Pub Date : 2025-01-03DOI: 10.1093/clinchem/hvae112
Jill L Maron, Sharon F Terry
{"title":"From the Perspective of the Child: Ethical Considerations for the Implementation of Genomic Sequencing into Neonatal and Pediatric Care.","authors":"Jill L Maron, Sharon F Terry","doi":"10.1093/clinchem/hvae112","DOIUrl":"https://doi.org/10.1093/clinchem/hvae112","url":null,"abstract":"","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"18-20"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-03DOI: 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.
{"title":"Structural Variation Interpretation in the Genome Sequencing Era: Lessons from Cytogenetics.","authors":"Lucilla Pizzo, M Katharine Rudd","doi":"10.1093/clinchem/hvae186","DOIUrl":"https://doi.org/10.1093/clinchem/hvae186","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Content: </strong>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.</p><p><strong>Summary: </strong>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.</p>","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"119-128"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-03DOI: 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。
{"title":"DNA Sequencing in Newborn Screening: Opportunities, Challenges, and Future Directions.","authors":"Médéric Jeanne, Wendy K Chung","doi":"10.1093/clinchem/hvae180","DOIUrl":"https://doi.org/10.1093/clinchem/hvae180","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Content: </strong>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.</p><p><strong>Summary: </strong>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.</p>","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"77-86"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-03DOI: 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.
{"title":"Virus Evolution in Prolonged Infections of Immunocompromised Individuals.","authors":"Zoe Raglow, Adam S Lauring","doi":"10.1093/clinchem/hvae150","DOIUrl":"10.1093/clinchem/hvae150","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Content: </strong>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.</p><p><strong>Summary: </strong>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.</p>","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"109-118"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-03DOI: 10.1093/clinchem/hvae090
Brianna Guarino, Adam S Ptolemy, Michelle A Baum, Melinda J Palma, Mark D Kellogg, Roy W A Peake
{"title":"Diagnostic Odyssey in a Child with Red-Colored Urine and Proteinuria.","authors":"Brianna Guarino, Adam S Ptolemy, Michelle A Baum, Melinda J Palma, Mark D Kellogg, Roy W A Peake","doi":"10.1093/clinchem/hvae090","DOIUrl":"https://doi.org/10.1093/clinchem/hvae090","url":null,"abstract":"","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"31-34"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-03DOI: 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.
{"title":"Polygenic Risk Scores in Human Disease.","authors":"Dimitri J Maamari, Roukoz Abou-Karam, Akl C Fahed","doi":"10.1093/clinchem/hvae190","DOIUrl":"https://doi.org/10.1093/clinchem/hvae190","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Content: </strong>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.</p><p><strong>Summary: </strong>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.</p>","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"69-76"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-03DOI: 10.1093/clinchem/hvae085
Marcus J Miller
{"title":"Commentary on Diagnostic Odyssey in a Child with Red-Colored Urine and Proteinuria.","authors":"Marcus J Miller","doi":"10.1093/clinchem/hvae085","DOIUrl":"https://doi.org/10.1093/clinchem/hvae085","url":null,"abstract":"","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"34-35"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-03DOI: 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。
{"title":"Detection of Clinically Relevant Monogenic Copy-Number Variants by a Comprehensive Genome-Wide Microarray with Exonic Coverage.","authors":"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","doi":"10.1093/clinchem/hvae188","DOIUrl":"https://doi.org/10.1093/clinchem/hvae188","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"141-154"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-03DOI: 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.
{"title":"Integrating Pharmacogenomics into the Broader Construct of Genomic Medicine: Efforts by the ClinGen Pharmacogenomics Working Group (PGxWG).","authors":"Li Gong, Clarissa J Klein, Kelly E Caudle, Ann M Moyer, Stuart A Scott, Michelle Whirl-Carrillo, Teri E Klein","doi":"10.1093/clinchem/hvae181","DOIUrl":"10.1093/clinchem/hvae181","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"36-44"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-03DOI: 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.
{"title":"Low-Pass Whole Genome Sequencing of Cell-Free DNA from Cerebrospinal Fluid: A Focus on Pediatric Central Nervous System Tumors.","authors":"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","doi":"10.1093/clinchem/hvae140","DOIUrl":"https://doi.org/10.1093/clinchem/hvae140","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Content: </strong>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.</p><p><strong>Summary: </strong>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.</p>","PeriodicalId":10690,"journal":{"name":"Clinical chemistry","volume":"71 1","pages":"87-96"},"PeriodicalIF":7.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}