Department of Prenatal Diagnosis, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China.
Department of Prenatal Diagnosis, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China.
Am J Obstet Gynecol. 2023 Sep;229(3):302.e1-302.e18. doi: 10.1016/j.ajog.2023.03.005. Epub 2023 Mar 11.
Emerging studies suggest that whole genome sequencing provides additional diagnostic yield of genomic variants when compared with chromosomal microarray analysis in the etiologic diagnosis of infants and children with suspected genetic diseases. However, the application and evaluation of whole genome sequencing in prenatal diagnosis remain limited.
This study aimed to evaluate the accuracy, efficacy, and incremental yield of whole genome sequencing in comparison with chromosomal microarray analysis for routine prenatal diagnosis.
In this prospective study, a total of 185 unselected singleton fetuses with ultrasound-detected structural anomalies were enrolled. In parallel, each sample was subjected to whole genome sequencing and chromosomal microarray analysis. Aneuploidies and copy number variations were detected and analyzed in a blinded fashion. Single nucleotide variations and insertions and deletions were confirmed by Sanger sequencing, and trinucleotide repeats expansion variants were verified using polymerase chain reaction plus fragment-length analysis.
Overall, genetic diagnoses using whole genome sequencing were obtained for 28 (15.1%) cases. Whole genome sequencing not only detected all these aneuploidies and copy number variations in the 20 (10.8%) diagnosed cases identified by chromosomal microarray analysis, but also detected 1 case with an exonic deletion of COL4A2 and 7 (3.8%) cases with single nucleotide variations or insertions and deletions. In addition, 3 incidental findings were detected including an expansion of the trinucleotide repeat in ATXN3, a splice-sites variant in ATRX, and an ANXA11 missense mutation in a case of trisomy 21.
Compared with chromosomal microarray analysis, whole genome sequencing increased the additional detection rate by 5.9% (11/185). Using whole genome sequencing, we detected not only aneuploidies and copy number variations, but also single nucleotide variations and insertions and deletions, trinucleotide repeat expansions, and exonic copy number variations with high accuracy in an acceptable turnaround time (3-4 weeks). Our results suggest that whole genome sequencing has the potential to be a new promising prenatal diagnostic test for fetal structural anomalies.
新兴研究表明，与染色体微阵列分析相比，全基因组测序在疑似遗传疾病的婴儿和儿童的病因诊断中提供了额外的基因组变异诊断率。然而，全基因组测序在产前诊断中的应用和评估仍然有限。
本研究旨在评估全基因组测序与染色体微阵列分析相比在常规产前诊断中的准确性、功效和增量收益。
在这项前瞻性研究中，共纳入了 185 例超声检测到结构异常的未经选择的单胎胎儿。同时，对每个样本进行全基因组测序和染色体微阵列分析。以盲法检测和分析非整倍体和拷贝数变异。通过 Sanger 测序确认单核苷酸变异和插入缺失，通过聚合酶链反应加片段长度分析验证三核苷酸重复扩展变异。
总体而言，使用全基因组测序获得了 28 例（15.1%）病例的遗传诊断。全基因组测序不仅检测到了 20 例（10.8%）经染色体微阵列分析诊断的病例中的所有这些非整倍体和拷贝数变异，还检测到了 1 例 COL4A2 外显子缺失和 7 例（3.8%）单核苷酸变异或插入缺失。此外，还检测到了 3 例偶然发现，包括 ATXN3 中三核苷酸重复扩展、ATRX 中剪接位点变异和 21 三体病例中 ANXA11 错义突变。
与染色体微阵列分析相比，全基因组测序增加了额外的检测率 5.9%（11/185）。使用全基因组测序，我们不仅检测到了非整倍体和拷贝数变异，还以可接受的周转时间（3-4 周）检测到了单核苷酸变异和插入缺失、三核苷酸重复扩展、外显子拷贝数变异，具有高准确性。我们的结果表明，全基因组测序有可能成为一种新的有前途的胎儿结构异常产前诊断测试。
