Zhang Haoqing, He Xinglan, Wang Yuankun, Li Caiyun, Jiang Hongguo, Hou Shuai, Huang Dongqun, Zhang Wenqian, Tan Jufang, Du Xiaoyun, Cao Yinli, Chen Danjing, Yan Haiying, Peng Lingling, Lei Dongzhu
Center of Prenatal Diagnosis, The Affiliated Chenzhou Hospital, Hengyang Medical School, University of South China, Chenzhou, 423000, China.
Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Heliyon. 2024 Oct 15;10(20):e39392. doi: 10.1016/j.heliyon.2024.e39392. eCollection 2024 Oct 30.
Fetal structural anomalies are detected by ultrasound in approximately 3 % of pregnancies. Numerous genetic diagnostic strategies have been widely applied to identify the genetic causes of prenatal abnormalities. We aimed to assess the value of simultaneous copy number variation sequencing (CNV-seq) and whole exome sequencing (WES) in diagnosing fetuses with structural anomalies.
Fetuses with structural anomalies detected by ultrasound were included for eligibility. After genetic counseling, WES and CNV-seq were performed on DNA samples of fetuses and their parents. All detected variants were evaluated for pathogenicity according to ACMG criteria, with the final diagnosis was determined based on ultrasound results and relevant family history.
The diagnostic rate of 174 fetuses with prenatal ultrasound abnormalities was 26.44 %, higher than that achieved through either CNV or WES analysis alone. Furthermore, the highest diagnostic rate was observed in fetuses with multiple system anomalies, accounting for 50 % of the total diagnostic yield, followed by skeletal system anomalies at 45.45 %. Three cases with multiple system abnormalities were found to have a dual diagnosis of pathogenic CNVs and SNV variants, representing 1.72 % of the total cohort. 38 pregnant women in their third trimester of pregnancy (27 weeks+) participated in this study, and 23.68 % received a confirmed genetic diagnosis. Finally, 31 women (67.39 %) voluntarily terminated their pregnancy following the testing and extensive genetic counseling.
Our study demonstrated that the simultaneous CNV-seq and WES analyses are beneficial for the molecular diagnosis of underlying unexplained structural anomalies in fetuses. This strategy is more efficient in elucidating prenatal abnormalities with compound problems, such as dual diagnoses. Furthermore, the simultaneous strategy has a shorter turnaround time and is particularly suitable for families with structural anomalies found in the third trimester of pregnancy.
超声检查可在约3%的妊娠中检测到胎儿结构异常。众多基因诊断策略已被广泛应用于确定产前异常的遗传原因。我们旨在评估同时进行拷贝数变异测序（CNV-seq）和全外显子测序（WES）在诊断有结构异常胎儿中的价值。
纳入经超声检测出有结构异常的胎儿。经过遗传咨询后，对胎儿及其父母的DNA样本进行WES和CNV-seq检测。根据美国医学遗传学与基因组学学会（ACMG）标准评估所有检测到的变异的致病性，最终诊断基于超声结果和相关家族史确定。
174例产前超声异常胎儿的诊断率为26.44%，高于单独通过CNV或WES分析所达到的诊断率。此外，在多系统异常胎儿中观察到最高诊断率，占总诊断阳性率的50%，其次是骨骼系统异常，占45.45%。发现3例多系统异常病例同时诊断出致病性CNV和单核苷酸变异（SNV），占总队列的1.72%。38名妊娠晚期（27周以上）孕妇参与了本研究，其中23.68%获得了确诊的基因诊断。最后，31名女性（67.39%）在检测和广泛的遗传咨询后自愿终止妊娠。
我们的研究表明，同时进行CNV-seq和WES分析有助于对胎儿潜在的不明原因结构异常进行分子诊断。该策略在阐明伴有复合问题（如双重诊断）的产前异常方面更有效。此外，同时检测策略周转时间更短，特别适用于在妊娠晚期发现有结构异常的家庭。
