基于相对单倍型剂量变化的隐性单基因遗传病无创产前诊断的应用价值  

Application value of non-invasive prenatal diagnosis for recessive monogenic genetic diseases based on relative haplotype dosage changes

作　　者：李焕云 赵振华[1] 孔令蓉 付欣雨 朱静琦 吴世彤 孙路明 孔祥东[1] Li Huanyun;Zhao Zhenhua;Kong Lingrong;Fu Xinyu;Zhu Jingqi;Wu Shitong;Sun Luming;Kong Xiangdong(Genetic and Prenatal Diagnosis Center,Department of Obstetrics and Gynecology,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450000,China)

机构地区：[1]郑州大学第一附属医院遗传与产前诊断中心,郑州450000 [2]同济大学医学院附属第一妇婴保健院胎儿医学科及产前诊断中心,上海201204

出　　处：《中华医学杂志》2025年第6期459-464,共6页National Medical Journal of China

基　　金：河南省高等学校重点科研项目(25B320006)。

摘　　要：目的探讨基于相对单倍型剂量变化(RHDO)结合贝叶斯因子(BF)算法在孕早期进行隐性单基因遗传病无创产前诊断(NIPD-M)的价值。方法前瞻性收集2022年9月至2023年11月就诊于郑州大学第一附属医院的206个隐性遗传病高风险孕妇家系数据,提取孕妇外周血细胞游离DNA(cfDNA)以及家系基因组(gDNA),针对DMD、SMN1、PAH、MMACHC、MMUT、F8、F9、SLC26A4、GJB2、CYP21A2共10个基因进行NIPD-M。通过靶向测序,筛选信息性单核苷酸多态性(SNP)位点并构建致病单倍型,根据RHDO计算胎儿继承致病单倍型的BF值,应用环状二元切割算法排除重组事件对结果的干扰,通过质控后得到准确NIPD-M结果,经侵入性产前诊断(IPD)或新生儿基因诊断进行验证。结果纳入206个单基因病高风险家系,孕妇年龄[M(Q 1,Q 3)]32(27,38)岁,采血孕周8+2(8,9+2)周,胎儿分数(FF)5.21%(3.56%,7.64%)。190例检测成功,16例检测失败,成功率为92.2%(190/206)。IPD或新生儿基因诊断结果与NIPD-M结果一致,准确率为100%(190/190)。结论基于RHDO的NIPD-M为隐性单基因遗传病高风险孕妇提供了一种早期、安全、可靠的产前诊断手段。ObjectiveTo explore the value of noninvasive prenatal diagnosis for monogenic disorders(NIPD-M)based on relative haplotype dosage(RHDO)and Bayes factor(BF)for pregnant women with high-risk recessive genetic disease in the first trimester.MethodsA total of 206 pregnant women with high-risk recessive genetic disease and pedigree samples at the First Affiliated Hospital of Zhengzhou University between September 2022 and November 2023 were collected.The cell-free DNA(cfDNA)was extracted from the pregnant woman′s plasma and the genomic DNA(gDNA)was extracted from the pedigree blood samples.The designed capture panel covered 10 genes(DMD,SMN1,PAH,MMACHC,MMUT,F8,F9,SLC26A4,GJB2,CYP21A2).Sequencing of target regions was performed through high-throughput sequencing platforms,informative single nucleotide polymorphism(SNP)was screened,and pathogenic haplotypes were constructed.The fetal genotype was determined based on the dose change of the informative SNPs in cfDNA combined with the BF algorithm.The circular binary segmentation(CBS)algorithm was used to exclude the interference of recombination events.All NIPD-M results were validated by invasive prenatal diagnosis or newborn genetic testing.ResultsAmong the recruited families,the median(Q 1,Q 3)age of the 206 pregnant women was 32(27,38)years,and the earliest blood collection was at 7 weeks of pregnancy,with the median(Q 1,Q 3)blood collection time of 8+2(8,9+2)weeks and fetal fraction(FF)of 5.21%(3.56%,7.64%).A total of 190 cases were successfully tested,while 16 failed the test,with a success rate of 92.2%(190/206).The NIPD-M results were consistent with the invasive prenatal diagnosis and newborn genetic testing,with the accuracy rate of 100%(190/190).ConclusionNIPD-M provides an earlier and safer means of prenatal diagnosis for high-risk pregnant women with recessive genetic diseases,with high accuracy and rapid response.

关 键 词：产前诊断 单倍型 贝叶斯因子 胎儿 单基因隐性遗传病 

分 类 号：R714.5[医药卫生—妇产科学]