无创产前检测的临床研究新进展：从非整倍体到单基因病的全面筛查

New Advances in Clinical Research of Non-Invasive Prenatal Testing: Comprehensive Screening from Aneuploidy to Monogenic Diseases

摘要: 无创产前检测(NIPT)自其概念诞生以来，已彻底改变了产前筛查的格局，带领这一领域进入了一个新的时代。其技术核心是对母体外周血中循环的细胞游离DNA (cfDNA)进行高通量测序与生物信息学分析，以实现对胎儿遗传物质变异的精准、无创筛查。历经十余年的飞速发展，NIPT的应用范围已从最初的染色体非整倍体(如T21、T18、T13)扩展至性染色体非整倍体(SCA)、微缺失/微重复综合征(即NIPT-plus)，并朝着无创检测孟德尔单基因遗传病(NIPT 2.0)的目标迈进。这些突破性进展不仅得益于测序成本的指数级下降，更依赖于生物信息学算法的日益精进以及对cfDNA生物学特性(如片段组学)的深刻理解。本文旨在系统回顾NIPT的技术起源与核心原理，详细阐述其从基础到前沿的临床应用范围扩展，重点深度分析NIPT-plus与NIPT 2.0的最新研究进展、临床价值与实施挑战，并对其未来的发展方向，如多组学整合、人工智能应用及从筛查到诊断的范式转变，进行全面的展望与探讨。

Abstract: Since its concept was born, non-invasive prenatal testing (NIPT) has completely transformed the landscape of prenatal screening and led this field into a new era. The core of its technology lies in conducting high-throughput sequencing and bioinformatics analysis on the circulating cell-free DNA (cfDNA) in maternal peripheral blood to achieve accurate and non-invasive screening for genetic material variations in the fetus. After more than ten years of rapid development, the application scope of NIPT has expanded from the initial chromosomal aneuploidy (such as T21, T18, T13) to sex chromosome aneuploidy (SCA), microdeletion/microduplication syndrome (i.e., NIPT-PLUS), and is moving towards the goal of non-invasive detection of Mendel single-gene genetic diseases (NIPT 2.0). These breakthroughs are not only attributed to the exponential decline in sequencing costs, but also rely on the continuous improvement of bioinformatics algorithms and a profound understanding of the biological characteristics of cfDNA, such as fragment omics. This article aims to systematically review the technical origin and core principles of NIPT, elaborate in detail on the expansion of its clinical application scope from the basic to the frontier, focus on in-depth analysis of the latest research progress, clinical value and implementation challenges of NIPT-Plus and NIPT 2.0, and discuss its future development direction. In addition, its future development directions, such as the integration of multi-omics, the application of artificial intelligence and the paradigm shift from screening to diagnosis, are comprehensively prospected and discussed.