新型胎儿游离核酸多维整合分析技术揭示染色体非整倍体发生机制与临床应用

目前产前无创筛查（NIPS）技术仅用于常见染色体非整倍体及部分染色体微小缺失/重复疾病的筛查。本课题利用一种自主研发的新型NIPS技术采用协同等位基因靶标富集的方法，降低捕获探针对基因组范围内等位基因座内和不同基因座之间液相杂交动力学偏差，大幅提高对目标区域捕获均一性和效率。通过二代测序对捕获的目标区母源和胎源性单核苷酸多态性基因型进行定量分析和贝叶斯统计方法将游离DNA的多项检测指标与不同疾病风险因素进行多维整合分析，实现对不同亲本来源、不同染色体片段大小及不同细胞遗传学机制的染色体变异进行多方位解析。该技术不仅可同时检测胎儿染色体非整倍体、微小缺失/重复、多倍体、母源性染色体疾病等还将产生此前全基因组测序（WGS）无法提供的人群母子等位基因座的分型数据。运用这些数据我们进行了染色体非整倍体产生的亲源性细胞遗传学机制研究，为复杂妊娠的遗传咨询和综合防治提供基于重要基础数据与理论支持。

The discovery of circulating fetal cell-free DNA in maternal blood enabled non-invasive prenatal screening (NIPS) for human genetic diseases. Although proven effective, current NIPS is mostly used for common chromosome aneuploidies/microdeletion or duplication syndromes. Here we described a novel strategy that utilizes multidimensional integration analysis to deconvolute fetal genome from maternal plasma for the detection of fetal chromosomal defects. Next-generation sequencing was used to analyze targeted region followed by quantification of fetal fraction adjusted for cell-free DNA (cfDNA) fragment lengths, allele ratios of single-nucleotide polymorphisms (SNPs). Such cfDNA-based measurements were then integrated with disease risk factors including maternal genotype as well as plausible disease transmission/occurrence modes by a Bayesian statistical method. This multidimensional integration analysis facilitated a comprehensive assessment of individual mother/fetus pair for their risks of all known chromosomal disorders. Overall, this study demonstrated a major advance over current NIPS methods which allows a highly accurate and comprehensive prenatal risk assessment for essentially all categories of known human chromosomal diseases.