Maternal Mosaicism Is a Significant Contributor to Discordant Sex Chromosomal Aneuploidies Associated with Noninvasive Prenatal Testing
Maternal Mosaicism Is a Significant Contributor to Discordant Sex Chromosomal Aneuploidies Associated with Noninvasive Prenatal Testing
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DOI：
10.1373/clinchem.2013.215145
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发表时间：
2014-01-01
影响因子：
9.3
通讯作者：
Cheng, Weiwei
中科院分区：
文献类型：
--
作者：
Wang, Yanlin;Chen, Yan;Cheng, Weiwei
背景：在人类胎儿中，性染色体非整倍体（SCA）与常见的常染色体21、18和13三体一样普遍。目前，大多数无创产前检测（NIPT）仅提供21、18和13号染色体的筛查，因为其敏感性和特异性明显高于性染色体。有限的研究表明，与检测 SCA 相关的准确性降低是由于胎盘局限性、胎盘或真正的胎儿嵌合体所致。我们假设母体核型的改变也可能是导致 SCA NIPT 结果不一致的重要因素。方法：我们开发了一种快速核型分析方法，该方法使用大规模并行测序来测量染色体嵌合程度。该方法通过模拟 XXX 和 XO 嵌合体的 DNA 模型进行了验证，然后应用于来自 SCA NIPT 结果不一致的患者的母体白细胞 (WBC) DNA。 结果：测序核型分析检测到 X 染色体 (ChrX) 嵌合体低至 5%，从而可以准确分配母体 X 核型。在一项前瞻性 NIPT 研究中，我们发现 181 例阳性 SCA 中的 16 例 (8.6%) 是由于母体 ChrX 核型异常，掩盖了胎儿 ChrX DNA 片段的真实贡献。结论：通过将母体血浆测序结果与母体 WBC 测序结果相结合，可以大大提高 NIPT 对 ChrX 和 ChrY 的准确性。母体嵌合发生率相对较高，因此在发现潜在的胎儿 SCA 后，需要在鸟枪法测序和基于单核苷酸多态性的临床 NIPT 中进行强制性白细胞检测。 (C) 2013年美国临床化学协会
BACKGROUND: In the human fetus, sex chromosome aneuploidies (SCAs) are as prevalent as the common autosomal trisomies 21, 18, and 13. Currently, most noninvasive prenatal tests (NIPTs) offer screening only for chromosomes 21, 18, and 13, because the sensitivity and specificity are markedly higher than for the sex chromosomes. Limited studies suggest that the reduced accuracy associated with detecting SCAs is due to confined placental, placental, or true fetal mosaicism. We hypothesized that an altered maternal karyotype may also be an important contributor to discordant SCA NIPT results.METHODS: We developed a rapid karyotyping method that uses massively parallel sequencing to measure the degree of chromosome mosaicism. The method was validated with DNA models mimicking XXX and XO mosaicism and then applied to maternal white blood cell (WBC) DNA from patients with discordant SCA NIPT results.RESULTS: Sequencing karyotyping detected chromosome X (ChrX) mosaicism as low as 5%, allowing an accurate assignment of the maternal X karyotype. In a prospective NIPT study, we showed that 16 (8.6%) of 181 positive SCAs were due to an abnormal maternal ChrX karyotype that masked the true contribution of the fetal ChrX DNA fraction.CONCLUSIONS: The accuracy of NIPT for ChrX and ChrY can be improved substantially by integrating the results of maternal-plasma sequencing with those for maternal-WBC sequencing. The relatively high frequency of maternal mosaicism warrants mandatory WBC testing in both shotgun sequencing- and single-nucleotide polymorphism-based clinical NIPT after the finding of a potential fetal SCA. (C) 2013 American Association for Clinical Chemistry