Department of Obstetrics and Gynecology, University Hospital Brugmann, Université Libre de Bruxelles, Brussels, Belgium.
Prenatal Diagnosis and Human Genetics, Berlin, Germany.
Ultrasound Obstet Gynecol. 2021 Oct;58(4):597-602. doi: 10.1002/uog.23699.
22q11.2 deletion is more common than trisomies 18 and 13 combined, yet no routine approach to prenatal screening for this microdeletion has been established. This study evaluated the clinical sensitivity and specificity of a targeted cell-free DNA (cfDNA) test to screen for fetal 22q11.2 deletion in a large cohort, using blinded analysis of prospectively enrolled pregnancies and stored clinical samples.
In order to ensure that the analysis included a meaningful number of cases with fetal 22q11.2 deletion, maternal plasma samples were obtained by prospective, multicenter enrolment of pregnancies with a fetal cardiac abnormality and from stored clinical samples from a research sample bank. Fetal genetic status, as evaluated by microarray analysis, karyotyping with fluorescence in-situ hybridization or a comparable test, was available for all cases. Samples were processed as described previously for the Harmony prenatal test, with the addition of DANSR (Digital Analysis of Selected Regions) assays targeting the 3.0-Mb region of 22q11.2 associated with 22q11.2 deletion syndrome. Operators were blinded to fetal genetic status. Sensitivity and specificity of the cfDNA test for 22q11.2 deletion were calculated based on concordance between the cfDNA result and fetal genotype.
The final study group consisted of 735 clinical samples, including 358 from prospectively enrolled pregnancies and 377 stored clinical samples. Of 46 maternal plasma samples from pregnancies with a 22q11.2 deletion, ranging in size from 1.25 to 3.25 Mb, 32 had a cfDNA result indicating a high probability of 22q11.2 deletion (sensitivity, 69.6% (95% CI, 55.2-80.9%)). All 689 maternal plasma samples without a 22q11.2 deletion were classified correctly by the cfDNA test as having no evidence of a 22q11.2 deletion (specificity, 100% (95% CI, 99.5-100%)).
The results of this large-scale prospective clinical evaluation of the sensitivity and specificity of a targeted cfDNA test for fetal 22q11.2 deletion demonstrate that this test can detect the common and smaller, nested 22q11.2 deletions with a low (0-0.5%) false-positive rate. Although the positive predictive value (PPV) observed in this study population was 100%, the expected PPV in the general pregnant population is estimated to be 12.2% at 99.5% specificity and 41.1% at 99.9% specificity. The use of this cfDNA test to screen for 22q11.2 deletion could enhance identification of pregnancies at risk for 22q11.2 deletion syndrome without significantly increasing the likelihood of maternal anxiety and unnecessary invasive procedures related to a false-positive result. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
22q11.2 缺失比 18 三体和 13 三体的总和更为常见，但尚未建立针对这种微缺失的常规产前筛查方法。本研究通过对前瞻性纳入的妊娠和存储的临床样本进行盲法分析，评估了靶向游离 DNA(cfDNA)检测筛查胎儿 22q11.2 缺失的临床灵敏度和特异性。
为了确保分析包括大量胎儿 22q11.2 缺失的病例，通过前瞻性多中心纳入胎儿心脏异常的妊娠和从研究样本库中存储的临床样本中获得母体血浆样本。所有病例均通过微阵列分析、荧光原位杂交或类似的检测进行胎儿遗传状态评估。对所有样本均按先前报道的 Harmony 产前检测方法进行处理，并增加了靶向与 22q11.2 缺失综合征相关的 3.0-Mb 区域的 DANSR（选定区域的数字分析）检测。操作人员对胎儿遗传状态进行盲法分析。根据 cfDNA 结果与胎儿基因型的一致性，计算 cfDNA 检测 22q11.2 缺失的灵敏度和特异性。
最终的研究组包括 735 例临床样本，其中 358 例来自前瞻性纳入的妊娠，377 例来自存储的临床样本。在 46 例大小为 1.25-3.25Mb 的 22q11.2 缺失妊娠的母体血浆样本中，有 32 例 cfDNA 结果提示 22q11.2 缺失的可能性较高（灵敏度为 69.6%（95%CI，55.2-80.9%））。所有 689 例无 22q11.2 缺失的母体血浆样本均被 cfDNA 检测正确分类为无 22q11.2 缺失（特异性为 100%（95%CI，99.5-100%））。
本研究对靶向 cfDNA 检测胎儿 22q11.2 缺失的灵敏度和特异性进行了大规模前瞻性临床评估，结果表明，该检测可检测到常见的较小的嵌套 22q11.2 缺失，假阳性率较低（0-0.5%）。尽管本研究人群中的阳性预测值（PPV）为 100%，但预计在 99.5%特异性下，一般孕妇人群中的预期 PPV 为 12.2%，而在 99.9%特异性下为 41.1%。使用这种 cfDNA 检测筛查 22q11.2 缺失可以在不显著增加与假阳性结果相关的母体焦虑和不必要的侵入性程序的情况下，提高对 22q11.2 缺失综合征风险妊娠的识别能力。 © 2021 作者。超声在妇产科由约翰威立父子公司出版代表国际超声在妇产科协会。
