High Concordance of Copy Number Variants Detected by Chromosomal Microarray and Exome Sequencing in Clinical Diagnostics.

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Rivka Birnbaum, Maya Slovik, Shamir Zenvirt, Ilana Livyatan, Israel Altman, Shiri Gershon, Jonathan Rips, Hagit Daum, Chaggai Rosenbluh, Orly Elpeleg, Vardiella Meiner, Ayala Frumkin, Hagar Mor-Shaked, Tamar Harel
{"title":"High Concordance of Copy Number Variants Detected by Chromosomal Microarray and Exome Sequencing in Clinical Diagnostics.","authors":"Rivka Birnbaum, Maya Slovik, Shamir Zenvirt, Ilana Livyatan, Israel Altman, Shiri Gershon, Jonathan Rips, Hagit Daum, Chaggai Rosenbluh, Orly Elpeleg, Vardiella Meiner, Ayala Frumkin, Hagar Mor-Shaked, Tamar Harel","doi":"10.1111/cge.70079","DOIUrl":null,"url":null,"abstract":"<p><p>Exome sequencing (ES), originally developed to detect single nucleotide variants (SNVs), has been increasingly leveraged to detect copy number variants (CNVs) through read-depth analysis, enhancing diagnostic yield with minimal computational overhead. However, chromosomal microarray (CMA) testing remains widely used. To evaluate the utility of ES as a first-tier clinical diagnostic test, we compared the sensitivity of CNV detection by ES to that of CMA in individuals who underwent both tests, and developed triploidy screening based on ES data. ES identified most clinically relevant CNVs, with a 98.91% concordance for regions adequately captured. A retrospective analysis of CNVs detected from ES over a ~3-year period, comprising 1563 prenatal and 4884 postnatal cases, revealed CNVs in 3.8% of prenatal and 4.4% of postnatal samples. The relatively low percentage stems from the fact that most cases underwent CMA before ES. Pathogenic or likely pathogenic variants constituted 78.7% and 78.0% of these subgroups, with the remainder classified as variants of unknown significance. We highlight clinically relevant examples of CNVs across a range of sizes, including cases involving both CNVs and SNVs. The high consanguinity rate of the cohort allowed for systematic analysis of homozygous CNVs. Additionally, we demonstrate that ES can capture other diagnostic utilities traditionally associated with CMA, specifically uniparental disomy (UPD) and triploidy. Overall, our findings support ES as a robust, cost-effective alternative to CMA and advocate for its broader use as a first-tier diagnostic test for neurodevelopmental delay and congenital malformations, particularly until whole genome sequencing becomes more accessible and affordable.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3000,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/cge.70079","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0

Abstract

Exome sequencing (ES), originally developed to detect single nucleotide variants (SNVs), has been increasingly leveraged to detect copy number variants (CNVs) through read-depth analysis, enhancing diagnostic yield with minimal computational overhead. However, chromosomal microarray (CMA) testing remains widely used. To evaluate the utility of ES as a first-tier clinical diagnostic test, we compared the sensitivity of CNV detection by ES to that of CMA in individuals who underwent both tests, and developed triploidy screening based on ES data. ES identified most clinically relevant CNVs, with a 98.91% concordance for regions adequately captured. A retrospective analysis of CNVs detected from ES over a ~3-year period, comprising 1563 prenatal and 4884 postnatal cases, revealed CNVs in 3.8% of prenatal and 4.4% of postnatal samples. The relatively low percentage stems from the fact that most cases underwent CMA before ES. Pathogenic or likely pathogenic variants constituted 78.7% and 78.0% of these subgroups, with the remainder classified as variants of unknown significance. We highlight clinically relevant examples of CNVs across a range of sizes, including cases involving both CNVs and SNVs. The high consanguinity rate of the cohort allowed for systematic analysis of homozygous CNVs. Additionally, we demonstrate that ES can capture other diagnostic utilities traditionally associated with CMA, specifically uniparental disomy (UPD) and triploidy. Overall, our findings support ES as a robust, cost-effective alternative to CMA and advocate for its broader use as a first-tier diagnostic test for neurodevelopmental delay and congenital malformations, particularly until whole genome sequencing becomes more accessible and affordable.

染色体微阵列和外显子组测序检测拷贝数变异在临床诊断中的高一致性
外显子组测序(ES)最初用于检测单核苷酸变异(snv),现在越来越多地用于通过读取深度分析检测拷贝数变异(cnv),以最小的计算开销提高诊断产量。然而,染色体微阵列(CMA)检测仍然被广泛使用。为了评估ES作为一级临床诊断测试的效用,我们比较了在接受这两种测试的个体中,ES和CMA检测CNV的敏感性,并基于ES数据开发了三倍体筛查。ES识别出大多数临床相关的CNVs,对于充分捕获的区域,一致性为98.91%。回顾性分析了1563例产前和4884例产后ES中检测到的CNVs,发现产前和产后CNVs分别占3.8%和4.4%。相对较低的百分比源于大多数病例在ES之前进行了CMA。致病性或可能致病性变异分别占这些亚组的78.7%和78.0%,其余的被归类为意义未知的变异。我们重点介绍了不同规模的CNVs的临床相关例子,包括CNVs和SNVs的病例。该队列的高亲缘率允许对纯合CNVs进行系统分析。此外,我们证明ES可以捕获传统上与CMA相关的其他诊断工具,特别是单亲二体(UPD)和三倍体。总的来说,我们的研究结果支持ES作为CMA的一种可靠、经济的替代方法,并提倡将其广泛用作神经发育迟缓和先天性畸形的一线诊断测试,特别是在全基因组测序变得更容易获得和负担得起之前。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信