1016/j.xhgg.2025.100522","url":null,"abstract":"The hexanucleotide (G4C2) repeat expansion in the promoter region of C9orf72 is the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this study, we conducted a genome-wide DNA methylation (DNAm) analysis using EPIC version 2 (EPICv2) arrays on an FTD cohort comprising 27 carriers and 250 non-carriers of the pathogenic C9orf72 repeat expansion from the Amsterdam Dementia Cohort. We identified differentially methylated CpGs probes associated with the pathogenic C9orf72 expansion and used these findings to create a DNAm Least Absolute Shrinkage and Selection Operator (LASSO) predictor to identify repeat expansion carriers. Eight CpG sites at the C9orf72 locus were significantly differentially hypermethylated in repeat expansion carriers compared to non-carriers. The LASSO model predicted repeat expansion status with an average accuracy of 98.6%. The LASSO predictor was further validated in a separate, independent validation cohort containing 1,589 bipolar disorder patients, 580 first degree relatives, and 289 independent controls with available EPICv2 data, identifying four C9orf72 repeat expansion carriers, subsequently confirmed by repeat-primed PCR. This result highlights the accuracy and generalizability of the DNAm predictor of C9orf72 repeat expansion carriers. The identification of a highly accurate DNAm biomarker for a repeat expansion locus associated with neurodegenerative disorders may provide great value for studying this locus. The approach holds significant promise for investigating this and other repeat expansion loci, particularly given the growing interest in epigenetic epidemiological studies involving large cohorts with available DNAm data.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100522"},"PeriodicalIF":3.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193288","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}

引用次数: 0

Biallelic variants in BCAT1 impair mitochondrial function and are associated with a candidate neurometabolic disorder. BCAT1的双等位基因变异损害线粒体功能，并与一种候选神经代谢疾病有关。

IF 3.6

HGG Advances Pub Date : 2025-09-29 DOI: 10.1016/j.xhgg.2025.100525

Brianna L DiSanza, Giulia S Porcari, Livia Sertori Finoti, Leonardo Ramos-Rodriguez, Devin M Burris, Justin A McDonough, Gang Ning, Grace Fagan, Guy T Helman, Erin Weiss, Ryan J Taft, Amy Pizzino, Matthew T Whitehead, Amy Waldman, Cas Simons, Xilma Ortiz-Gonzalez, William C Skarnes, Adeline Vanderver, Elizabeth J Bhoj, Rebecca C Ahrens-Nicklas

{"title":"Biallelic variants in BCAT1 impair mitochondrial function and are associated with a candidate neurometabolic disorder.","authors":"Brianna L DiSanza, Giulia S Porcari, Livia Sertori Finoti, Leonardo Ramos-Rodriguez, Devin M Burris, Justin A McDonough, Gang Ning, Grace Fagan, Guy T Helman, Erin Weiss, Ryan J Taft, Amy Pizzino, Matthew T Whitehead, Amy Waldman, Cas Simons, Xilma Ortiz-Gonzalez, William C Skarnes, Adeline Vanderver, Elizabeth J Bhoj, Rebecca C Ahrens-Nicklas","doi":"10.1016/j.xhgg.2025.100525","DOIUrl":"10.1016/j.xhgg.2025.100525","url":null,"abstract":"Branched-chain amino acid transaminase-1 (BCAT1) initiates the catabolism of branched-chain amino acids (BCAA), which are essential for neurologic function. However, the role of BCAT1 in neurodevelopment is largely unknown. Here, we identify compound heterozygous BCAT1 variants in a patient with a severe progressive neurodevelopmental syndrome. To investigate the functional consequences, we established patient variant (BCAT1: c.792T>A p.(Phe264Leu); c.1042G>A p.(Glu348Lys)) and BCAT1 knockout hiPSC models. Both disease models show profound defects in cortical neuron differentiation and neurite outgrowth. Furthermore, metabolic analysis revealed evidence of mitochondrial dysfunction associated with increased levels of tricarboxylic acid (TCA) cycle intermediates, glutamate, and glutamine. This increase is linked to altered oxygen consumption rates, superoxide production, and upregulation of UCP2 in BCAT1-disease neurons, suggesting a downstream impact on electron-transport chain homeostasis. These findings establish a regulatory role for BCAT1 in mitochondrial function and further define a role for genomic variants in BCAT1 in neurometabolic disorders.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100525"},"PeriodicalIF":3.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201664","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}

引用次数: 0

Researcher Attitudes towards Hypothetical Genetic Research with Navajo People: Results from an Online Survey. 研究人员对纳瓦霍人假设基因研究的态度：来自在线调查的结果。

IF 3.6

HGG Advances Pub Date : 2025-09-27 DOI: 10.1016/j.xhgg.2025.100524

Carissa A Sherman, Nanibaa' A Garrison, Katrina G Claw

{"title":"Researcher Attitudes towards Hypothetical Genetic Research with Navajo People: Results from an Online Survey.","authors":"Carissa A Sherman, Nanibaa' A Garrison, Katrina G Claw","doi":"10.1016/j.xhgg.2025.100524","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100524","url":null,"abstract":"The Navajo Nation is reevaluating a moratorium on genetic research that was authorized in 2002. While the moratorium was instituted due to cultural concerns and the lack of a Navajo genetic research policy, there remains limited empirical work assessing the perspectives of Diné (Navajo) people and other interest holders regarding genetic research. To address this gap, this study examines the perspectives of research project leaders with protocols approved by the Navajo Nation Human Research Review Board (NNHRRB) as this group is aware of research expectations and cultural considerations. An online survey was designed to gauge researchers' interest in adding a genetic component to their research if the moratorium were lifted, while also examining potential benefits, risks, and ethical considerations. Survey participants (n=36) included 27% Diné researchers and 73% non-Diné researchers, and 50% of researchers (n=18) had collected human biospecimens in their research (e.g., blood, tissue). Our results indicate that if the moratorium on genetic research ended, 42% of researchers (n=15) would be unsure about adding a genetic component to their projects, while 31% (n=11) of researchers were interested. Participants were asked to rank ethical considerations related to five broad topics: community engagement; dissemination of results and data; privacy and rights; health, safety, and equity; and discrimination and mistrust. Participants ranked \"ensure that no research participants are harmed\" and \"give presentations to the community\" as very important whereas \"sharing data with other researchers\" was of low importance. We provide valuable perspectives to guide potential genetic policy development for the Navajo Nation.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100524"},"PeriodicalIF":3.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186785","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}

引用次数: 0

Long-read DNA and RNA sequencing reveal an intronic retrotransposon insertion in TCOF1 causing Treacher Collins syndrome. 长读DNA和RNA测序揭示了TCOF1中一个内含子反转录转座子插入导致Treacher Collins综合征。

IF 3.6

HGG Advances Pub Date : 2025-09-27 DOI: 10.1016/j.xhgg.2025.100523

Federico Ferraro, Nikolas Kühn, Dmitrijs Rots, Herma C van der Linde, Banin Mohseni, Leontine van Unen, Mark Drost, Mark Nellist, Marieke Koekkoek, Rachel Schot, Henriette W de Gier, Mieke Pleumeekers, Tahsin Stefan Barakat, Tjitske Kleefstra, Marjolein Weerts, Marieke F van Dooren, Tjakko J van Ham

{"title":"Long-read DNA and RNA sequencing reveal an intronic retrotransposon insertion in TCOF1 causing Treacher Collins syndrome.","authors":"Federico Ferraro, Nikolas Kühn, Dmitrijs Rots, Herma C van der Linde, Banin Mohseni, Leontine van Unen, Mark Drost, Mark Nellist, Marieke Koekkoek, Rachel Schot, Henriette W de Gier, Mieke Pleumeekers, Tahsin Stefan Barakat, Tjitske Kleefstra, Marjolein Weerts, Marieke F van Dooren, Tjakko J van Ham","doi":"10.1016/j.xhgg.2025.100523","DOIUrl":"https://doi.org/10.1016/j.xhgg.2025.100523","url":null,"abstract":"Treacher Collins syndrome (TCS) is a craniofacial genetic disorder caused by loss of function variants in TCOF1, POLR1B, POLR1C or POLR1D. Here we describe two previously undiagnosed paternal half-siblings affected with clinical TCS, and their apparently unaffected father. Diagnostic short-read RNA-sequencing (srRNA-Seq) identified aberrant expression of TCOF1 and optical genome mapping detected a large genomic insertion therein. Long-read genome sequencing (lrGS) resolved a deep intronic 3.5 kb SINE-VNTR-Alu (SVA) retrotransposon insertion in intron 17 of TCOF1. Long-read RNA-seq (lrRNA-Seq) demonstrated that the insertion was partially exonized inducing isoform switch to the shorter non-canonical TCOF1 isoform c. SVA-insertion was confirmed in both half-siblings, and we detected mosaicism in the father. This work demonstrates the potential of lrRNA-Seq and lrGS, to identify pathogenic variants in unexplained genetic disorders.","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100523"},"PeriodicalIF":3.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186443","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}

引用次数: 0