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Best practices for germline variant and DNA methylation analysis of second- and third-generation sequencing data. 对第二代和第三代测序数据进行种系变异和 DNA 甲基化分析的最佳实践。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-05 DOI: 10.1186/s40246-024-00684-8
Ferdinando Bonfiglio, Andrea Legati, Vito Alessandro Lasorsa, Flavia Palombo, Giulia De Riso, Federica Isidori, Silvia Russo, Simone Furini, Giuseppe Merla, Fabio Coppedè, Marco Tartaglia, Alessandro Bruselles, Tommaso Pippucci, Andrea Ciolfi, Michele Pinelli, Mario Capasso

This comprehensive review provides insights and suggested strategies for the analysis of germline variants using second- and third-generation sequencing technologies (SGS and TGS). It addresses the critical stages of data processing, starting from alignment and preprocessing to quality control, variant calling, and the removal of artifacts. The document emphasized the importance of meticulous data handling, highlighting advanced methodologies for annotating variants and identifying structural variations and methylated DNA sites. Special attention is given to the inspection of problematic variants, a step that is crucial for ensuring the accuracy of the analysis, particularly in clinical settings where genetic diagnostics can inform patient care. Additionally, the document covers the use of various bioinformatics tools and software that enhance the precision and reliability of these analyses. It outlines best practices for the annotation of variants, including considerations for problematic genetic alterations such as those in the human leukocyte antigen region, runs of homozygosity, and mitochondrial DNA alterations. The document also explores the complexities associated with identifying structural variants and copy number variations, underscoring the challenges posed by these large-scale genomic alterations. The objective is to offer a comprehensive framework for researchers and clinicians, ensuring that genetic analyses conducted with SGS and TGS are both accurate and reproducible. By following these best practices, the document aims to increase the diagnostic accuracy for hereditary diseases, facilitating early diagnosis, prevention, and personalized treatment strategies. This review serves as a valuable resource for both novices and experts in the field, providing insights into the latest advancements and methodologies in genetic analysis. It also aims to encourage the adoption of these practices in diverse research and clinical contexts, promoting consistency and reliability across studies.

这篇综合性综述为使用第二代和第三代测序技术(SGS 和 TGS)分析种系变异提供了见解和建议策略。它探讨了数据处理的关键阶段,从比对和预处理到质量控制、变异调用和去除伪影。文件强调了细致数据处理的重要性,重点介绍了注释变异、识别结构变异和甲基化 DNA 位点的先进方法。文件特别关注对有问题变异的检查,这一步骤对于确保分析的准确性至关重要,尤其是在临床环境中,因为基因诊断可为患者护理提供依据。此外,文件还介绍了各种生物信息学工具和软件的使用方法,以提高这些分析的准确性和可靠性。文件概述了变异注释的最佳实践,包括对有问题的基因改变的考虑,如人类白细胞抗原区域的基因改变、同基因遗传变异和线粒体 DNA 改变。文件还探讨了与识别结构变异和拷贝数变异相关的复杂性,强调了这些大规模基因组改变所带来的挑战。其目的是为研究人员和临床医生提供一个全面的框架,确保使用 SGS 和 TGS 进行的基因分析既准确又具有可重复性。通过遵循这些最佳实践,本文件旨在提高遗传性疾病诊断的准确性,促进早期诊断、预防和个性化治疗策略。本综述为该领域的新手和专家提供了宝贵的资源,让他们深入了解遗传分析的最新进展和方法。它还旨在鼓励在不同的研究和临床环境中采用这些方法,促进各项研究的一致性和可靠性。
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引用次数: 0
Drosophila Toxicogenomics: genetic variation and sexual dimorphism in susceptibility to 4-Methylimidazole. 果蝇毒物基因组学:4-甲基咪唑易感性的遗传变异和性双态性。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-11-04 DOI: 10.1186/s40246-024-00689-3
Katelynne M Collins, Elisabeth Howansky, Sarah C Macon-Foley, Maria E Adonay, Vijay Shankar, Richard F Lyman, Nestor Octavio Nazario-Yepiz, Jordyn K Brooks, Rachel A Lyman, Trudy F C Mackay, Robert R H Anholt

Background: 4-methylimidazole is a ubiquitous and potentially carcinogenic environmental toxicant. Genetic factors that contribute to variation in susceptibility to its toxic effects are challenging to assess in human populations. We used the Drosophila melanogaster Genetic Reference Panel (DGRP), a living library of natural genetic variation, to identify genes with human orthologs associated with variation in susceptibility to 4-methylimidazole.

Results: We screened 204 DGRP lines for survival following 24-hour exposure to 4-methylimidazole. We found extensive genetic variation for survival, with a broad sense heritability of 0.82; as well as genetic variation in sexual dimorphism, with a cross-sex genetic correlation of 0.59. Genome-wide association analyses identified a total of 241 candidate molecular polymorphisms in or near 273 unique genes associated with survival. These polymorphisms had either sex-specific or sex-antagonistic effects, and most had putative regulatory effects. We generated interaction networks using these candidate genes as inputs and computationally recruited genes with known physical or genetic interactions. The network genes were significantly over-represented for gene ontology terms involving all aspects of development (including nervous system development) and cellular and organismal functions as well as canonical signaling pathways, and most had human orthologs.

Conclusions: The genetic basis of variation in sensitivity to acute exposure to 4-methylimidazole in Drosophila is attributable to variation in genes and networks of genes known for their effects on multiple developmental and cellular processes, including possible neurotoxicity. Given evolutionary conservation of the underlying genes and pathways, these insights may be applicable to humans.

背景:4 甲基咪唑是一种无处不在的潜在致癌环境毒物。在人类群体中评估导致对其毒性作用易感性变异的遗传因素具有挑战性。我们利用黑腹果蝇遗传参照组(DGRP)--一个活的自然遗传变异库--来鉴定与4-甲基咪唑易感性变异相关的人类直向同源基因:我们对 204 个 DGRP 株系进行了筛选,以检测它们在暴露于 4-甲基咪唑 24 小时后的存活率。我们发现了存活率的广泛遗传变异,广义遗传率为 0.82;以及性二态的遗传变异,跨性别遗传相关性为 0.59。全基因组关联分析在与存活率相关的 273 个独特基因中或其附近共发现了 241 个候选分子多态性。这些多态性要么具有性别特异性效应,要么具有性别拮抗效应,而且大多数具有假定的调控效应。我们利用这些候选基因作为输入,并通过计算招募了具有已知物理或遗传相互作用的基因,从而生成了相互作用网络。网络基因在涉及发育(包括神经系统发育)、细胞和生物体功能以及典型信号通路的基因本体术语中的代表性明显偏高,而且大多数基因都有人类直向同源物:果蝇对急性暴露于 4-甲基咪唑的敏感性差异的遗传基础可归因于基因和基因网络的差异,已知这些基因和基因网络对多个发育和细胞过程具有影响,包括可能的神经毒性。鉴于基本基因和途径的进化保护,这些见解可能适用于人类。
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引用次数: 0
Novel FLNC variants in pediatric cardiomyopathy: an insight into disease mechanisms. 小儿心肌病中的新型 FLNC 变异:对疾病机理的深入了解。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-29 DOI: 10.1186/s40246-024-00683-9
Rui Dong, Xin Zhou, Haiyan Zhang, Bingyi Shi, Guohua Liu, Yi Liu

Background: FLNC gene variants have predominantly been reported in adult populations with cardiomyopathies, and early-onset cases are less common. The genotype-phenotype relationship indicates that dilated cardiomyopathy (DCM) is often associated with FLNC truncating variants.

Methods: We conducted a comprehensive genetic analysis using next generation sequencing (NGS) to identify FLNC variants in patients with cardiovascular conditions. Detailed phenotypic and variant analyses were performed to characterize the clinical features and genetic alterations. Minigene assays and structural modeling were used to investigate the pathogenicity caused by the identified variants.

Results: In a cohort of 58 patients, novel heterozygous FLNC variants, c.3962A > T (p.Glu1321Val) and c.7543C > T (p.Leu2515Phe), were identified in patients presenting with dilated and mixed restrictive/hypertrophic cardiomyopathies, respectively. The c.3962A > T variant disrupted normal splicing, as demonstrated through the splicing prediction tool and minigene studies, further emphasizing its pathogenic potential.

Conclusion: For missense variants of FLNC in patients with DCM, the splicing effect of the variant should be carefully checked. Early detection and intervention are crucial given the high risk of sudden cardiac death and severe cardiac complications.

背景:FLNC基因变异主要见于成年心肌病患者,而早发病例较少见。基因型与表型的关系表明,扩张型心肌病(DCM)通常与 FLNC 截断变异有关:我们利用新一代测序技术(NGS)进行了全面的遗传分析,以确定心血管疾病患者的 FLNC 变异。我们进行了详细的表型和变异分析,以确定临床特征和基因改变的特点。利用微型基因检测和结构建模研究了所发现变异的致病性:结果:在一组 58 例患者中,发现了新型杂合子 FLNC 变异 c.3962A > T(p.Glu1321Val)和 c.7543C > T(p.Leu2515Phe),它们分别出现在扩张型和限制型/肥厚型混合型心肌病患者中。c.3962A > T变异破坏了正常剪接,剪接预测工具和迷你基因研究证明了这一点,进一步强调了其致病潜力:结论:对于DCM患者中的FLNC错义变异,应仔细检查该变异的剪接效应。鉴于心脏性猝死和严重心脏并发症的高风险,早期发现和干预至关重要。
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引用次数: 0
Mapping the evolving trend of research on leukocyte telomere length: a text-mining study. 绘制白细胞端粒长度研究的演变趋势图:文本挖掘研究。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-29 DOI: 10.1186/s40246-024-00687-5
Yuanjun Lyu, Hongjie Zhao, Guiping Zeng, Jia Yang, Qipeng Shao, Haiyang Wu

Background: Substantial evidence indicates that measuring leukocyte telomere length (LTL) is a useful tool that may be considered as a valuable biomarker of individual biological age, correlating with numerous chronic disorders. However, to date, there has been a lack of in-depth understanding regarding the current landscape and forthcoming developments in the LTL field. Therefore, this study aimed to utilize bibliometric methods to summarize the knowledge structure, current focus, and emerging directions in this field.

Method: Scientific publications on LTL spanning the period from 2000 to 2022 were acquired from the Web of Science Core Collection database. Several bibliometric tools including CiteSpace, VOSviewer, and an online website were utilized for bibliometric analysis. The primary evaluations encompassed investigating the major contributors and their collaborative relationships among countries/regions, institutions, and authors, conducting co-citation analyses of authors, journals, as well as reference, examining reference bursts, as well as performing co-occurrence analyses of keywords.

Results: There are 1818 papers with 66,668 citations identified. Both the annual publication and citation counts on LTL exhibited significant upward trends. The United States emerged as the most prominent contributor, as evidenced by the greatest volume of papers and the highest H-index value. University of California San Francisco and Aviv A were identified as the most productive institution and author in this domain, respectively. Reference analysis revealed that longitudinal study and mendelian randomization study are the most concerned research method in this field recently. Keywords analysis showed that the most concerned diseases in LTL fields were aging, inflammation, cardiovascular diseases, endocrine diseases, neurological and psychiatric diseases, and cancers. In addition, the following research directions such as "COPD", "mendelian randomization", "adiposity", "colorectal cancer", "National Health and Nutrition Examination Survey (NHNES)", "telomerase reverse transcriptase", "pregnancy" have garnered increasing attention in recent times and hold the potential to evolve into research foci in the foreseeable future.

Conclusion: This is the first bibliometric study that provides comprehensive overview of LTL research. The findings of this study could become valuable references for investigators to explore and address the current and emerging challenges in LTL research.

背景:大量证据表明,测量白细胞端粒长度(LTL)是一种有用的工具,可被视为个人生物年龄的重要生物标志物,与许多慢性疾病相关。然而,迄今为止,人们对LTL领域的现状和未来发展还缺乏深入了解。因此,本研究旨在利用文献计量学方法总结该领域的知识结构、当前重点和新兴方向:从 Web of Science Core Collection 数据库中获取了 2000 年至 2022 年期间有关 LTL 的科学出版物。文献计量分析使用了几种文献计量工具,包括 CiteSpace、VOSviewer 和一个在线网站。主要评估包括调查主要撰稿人及其在国家/地区、机构和作者之间的合作关系,对作者、期刊和参考文献进行共引分析,检查参考文献突发情况,以及对关键词进行共现分析:结果:共发现 1818 篇论文,引用次数达 66,668 次。LTL的年发表量和引用量都呈现出明显的上升趋势。论文数量最多、H 指数值最高的国家是美国。加利福尼亚大学旧金山分校和阿维夫A分别被认定为该领域最有贡献的机构和作者。参考文献分析显示,纵向研究和亡羊补牢式随机研究是该领域近期最受关注的研究方法。关键词分析显示,LTL 领域最受关注的疾病是衰老、炎症、心血管疾病、内分泌疾病、神经和精神疾病以及癌症。此外,"慢性阻塞性肺病"、"门德尔随机化"、"肥胖"、"结直肠癌"、"国家健康与营养调查(NHNES)"、"端粒酶逆转录酶"、"妊娠 "等研究方向近来也日益受到关注,并有可能在可预见的未来发展成为研究热点:这是第一项全面概述长效语言研究的文献计量学研究。结论:这是第一份全面概述 LTL 研究的文献计量学研究报告,研究结果可为研究人员探索和应对 LTL 研究中当前和新出现的挑战提供有价值的参考。
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引用次数: 0
Computational approaches to investigate the relationship between periodontitis and cardiovascular diseases for precision medicine. 用计算方法研究牙周炎与心血管疾病之间的关系,实现精准医疗。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-19 DOI: 10.1186/s40246-024-00685-7
Sophia Duenas, Zachary McGee, Ishani Mhatre, Karthikeyan Mayilvahanan, Kush Ketan Patel, Habiba Abdelhalim, Atharv Jayprakash, Uzayr Wasif, Oluchi Nwankwo, William Degroat, Naveena Yanamala, Partho P Sengupta, Daniel Fine, Zeeshan Ahmed

Periodontitis is a highly prevalent inflammatory illness that leads to the destruction of tooth supporting tissue structures and has been associated with an increased risk of cardiovascular disease (CVD). Precision medicine, an emerging branch of medical treatment, aims can further improve current traditional treatment by personalizing care based on one's environment, genetic makeup, and lifestyle. Genomic databases have paved the way for precision medicine by elucidating the pathophysiology of complex, heritable diseases. Therefore, the investigation of novel periodontitis-linked genes associated with CVD will enhance our understanding of their linkage and related biochemical pathways for targeted therapies. In this article, we highlight possible mechanisms of actions connecting PD and CVD. Furthermore, we delve deeper into certain heritable inflammatory-associated pathways linking the two. The goal is to gather, compare, and assess high-quality scientific literature alongside genomic datasets that seek to establish a link between periodontitis and CVD. The scope is focused on the most up to date and authentic literature published within the last 10 years, indexed and available from PubMed Central, that analyzes periodontitis-associated genes linked to CVD. Based on the comparative analysis criteria, fifty-one genes associated with both periodontitis and CVD were identified and reported. The prevalence of genes associated with both CVD and periodontitis warrants investigation to assess the validity of a potential linkage between the pathophysiology of both diseases.

牙周炎是一种高发的炎症性疾病,会导致牙齿支撑组织结构的破坏,并与心血管疾病(CVD)风险的增加有关。精准医疗是医疗领域的一个新兴分支,其目的是根据个人的环境、基因构成和生活方式进行个性化治疗,从而进一步改善目前的传统治疗方法。基因组数据库阐明了复杂的遗传性疾病的病理生理学,为精准医疗铺平了道路。因此,研究与心血管疾病相关的新型牙周炎关联基因将加深我们对其关联性和相关生化途径的了解,从而为靶向治疗提供依据。在本文中,我们将强调牙周病和心血管疾病之间可能的作用机制。此外,我们还将深入探讨将二者联系起来的某些遗传性炎症相关途径。我们的目标是收集、比较和评估高质量的科学文献以及基因组数据集,以寻求建立牙周炎与心血管疾病之间的联系。研究范围主要集中在过去 10 年内发表的、被 PubMed Central 索引并提供的、分析与心血管疾病相关的牙周炎相关基因的最新真实文献。根据比较分析标准,确定并报告了 51 个与牙周炎和心血管疾病相关的基因。心血管疾病和牙周炎相关基因的普遍性值得研究,以评估这两种疾病的病理生理学之间潜在联系的有效性。
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引用次数: 0
Correction: Chromosome 16p11.2 microdeletion syndrome with microcephaly and Dandy-Walker malformation spectrum: expanding the known phenotype. 更正:染色体 16p11.2 微缺失综合征伴小头畸形和 Dandy-Walker 畸形谱系:扩展已知表型。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-15 DOI: 10.1186/s40246-024-00681-x
Liena Elbaghir Omer Elsayed, Norah Ayed AlHarbi, Ashwaq Mohammed Alqarni, Huda Hussein Elwasila Eltayeb, Noura Mostafa Mohamed Mostafa, Maha Mohammed Abdulrahim, Hadeel Ibrahim Bin Zaid, Latifah Mansour Alanzi, Sarah Abdullah Ababtain, Khawlah Aldulaijan, Sheka Yagub Aloyouni, Moneeb Abdullah Kassem Othman, Mohammad Abdullah Alkheilewi, Adel Mohammed Binduraihem, Hadeel Abdollah Alrukban, Hiba Yousif Ahmed, Faten Abdullah AlRadini, Hadil Mohammad Alahdal, Aziza Mufareh Mushiba, Omaima Abdulazeem Alzaher
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引用次数: 0
Fast and accurate DNASeq variant calling workflow composed of LUSH toolkit. 快速准确的 DNASeq 变异调用工作流程由 LUSH 工具包组成。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-10 DOI: 10.1186/s40246-024-00666-w
Taifu Wang, Youjin Zhang, Haoling Wang, Qiwen Zheng, Jiaobo Yang, Tiefeng Zhang, Geng Sun, Weicong Liu, Longhui Yin, Xinqiu He, Rui You, Chu Wang, Zhencheng Liu, Zhijian Liu, Jin'an Wang, Xiangqian Jin, Zengquan He

Background: Whole genome sequencing (WGS) is becoming increasingly prevalent for molecular diagnosis, staging and prognosis because of its declining costs and the ability to detect nearly all genes associated with a patient's disease. The currently widely accepted variant calling pipeline, GATK, is limited in terms of its computational speed and efficiency, which cannot meet the growing analysis needs.

Results: Here, we propose a fast and accurate DNASeq variant calling workflow that is purely composed of tools from LUSH toolkit. The precision and recall measurements indicate that both the LUSH and GATK pipelines exhibit high levels of consistency, with precision and recall rates exceeding 99% on the 30x NA12878 dataset. In terms of processing speed, the LUSH pipeline outperforms the GATK pipeline, completing 30x WGS data analysis in just 1.6 h, which is approximately 17 times faster than GATK. Notably, the LUSH_HC tool completes the processing from BAM to VCF in just 12 min, which is around 76 times faster than GATK.

Conclusion: These findings suggest that the LUSH pipeline is a highly promising alternative to the GATK pipeline for WGS data analysis, with the potential to significantly improve bedside analysis of acutely ill patients, large-scale cohort data analysis, and high-throughput variant calling in crop breeding programs. Furthermore, the LUSH pipeline is highly scalable and easily deployable, allowing it to be readily applied to various scenarios such as clinical diagnosis and genomic research.

背景:全基因组测序(WGS)在分子诊断、分期和预后方面的应用越来越普遍,因为它的成本不断降低,而且几乎能检测到与患者疾病相关的所有基因。目前广为接受的变异调用管道 GATK 在计算速度和效率方面存在局限性,无法满足日益增长的分析需求:在此,我们提出了一种快速、准确的 DNASeq 变异调用工作流程,该流程完全由 LUSH 工具包中的工具组成。精确度和召回率的测量结果表明,LUSH 和 GATK 管道都表现出了高度的一致性,在 30x NA12878 数据集上的精确度和召回率都超过了 99%。在处理速度方面,LUSH 管道优于 GATK 管道,仅用 1.6 小时就完成了 30 倍 WGS 数据分析,比 GATK 快约 17 倍。值得注意的是,LUSH_HC 工具仅用 12 分钟就完成了从 BAM 到 VCF 的处理,比 GATK 快约 76 倍:这些发现表明,在 WGS 数据分析方面,LUSH 管道是 GATK 管道的一个非常有前途的替代方案,有望显著改善急性病患者的床边分析、大规模队列数据分析以及作物育种项目中的高通量变异调用。此外,LUSH 管道具有高度可扩展性,易于部署,可随时应用于临床诊断和基因组研究等各种场景。
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引用次数: 0
Implementing differentially pigmented skin models for predicting drug response variability across human ancestries. 实施不同色素皮肤模型,预测不同人类祖先对药物反应的差异。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-09 DOI: 10.1186/s40246-024-00677-7
Sophie Zaaijer, Simon C Groen

Persistent racial disparities in health outcomes have catalyzed legislative reforms and heightened scientific focus recently. However, despite the well-documented properties of skin pigments in binding drug compounds, their impact on therapeutic efficacy and adverse drug responses remains insufficiently explored. This perspective examines the intricate relationships between variation in melanin-based skin pigmentation and pharmacokinetics and -dynamics, highlighting the need for considering diversity in skin pigmentation as a variable to advance the equitability of pharmacological interventions. The article provides guidelines on the selection of New Approach Methods (NAMs) to foster inclusive study designs in preclinical drug development pipelines, leading to an improved level of translatability to the clinic.

在健康结果方面持续存在的种族差异催生了立法改革,并在最近引起了科学界的高度关注。然而,尽管皮肤色素在结合药物化合物方面的特性已得到充分证明,但它们对疗效和药物不良反应的影响仍未得到充分探讨。本文探讨了以黑色素为基础的皮肤色素变化与药代动力学和动力学之间错综复杂的关系,强调有必要将皮肤色素的多样性作为一个变量来考虑,以促进药物干预的公平性。文章提供了选择新方法(NAM)的指南,以促进临床前药物开发流程中的包容性研究设计,从而提高临床转化水平。
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引用次数: 0
Comprehensive analysis of NGS-based expanded carrier screening and follow-up in southern and southwestern China: results from 3024 Chinese individuals. 中国华南和西南地区基于 NGS 的扩大携带者筛查和随访的综合分析:3024 名中国人的结果。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-08 DOI: 10.1186/s40246-024-00680-y
Qinlin Huang, Juan Wen, Hongyun Zhang, Yanling Teng, Wen Zhang, Huimin Zhu, Desheng Liang, Lingqian Wu, Zhuo Li

Background: This study aimed to screen southern and southwestern Chinese individuals using expanded carrier screening (ECS), which explores the carrier status of recessively inherited diseases in southern and southwestern China, evaluates the clinical effectiveness of ECS application, and helps recognize high-risk fetuses that may have genetic disorders early in pregnancy, to provide better reproductive guidance.

Methods: ECS for 220 diseases based on next-generation sequencing was performed on 3024 southern and southwestern Chinese individuals (1512 couples). Carrier status was analyzed; genes and loci with high frequencies of variants and on high-risk couples (ARCs) were focused to evaluate the clinical utility of our ECS technology and provide them precise fertility guidance.

Results: In total, Pathogenic/likely pathogenic(P/LP) variants were found in 1885 individuals, so the carrier frequency was 62.3%, and 23.2% of the individuals were carriers of multiple diseases. furthermore, 2837 variants were detected, and the average number of P/LP variants carried per subject was 0.938. Additionally, 128 ARCs carried P/LP variants of the same gene, and the theoretical incidence rate in their offspring was as high as 2.12%.

Conclusion: This study validated the application of our ECS technique for carrier screening in southern China, identifying carrier status and providing accurate carrier frequencies for hundreds of genetic diseases.

研究背景本研究旨在利用扩大携带者筛查(ECS)对华南和西南地区的个体进行筛查,探讨华南和西南地区隐性遗传病的携带者状况,评估ECS应用的临床效果,并帮助识别妊娠早期可能患有遗传疾病的高风险胎儿,以提供更好的生育指导:方法:对 3024 名华南和西南地区个体(1512 对夫妇)进行了基于新一代测序的 220 种疾病的 ECS。分析携带者状况;重点分析变异频率高的基因和位点以及高风险夫妇(ARCs),以评估我们的 ECS 技术的临床实用性,并为他们提供精确的生育指导:总共在 1885 个个体中发现了致病/可能致病(P/LP)变异,因此携带者频率为 62.3%,其中 23.2% 的个体是多种疾病的携带者。此外,128 名 ARC 携带同一基因的 P/LP 变异,其后代的理论发病率高达 2.12%:本研究验证了我们的 ECS 技术在华南地区携带者筛查中的应用,可确定携带者状态,并为数百种遗传病提供准确的携带者频率。
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引用次数: 0
Leveraging large-scale datasets and single cell omics data to develop a polygenic score for cisplatin-induced ototoxicity. 利用大规模数据集和单细胞 omics 数据开发顺铂诱发耳毒性的多基因评分。
IF 3.8 3区 医学 Q2 GENETICS & HEREDITY Pub Date : 2024-10-08 DOI: 10.1186/s40246-024-00679-5
Deanne Nixie R Miao, MacKenzie A P Wilke, John Pham, Feryal Ladha, Mansumeet Singh, Janilyn Arsenio, Emilia Luca, Alain Dabdoub, Wejian Yang, Jun J Yang, Britt I Drögemöller

Background: Cisplatin-induced ototoxicity (CIO), characterized by irreversible and progressive bilateral hearing loss, is a prevalent adverse effect of cisplatin chemotherapy. Alongside clinical risk factors, genetic variants contribute to CIO and genome-wide association studies (GWAS) have highlighted the polygenicity of this adverse drug reaction. Polygenic scores (PGS), which integrate information from multiple genetic variants across the genome, offer a promising tool for the identification of individuals who are at higher risk for CIO. Integrating large-scale hearing loss GWAS data with single cell omics data holds potential to overcome limitations related to small sample sizes associated with CIO studies, enabling the creation of PGSs to predict CIO risk.

Results: We utilized a large-scale hearing loss GWAS and murine inner ear single nuclei RNA-sequencing (snRNA-seq) data to develop two polygenic scores: a hearing loss PGS (PGSHL) and a biologically informed PGS for CIO (PGSCIO). The PGSCIO included only variants which mapped to genes that were differentially expressed within cochlear cells that showed differential abundance in the murine snRNA-seq data post-cisplatin treatment. Evaluation of the association of these PGSs with CIO in our target CIO cohort revealed that PGSCIO demonstrated superior performance (P = 5.54 × 10- 5) relative to PGSHL (P = 2.93 × 10- 3). PGSCIO was also associated with CIO in our test cohort (P = 0.04), while the PGSHL did not show a significant association with CIO (P = 0.52).

Conclusion: This study developed the first PGS for CIO using a large-scale hearing loss dataset and a biologically informed filter generated from cisplatin-treated murine inner ear snRNA-seq data. This innovative approach offers new avenues for developing PGSs for pharmacogenomic traits, which could contribute to the implementation of tailored therapeutic interventions. Further, our approach facilitated the identification of specific cochlear cells that may play critical roles in CIO. These novel insights will guide future research aimed at developing targeted therapeutic strategies to prevent CIO.

背景:顺铂诱导的耳毒性(CIO)是顺铂化疗的一种常见不良反应,其特征是不可逆转的进行性双侧听力损失。除临床风险因素外,遗传变异也是导致 CIO 的原因之一,而全基因组关联研究(GWAS)则强调了这种药物不良反应的多基因性。多基因评分(PGS)整合了来自全基因组多个基因变异的信息,为识别CIO高风险个体提供了一种前景广阔的工具。将大规模听力损失 GWAS 数据与单细胞 omics 数据相结合,有可能克服与 CIO 研究相关的样本量小的局限性,从而创建预测 CIO 风险的 PGS:我们利用大规模听力损失 GWAS 和小鼠内耳单核 RNA 序列(snRNA-seq)数据开发了两种多基因评分:听力损失 PGS(PGSHL)和针对 CIO 的生物知情 PGS(PGSCIO)。PGSCIO 只包含映射到在顺铂治疗后小鼠 snRNA-seq 数据中显示出不同丰度的耳蜗细胞内差异表达基因的变异。在我们的目标 CIO 队列中评估这些 PGS 与 CIO 的关联时发现,相对于 PGSHL(P = 2.93 × 10-3),PGSCIO 表现出更优越的性能(P = 5.54 × 10-5)。在我们的测试队列中,PGSCIO 与 CIO 也有关联(P = 0.04),而 PGSHL 与 CIO 没有显著关联(P = 0.52):本研究利用大规模听力损失数据集和顺铂处理的小鼠内耳 snRNA-seq 数据生成的生物信息过滤器,首次开发了针对 CIO 的 PGS。这种创新方法为开发药物基因组特征的 PGS 提供了新途径,有助于实施量身定制的治疗干预措施。此外,我们的方法还有助于鉴定可能在 CIO 中发挥关键作用的特定耳蜗细胞。这些新颖的见解将指导未来的研究,以开发预防 CIO 的靶向治疗策略。
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Human Genomics
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