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From the Perspective of the Child: Ethical Considerations for the Implementation of Genomic Sequencing into Neonatal and Pediatric Care. 从儿童的角度:在新生儿和儿科护理中实施基因组测序的伦理考虑。
IF 7.1 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2025-01-03 DOI: 10.1093/clinchem/hvae112
Jill L Maron, Sharon F Terry
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引用次数: 0
Structural Variation Interpretation in the Genome Sequencing Era: Lessons from Cytogenetics. 基因组测序时代的结构变异解释:来自细胞遗传学的教训。
IF 7.1 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2025-01-03 DOI: 10.1093/clinchem/hvae186
Lucilla Pizzo, M Katharine Rudd

Background: Structural variation (SV), defined as balanced and unbalanced chromosomal rearrangements >1 kb, is a major contributor to germline and neoplastic disease. Large variants have historically been evaluated by chromosome analysis and now are commonly recognized by chromosomal microarray analysis (CMA). The increasing application of genome sequencing (GS) in the clinic and the relatively high incidence of chromosomal abnormalities in sick newborns and children highlights the need for accurate SV interpretation and reporting. In this review, we describe SV patterns of common cytogenetic abnormalities for laboratorians who review GS data.

Content: GS has the potential to detect diverse chromosomal abnormalities and sequence breakpoint junctions to clarify variant structure. No single GS analysis pipeline can detect all SV, and visualization of sequence data is crucial to recognize specific patterns. Here we describe genomic signatures of translocations, inverted duplications adjacent to terminal deletions, recombinant chromosomes, marker chromosomes, ring chromosomes, isodicentric and isochromosomes, and mosaic aneuploidy. Distinguishing these more complex abnormalities from simple deletions and duplications is critical for phenotypic interpretation and recurrence risk recommendations.

Summary: Unlike single-nucleotide variant calling, identification of chromosome rearrangements by GS requires further processing and multiple callers. SV databases have caveats and limitations depending on the platform (CMA vs sequencing) and resolution (exome vs genome). In the rapidly evolving era of clinical genomics, where a single test can identify both sequence and structural variants, optimal patient care stems from the integration of molecular and cytogenetic expertise.

背景:结构变异(SV),定义为平衡和不平衡的染色体重排bbb1kb,是生殖系和肿瘤疾病的主要因素。大变异过去是通过染色体分析来评估的,现在通常通过染色体微阵列分析(CMA)来识别。基因组测序(GS)在临床中的应用越来越多,患病新生儿和儿童中染色体异常的发生率相对较高,这突出了准确解释和报告SV的必要性。在这篇综述中,我们描述了SV模式的常见细胞遗传学异常的实验室人员谁审查GS数据。内容:GS具有检测各种染色体异常和序列断点连接点以阐明变异结构的潜力。没有一个单一的GS分析管道可以检测到所有的SV,序列数据的可视化对于识别特定模式至关重要。在这里,我们描述了易位、末端缺失附近的反向复制、重组染色体、标记染色体、环染色体、等心和同工染色体以及马赛克非整倍体的基因组特征。区分这些更复杂的异常与简单的缺失和重复对于表型解释和复发风险建议至关重要。摘要:与单核苷酸变异召唤不同,GS对染色体重排的识别需要进一步的处理和多个呼叫者。根据平台(CMA vs测序)和分辨率(外显子组vs基因组),SV数据库有一些警告和限制。在快速发展的临床基因组学时代,一个单一的测试可以识别序列和结构变异,最佳的病人护理源于分子和细胞遗传学专业知识的整合。
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引用次数: 0
DNA Sequencing in Newborn Screening: Opportunities, Challenges, and Future Directions. 新生儿筛查中的DNA测序:机遇、挑战和未来方向。
IF 7.1 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2025-01-03 DOI: 10.1093/clinchem/hvae180
Médéric Jeanne, Wendy K Chung

Background: Newborn screening is a public health system designed to identify infants at risk for conditions early in life to facilitate timely intervention and treatment to prevent or mitigate adverse health outcomes. Newborn screening programs use tandem mass spectrometry as a platform to detect several treatable inborn errors of metabolism, and the T-cell receptor excision circle assay to detect some inborn errors of the immune system. Recent advancements in DNA sequencing have decreased the cost of sequencing and allow us to consider DNA sequencing as an additional platform to complement other newborn screening methods.

Content: This review provides an overview of DNA-based newborn screening, including its applications, opportunities, challenges, and future directions. We discuss the potential benefits of expanded DNA sequencing in newborn screening, such as expanding conditions screened and improved specificity and sensitivity of currently screened conditions. Additionally, we examine the ethical, legal, and social implications of implementing genomic sequencing in newborn screening programs, including issues related to consent, privacy, equity, data interpretation, scalability, and psychosocial impact on families. Additionally, we explore emerging strategies for addressing current limitations and advancing the field of newborn screening.

Summary: DNA sequencing in newborn screening has the potential to improve the diagnosis and management of rare diseases but also presents significant challenges that need to be addressed before implementation at the population level.

背景:新生儿筛查是一种公共卫生系统,旨在早期发现有患病风险的婴儿,以便及时干预和治疗,预防或减轻不良健康后果。新生儿筛查项目使用串联质谱作为平台,检测几种可治疗的先天性代谢错误,并使用 T 细胞受体切除圈检测法检测一些先天性免疫系统错误。DNA 测序技术的最新进展降低了测序成本,使我们可以考虑将 DNA 测序作为补充其他新生儿筛查方法的另一个平台:本综述概述了基于 DNA 的新生儿筛查,包括其应用、机遇、挑战和未来发展方向。我们讨论了扩大 DNA 测序在新生儿筛查中的潜在益处,如扩大筛查条件、提高目前筛查条件的特异性和灵敏度。此外,我们还探讨了在新生儿筛查项目中实施基因组测序的伦理、法律和社会影响,包括与同意、隐私、公平、数据解读、可扩展性和对家庭的社会心理影响有关的问题。此外,我们还探讨了解决目前局限性和推动新生儿筛查领域发展的新兴策略。摘要:新生儿筛查中的 DNA 测序有可能改善罕见病的诊断和管理,但也带来了巨大的挑战,需要在人群层面实施之前加以解决。
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引用次数: 0
Virus Evolution in Prolonged Infections of Immunocompromised Individuals. 免疫功能低下个体长期感染中的病毒进化
IF 7.1 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2025-01-03 DOI: 10.1093/clinchem/hvae150
Zoe Raglow, Adam S Lauring

Background: Many viruses can cause persistent infection and/or viral shedding in immunocompromised hosts. This is a well-described occurrence not only with SARS-CoV-2 but for many other viruses as well. Understanding how viruses evolve and mutate in these patients and the global impact of this phenomenon is critical as the immunocompromised population expands.

Content: In this review, we provide an overview of populations at risk for prolonged viral shedding, clinical manifestations of persistent viral infection, and methods of assessing viral evolution. We then review the literature on viral evolution in immunocompromised patients across an array of RNA viruses, including SARS-CoV-2, norovirus, influenza, and poliovirus, and discuss the global implications of persistent viral infections in these hosts.

Summary: There is significant evidence for accelerated viral evolution and accumulation of mutations in antigenic sites in immunocompromised hosts across many viral pathogens. However, the implications of this phenomenon are not clear; while there are rare reports of transmission of these variants, they have not clearly been shown to predict disease outbreaks or have significant global relevance. Emerging methods including wastewater monitoring may provide a more sophisticated understanding of the impact of variants that evolve in immunocompromised hosts on the wider host population.

背景:许多病毒可导致免疫力低下的宿主持续感染和/或病毒脱落。不仅 SARS-CoV-2 会出现这种情况,许多其他病毒也会出现这种情况。随着免疫力低下人群的扩大,了解病毒如何在这些患者体内进化和变异以及这种现象的全球影响至关重要:在这篇综述中,我们概述了病毒长期脱落的高危人群、持续病毒感染的临床表现以及评估病毒进化的方法。然后,我们回顾了一系列 RNA 病毒(包括 SARS-CoV-2、诺如病毒、流感和脊髓灰质炎病毒)在免疫力低下患者中病毒进化的文献,并讨论了这些宿主中持续病毒感染的全球影响。摘要:有大量证据表明,在许多病毒病原体中,免疫力低下宿主中的病毒进化加速,抗原位点的突变累积。然而,这一现象的影响尚不明确;虽然有关于这些变异体传播的罕见报道,但尚未明确表明它们可预测疾病爆发或具有重大的全球意义。包括废水监测在内的新兴方法可能会让人们更深入地了解在免疫力低下的宿主中演变的变异体对更广泛的宿主群体的影响。
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引用次数: 0
Diagnostic Odyssey in a Child with Red-Colored Urine and Proteinuria. 儿童红色尿和蛋白尿的诊断奥德赛。
IF 7.1 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2025-01-03 DOI: 10.1093/clinchem/hvae090
Brianna Guarino, Adam S Ptolemy, Michelle A Baum, Melinda J Palma, Mark D Kellogg, Roy W A Peake
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引用次数: 0
Polygenic Risk Scores in Human Disease. 人类疾病的多基因风险评分。
IF 7.1 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2025-01-03 DOI: 10.1093/clinchem/hvae190
Dimitri J Maamari, Roukoz Abou-Karam, Akl C Fahed

Background: Polygenic risk scores (PRS) are measures of genetic susceptibility to human health traits. With the advent of large data repositories combining genetic data and phenotypic information, PRS are providing valuable insights into the genetic architecture of complex diseases and are transforming the landscape of precision medicine.

Content: PRS have emerged as tools with clinical utility in human disease. Herein, details on how to develop PRS are provided, followed by 5 areas in which they can be used to improve human health: (a) augmenting risk prediction, (b) refining diagnosis, (c) guiding treatment choices, (d) making clinical trials more efficient, and (e) improving public health. Finally, some of the ongoing challenges to the clinical implementation of PRS are noted.

Summary: PRS can offer valuable information for providers and patients, including identifying risk of disease earlier in life and before the onset of clinical risk factors, guiding treatment decisions, improving public health outcomes, and making clinical trials more efficient. The future of genomic-informed risk assessments of disease is through integrated risk models that combine genetic factors including PRS, monogenic, and somatic DNA information with nongenetic risk factors such as clinical risk estimators and multiomic data. However, adopting PRS in a clinical setting at scale faces some challenges, including cross-ancestry performance, standardization and calibration of risk models, downstream clinical decision-making from risk information, and seamless integration into existing health systems.

背景:多基因风险评分(PRS)是衡量人类健康性状遗传易感性的指标。随着结合遗传数据和表型信息的大型数据存储库的出现,PRS正在为复杂疾病的遗传结构提供有价值的见解,并正在改变精准医学的格局。PRS已成为人类疾病临床应用的工具。本文详细介绍了如何发展PRS,然后介绍了它们可用于改善人类健康的5个领域:(a)增强风险预测,(b)改进诊断,(c)指导治疗选择,(d)提高临床试验效率,以及(e)改善公共卫生。最后,指出了临床实施PRS的一些持续挑战。摘要:PRS可以为提供者和患者提供有价值的信息,包括在生命早期和临床风险因素发生之前识别疾病风险,指导治疗决策,改善公共卫生结果,并使临床试验更有效。基于基因组的疾病风险评估的未来是通过综合风险模型,将遗传因素(包括PRS、单基因和体细胞DNA信息)与非遗传风险因素(如临床风险估计值和多组数据)结合起来。然而,在临床环境中大规模采用PRS面临着一些挑战,包括跨祖先绩效、风险模型的标准化和校准、基于风险信息的下游临床决策以及与现有卫生系统的无缝集成。
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引用次数: 0
Commentary on Diagnostic Odyssey in a Child with Red-Colored Urine and Proteinuria. 红色尿和蛋白尿儿童诊断的奥德赛评论。
IF 7.1 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2025-01-03 DOI: 10.1093/clinchem/hvae085
Marcus J Miller
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引用次数: 0
Detection of Clinically Relevant Monogenic Copy-Number Variants by a Comprehensive Genome-Wide Microarray with Exonic Coverage. 用外显子覆盖的全基因组微阵列检测临床相关的单基因拷贝数变异。
IF 7.1 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2025-01-03 DOI: 10.1093/clinchem/hvae188
Matthew Hoi Kin Chau, Stephanie A Anderson, Rodger Song, Lance Cooper, Patricia A Ward, Bo Yuan, Chad Shaw, Paweł Stankiewicz, Sau Wai Cheung, Liesbeth Vossaert, Yue Wang, Nichole M Owen, Janice Smith, Carlos A Bacino, Katharina V Schulze, Weimin Bi

Background: Disease-causing copy-number variants (CNVs) often encompass contiguous genes and can be detected using chromosomal microarray analysis (CMA). Conversely, CNVs affecting single disease-causing genes have historically been challenging to detect due to their small sizes.

Methods: A custom comprehensive CMA (Baylor College of Medicine - BCM v11.2) containing 400k probes and featuring exonic coverage for >4200 known or candidate disease-causing genes was utilized for the detection of CNVs at single-exon resolution. CMA results across a consecutive clinical cohort of more than 13 000 patients referred for genetic investigation at Baylor Genetics were examined. The genomic characteristics of CNVs impacting single protein-coding genes were investigated.

Results: Pathogenic or likely pathogenic (P/LP) CNVs (n = 190) affecting single protein-coding genes were detected in 188 patients, accounting for 9.9% (188/1894) of patients with P/LP CMA findings. The P/LP monogenic CNVs accounted for 9.2% (190/2058) of all P/LP nuclear CNVs detected by CMA. A total of 57.9% (110/190) of P/LP monogenic CNVs were smaller than 50 kb in size. Single exons were affected by 26.3% (50/190) of P/LP monogenic CNVs while 13.2% (25/190) affected 2 exons. CNVs were detected across 107 unique genes associated with predominantly autosomal dominant (AD) and X-linked (XL) conditions but also contributed to autosomal recessive (AR) conditions.

Conclusions: CMA with exon-targeted coverage of disease-associated genes facilitated the detection of small CNVs affecting single protein-coding genes, adding substantial clinical sensitivity to comprehensive CNV investigation. This approach resolved monogenic CNVs associated with autosomal and X-linked monogenic etiologies and yielded multiple significant findings. Monogenic CNVs represent an underrecognized subset of disease-causing alleles for Mendelian disorders.

背景:致病拷贝数变异(CNVs)通常包含连续基因,可以使用染色体微阵列分析(CMA)检测。相反,影响单个致病基因的CNVs由于体积小,历来难以检测。方法:使用定制的综合CMA (Baylor College of Medicine - BCM v11.2),包含400k个探针,具有bb104200个已知或候选致病基因的外显子覆盖率,用于单外显子分辨率检测CNVs。对在贝勒遗传学中心接受遗传调查的13000多名患者的连续临床队列的CMA结果进行了检查。研究了影响单蛋白编码基因的CNVs的基因组特征。结果:188例患者中检测到影响单个蛋白编码基因的致病性或可能致病性(P/LP) CNVs (n = 190),占P/LP CMA患者的9.9%(188/1894)。在CMA检测到的所有P/LP核CNVs中,P/LP单基因CNVs占9.2%(190/2058)。共有57.9%(110/190)的P/LP单基因CNVs的大小小于50 kb。P/LP单基因CNVs受单外显子影响的占26.3%(50/190),受2外显子影响的占13.2%(25/190)。在107个与常染色体显性显性(AD)和x连锁(XL)疾病相关的独特基因中检测到CNVs,但也与常染色体隐性(AR)疾病相关。结论:外显子靶向覆盖疾病相关基因的CMA有助于检测影响单个蛋白质编码基因的小CNV,为全面的CNV研究增加了实质性的临床敏感性。该方法解决了与常染色体和x连锁单基因病因相关的单基因CNVs,并产生了多个重要发现。单基因CNVs代表了孟德尔疾病致病等位基因的一个未被充分认识的子集。
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引用次数: 0
Integrating Pharmacogenomics into the Broader Construct of Genomic Medicine: Efforts by the ClinGen Pharmacogenomics Working Group (PGxWG). 将药物基因组学整合到更广泛的基因组医学构建中:ClinGen药物基因组学工作组(PGxWG)的努力。
IF 7.1 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2025-01-03 DOI: 10.1093/clinchem/hvae181
Li Gong, Clarissa J Klein, Kelly E Caudle, Ann M Moyer, Stuart A Scott, Michelle Whirl-Carrillo, Teri E Klein

Pharmacogenomics (PGx) is focused on the relationship between an individual's genetic makeup and their response to medications, with the overarching aim of guiding prescribing decisions to improve drug efficacy and reduce adverse events. The PGx and genomic medicine communities have worked independently for over 2 decades, developing separate standards and terminology, making implementation of PGx across all areas of genomic medicine difficult. To address this issue, the Clinical Genome Resource (ClinGen) Pharmacogenomics Working Group (PGxWG) was established by the National Institutes of Health (NIH)-funded ClinGen to initially create frameworks for evaluating gene-drug response clinical validity and actionability aligned with the ClinGen frameworks for evaluating monogenic gene-disease relationships, and a framework for classifying germline PGx variants similar to the American College of Medical Genetics (ACMG) and Association of Molecular Pathology (AMP) system for interpretation of disease-causing variants. These frameworks will leverage decades of work from well-established PGx resources facilitating buy-in among PGx stakeholders. In this report, we describe the background and major activities of the ClinGen PGxWG, and how this initiative will facilitate the critical inclusion of PGx into the larger context of genomic medicine.

药物基因组学(PGx)专注于研究个体基因组成与其对药物反应之间的关系,其总体目标是指导处方决策,以提高药物疗效并减少不良事件。PGx和基因组医学社区已经独立工作了20多年,制定了单独的标准和术语,使PGx在基因组医学的所有领域的实施变得困难。为了解决这一问题,临床基因组资源(ClinGen)药物基因组学工作组(PGxWG)由美国国立卫生研究院(NIH)资助的ClinGen成立,旨在初步创建评估基因-药物反应、临床有效性和可操作性的框架,与评估单基因基因-疾病关系的ClinGen框架保持一致。与美国医学遗传学学院(ACMG)和分子病理学协会(AMP)解释致病变异的系统相似的种系PGx变异分类框架。这些框架将利用数十年来完善的PGx资源,促进PGx利益相关者的参与。在本报告中,我们描述了ClinGen PGxWG的背景和主要活动,以及这一倡议将如何促进PGx进入更大的基因组医学背景。
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引用次数: 0
Low-Pass Whole Genome Sequencing of Cell-Free DNA from Cerebrospinal Fluid: A Focus on Pediatric Central Nervous System Tumors. 脑脊液无细胞DNA的低通全基因组测序:儿童中枢神经系统肿瘤的焦点。
IF 7.1 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pub Date : 2025-01-03 DOI: 10.1093/clinchem/hvae140
Katrina O'Halloran, Eirini Christodoulou, Vera A Paulson, Bonnie L Cole, Ashley S Margol, Jaclyn A Biegel, Sarah E S Leary, Christina M Lockwood, Erin E Crotty

Background: Cell-free DNA (cfDNA) technology has allowed for cerebrospinal fluid (CSF), a previously underutilized biofluid, to be analyzed in new ways. The interrogation of CSF-derived cfDNA is giving rise to novel molecular insights, particularly in pediatric central nervous system (CNS) tumors, where invasive tumor tissue acquisition may be challenging. Contemporary disease monitoring is currently restricted to radiographic surveillance by magnetic resonance imaging and CSF cytology to directly detect abnormal cells and cell clusters. Alternatively, cfDNA is often present in the CSF from pediatric patients with both malignant and nonmalignant CNS tumors and can be accessed by minimally invasive lumbar puncture and other CSF-liberating procedures, offering a promising alternative for longitudinal molecular disease analysis and surveillance.

Content: This review explores the use of low-pass whole genome sequencing (LP-WGS) to analyze cfDNA from the CSF of pediatric patients with CNS tumors. This platform is uniquely poised for the detection of tumors harboring copy number variants, which are prevalent in this population. The utility and sensitivity of LP-WGS as a clinical tool is explored and discussed in the context of alternative CSF liquid biopsy interrogation modalities, including nanopore sequencing and methylation array.

Summary: Analysis of CSF-derived cfDNA by LP-WGS has broad diagnostic, prognostic, and clinical implications for pediatric patients with CNS tumors. Careful interpretation of LP-WGS results may aid in therapeutic targeting of pediatric CNS tumors and may provide insight into tumor heterogeneity and evolution over time, without the need for invasive and potentially risky tissue sampling.

背景:无细胞DNA (cfDNA)技术允许以新的方式分析脑脊液(CSF),这是一种以前未充分利用的生物流体。对csf衍生的cfDNA的研究正在产生新的分子见解,特别是在儿童中枢神经系统(CNS)肿瘤中,在这些肿瘤组织的侵入性获取可能具有挑战性。当代疾病监测目前仅限于通过磁共振成像和脑脊液细胞学进行放射学监测,直接检测异常细胞和细胞簇。另外,cfDNA通常存在于患有恶性和非恶性中枢神经系统肿瘤的儿童患者的脑脊液中,可以通过微创腰椎穿刺和其他释放脑脊液的手术获得,为纵向分子疾病分析和监测提供了一个有希望的替代方案。内容:本文探讨了利用低通全基因组测序(LP-WGS)分析小儿中枢神经系统肿瘤患者脑脊液cfDNA的方法。这个平台是唯一的准备为检测肿瘤窝藏拷贝数变异,这是普遍存在于这一人群。LP-WGS作为临床工具的实用性和敏感性在替代脑脊液活检询问方式的背景下进行了探索和讨论,包括纳米孔测序和甲基化阵列。摘要:通过LP-WGS分析csf来源的cfDNA对小儿中枢神经系统肿瘤患者具有广泛的诊断、预后和临床意义。仔细解释LP-WGS结果可能有助于儿科中枢神经系统肿瘤的治疗靶向,并可能提供肿瘤异质性和随时间演变的见解,而无需侵入性和潜在风险的组织采样。
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引用次数: 0
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Clinical chemistry
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