Bianchi Diana W
Section on Prenatal Genomics and Fetal Therapy, Medical Genetics Branch, National Human Genome Research Institute, and Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
Am J Med Genet C Semin Med Genet. 2019 Jan 31. doi: 10.1002/ajmg.c.31675.
In some parts of the world, prenatal screening using analysis of circulating cell-free (cf) DNA in the plasma of pregnant women has become part of routine prenatal care with limited professional guidelines and without significant input from the Turner syndrome community. In contrast to the very high positive predictive values (PPVs) achieved with cfDNA analysis for trisomy 21 (91% for high-risk and 82% for low-risk cases), the PPVs for monosomy X are much lower (~26%). This is because the maternal plasma sample contains both maternal cfDNA and placental DNA, which is a proxy for the fetal genome. Underlying biological mechanisms for false positive monosomy X screening results include confined placental mosaicism, co-twin demise, and maternal mosaicism. Somatic loss of a single X chromosome in the mother is a natural phenomenon that occurs with aging; this could explain many of the false positive cfDNA results. There is also increased awareness of women who have constitutional mosaicism for 45, X who are fertile. It is important to recognize that a positive cfDNA screen for 45, X does not mean that the fetus has Turner syndrome. A follow-up diagnostic test, either amniocentesis or neonatal karyotype/chromosome microarray, is recommended. Research studies on cell-free mRNA in second trimester amniotic fluid, which is almost exclusively fetal, demonstrate consistent dysregulation of genes involved in the hematologic, immune, and neurologic systems. This suggests that some of the pathophysiology of Turner syndrome occurs early in fetal life and presents novel opportunities for consideration of antenatal treatments.
在世界上的一些地区，通过分析孕妇血浆中循环游离（cf）DNA进行产前筛查已成为常规产前护理的一部分，但专业指南有限，且特纳综合征患者群体的参与度不高。与cfDNA分析对21三体综合征所取得的非常高的阳性预测值（PPV，高危病例为91%，低危病例为82%）相比，X单体型的PPV要低得多（约26%）。这是因为母体血浆样本中既含有母体cfDNA，也含有胎盘DNA，后者可替代胎儿基因组。X单体型筛查结果出现假阳性的潜在生物学机制包括局限型胎盘嵌合体、双胎之一死亡和母体嵌合体。母亲体细胞中单个X染色体的丢失是随着年龄增长而出现的自然现象，这可以解释许多cfDNA假阳性结果。对于具有45,X染色体组成性嵌合体且可生育的女性，人们的认识也在不断提高。必须认识到，cfDNA筛查显示45,X阳性并不意味着胎儿患有特纳综合征。建议进行后续诊断检测，即羊水穿刺或新生儿核型分析/染色体微阵列分析。对孕中期几乎完全来自胎儿的羊水细胞中游离mRNA的研究表明，参与血液、免疫和神经系统的基因存在持续的失调。这表明特纳综合征的一些病理生理学现象在胎儿生命早期就已出现，并为考虑产前治疗提供了新的机会。
