产前诊断领域全外显子组测序的应用现况与未来展望

Current application status and future perspectives of whole exome sequencing in prenatal diagnosis

摘要

出生缺陷是婴儿死亡的主要原因和致残的关键因素,其防控受到我国政府的高度重视.作为重要的二级防控手段,产前诊断可以通过为缺陷儿的产前干预提供有效信息,来减少患儿出生带来的负担.二代测序(NGS)是一种高通量DNA测序方法,能够以低成本对基因组进行高分辨率检测,有效弥补染色体核型分析和染色体微阵列分析(CMA)的不足.其中,拷贝数变异测序(CNV-seq)已在2019年被推荐为我国产前诊断的一线遗传检测方法之一.然而,婴幼儿时期占比较高的单基因疾病主要由单碱基变异(SNVs)及小片段的插入或缺失(INDELs)引起,CNV-seq无法对其进行诊断,需要全外显子组测序(WES)深入核苷酸水平进行检测.因此,WES在产前诊断中被逐渐广泛应用.然而,受限于技术本身及基因疾病谱的全面性等问题,WES在产前诊断的应用中仍面临一定的挑战.未来,随着遗传检测技术的进步和对出生缺陷发生发展机制的深入认识,有望形成更精准地匹配临床表型和遗传检测技术的个性化诊断方式.

Abstract

Birth defects are the leading cause of infant mortality and a critical factor contributing to disability, making their prevention and control a priority for Chinese government. As a key secondary prevention measure, prenatal diagnosis could reduce burden of giving birth by providing essential information for effective prenatal interventions to defected infants. Next generation sequencing (NGS) is a high-throughput DNA sequencing method that allows cost-effective, high-resolution genome testing and effectively complement limitations of karyotyping and chromosomal microarray analysis (CMA). Copy number variant sequencing (CNV-seq) was recommended in 2019 as one of primary genetic testing methods for prenatal diagnosis in China. However, a large proportion of monogenic diseases in infants and young children are primarily caused by single nucleotide variants (SNVs) and insertions/deletions (INDELs), which cannot be diagnosed by CNV-seq. These conditions require whole exome sequencing (WES) for comprehensive testing at the nucleotide level. As a result, WES has been increasingly applied in prenatal diagnosis. Nevertheless, the application of WES in prenatal diagnosis still faces certain challenges due to limitations of the technology itself and comprehensiveness of the gene-disease spectrum. In the future, as genetic testing technology advances and our understanding of the mechanisms underlying occurrence and development of birth defects deepens, a personalized diagnostic approach is expected to be developed. This diagnostic approach will more accurately match clinical phenotypes with genetic testing technologies.

关键词

出生缺陷 / 产前诊断 / 二代测序 / 全外显子组测序 / 无创产前检测

Key words

birth defect / prenatal diagnosis / next generation sequencing / whole exome sequencing / non-invasive prenatal testing

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基金资助

国家自然科学基金资助项目(81602295)

陕西省重点研发计划项目(2023GYBSFG232)