Natera, Inc, San Carlos, CA.
Department of Pediatrics, George Washington University of Health Sciences, Washington, DC; The Focus Foundation, Davidsonville, MD; Department of Human and Molecular Genetics, Florida International University, Miami, FL.
Am J Obstet Gynecol MFM. 2020 Aug;2(3):100152. doi: 10.1016/j.ajogmf.2020.100152. Epub 2020 Jun 25.
Maternal X chromosome abnormalities may cause discordant results between noninvasive prenatal screening tests and diagnostic evaluation of the fetus/newborn, leading to unnecessary invasive testing. Women with X chromosome abnormalities are at increased risk for reproductive, pregnancy, or other health complications, which may be reduced or ameliorated by early diagnosis, monitoring, and intervention.
This study aimed to validate a single nucleotide polymorphism-based noninvasive prenatal test to identify X chromosome abnormalities of maternal origin.
All tests unable to evaluate fetal risk for aneuploidy because of uninformative algorithm results were eligible for inclusion. Two groups of cases were prospectively identified: Group A (n=106) where a maternal X chromosome abnormality was suspected and Group B (control group, n=107) where a fetal chromosome abnormality involving chromosome 13, 18, 21, or X was suspected but did not meet criteria for reporting. Maternal DNA was isolated from the plasma-depleted cellular pellet and sent to a reference laboratory for blinded analysis using chromosomal microarray. A chromosome abnormality involving chromosomes 13, 18, 21, or X was reported by the reference laboratory if ≥5 Mb in size and present in ≥20% of the DNA.
A maternal X chromosome abnormality was suspected in 1/1305 tests (149/194,385; 0.08%). In Group A, a maternal X chromosome abnormality was confirmed in 100/106 cases (94.3% positive predictive value, 1-sided 97.5% confidence interval, 88.1%-100.0%). Turner syndrome was the most commonly suspected maternal abnormality (58/106, 54.7%), with confirmation of mosaic or nonmosaic 45,X by microarray in 38/58 (65.5%) cases. Noninvasive prenatal screening tests suspected the presence of maternal 47,XXX with or without mosaicism in 40/106 (37.7%) cases, confirmed by microarray in 38/40 (95.0%). In Group B (n=107), no maternal microarray abnormalities were reported, providing a negative predictive value of 100% (1-sided 97.5% confidence interval, 96.6%-100.0%).
When noninvasive prenatal testing suspected a maternal X chromosome abnormality, maternal microarray confirmed an X chromosome abnormality with 94.3% positive predictive value. Of the maternal X chromosome abnormalities detected by array, >50% were 45,X. When fetal chromosome abnormalities involving chromosomes 13, 18, 21, or X were suspected, no maternal chromosome abnormalities were reported, yielding a negative predictive value of 100%. Women with maternal X abnormalities suspected with noninvasive prenatal testing may be at increased risk for reproductive and health complications; early evaluation and treatment may prevent long-term consequences or disability.
母体 X 染色体异常可能导致非侵入性产前筛查测试与胎儿/新生儿的诊断评估结果不一致，从而导致不必要的侵入性检测。X 染色体异常的女性生殖、妊娠或其他健康并发症的风险增加，通过早期诊断、监测和干预，这些风险可能会降低或减轻。
本研究旨在验证一种基于单核苷酸多态性的非侵入性产前检测方法，以识别母体来源的 X 染色体异常。
所有因算法结果无信息而无法评估胎儿非整倍体风险的检测均符合纳入标准。前瞻性地确定了两组病例：A 组（n=106）怀疑存在母体 X 染色体异常，B 组（对照组，n=107）怀疑胎儿染色体异常涉及 13、18、21 或 X 染色体，但不符合报告标准。从血浆 depleted 细胞沉淀中提取母体 DNA，并送至参考实验室进行盲法分析，使用染色体微阵列。参考实验室报告染色体 13、18、21 或 X 染色体异常，如果大小≥5 Mb，且存在于≥20%的 DNA 中。
149/194385（0.08%）的 1305 次检测中怀疑存在母体 X 染色体异常。在 A 组中，106 例中确认存在母体 X 染色体异常（100/106；阳性预测值，1 侧 97.5%置信区间，88.1%-100.0%）。最常见的母体异常是特纳综合征（58/106，54.7%），58 例中的 38 例（65.5%）经微阵列证实为镶嵌或非镶嵌 45,X。40/106（37.7%）例非侵入性产前筛查检测怀疑存在母体 47,XXX 伴或不伴镶嵌，38/40（95.0%）例经微阵列证实。B 组（n=107）未报告母体微阵列异常，阴性预测值为 100%（1 侧 97.5%置信区间，96.6%-100.0%）。
当非侵入性产前检测怀疑存在母体 X 染色体异常时，母体微阵列可确认 X 染色体异常，阳性预测值为 94.3%。通过微阵列检测到的 X 染色体异常中，超过 50%为 45,X。当怀疑胎儿染色体异常涉及 13、18、21 或 X 染色体时，未报告母体染色体异常，阴性预测值为 100%。怀疑非侵入性产前检测存在母体 X 染色体异常的女性可能有更高的生殖和健康并发症风险；早期评估和治疗可能预防长期后果或残疾。
