Sun Shiyu, Ji Yizhen, Shao Di, Xu Yasong, Yang Xiaomei, Sun Li, Li Nan, Huang Hui, Wu Qichang
Prenatal Diagnosis Center, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China.
BGI Genomics, Shenzhen, China.
Front Genet. 2024 Aug 14;15:1448383. doi: 10.3389/fgene.2024.1448383. eCollection 2024.
This study aimed to assess the efficiency of CNV-seq and WES in detecting genetic cause of congenital heart disease (CHDs) in prenatal diagnoses and to compare CNV detection rate between isolated and non-isolated CHD cases. We conducted a retrospective study of 118 Chinese fetuses diagnosed with CHD by prenatal ultrasound. Participants underwent CNV-seq and, if necessary, WES to detect chromosomal and single nucleotide variations. The overall detection rate for pathogenic or likely pathogenic chromosomal abnormalities was 16.9%, including 7.6% aneuploidies and 9.3% pathogenic/likely pathogenic copy number variations (CNVs), predominantly 22q11.2 deletion syndrome (54.4%). The sensitivity and specificity of CNV-Seq for detecting P/L CNVs were 95% and 100%, respectively. CNV-Seq offered a 6.7% improvement in detecting chromosomal abnormalities over karyotyping. WES further identified significant single nucleotide and small indel variations contributing to CHD in genes such as TMEM67, PLD1, ANKRD11, and PNKP, enhancing diagnostic yield by 14.8% in cases negative for CNVs. Non-isolated CHD cases exhibited higher rates of detectable chromosomal abnormalities compared to isolated cases (32.4% vs. 9.9%, = 0.005), underlining the genetic complexity of these conditions. The combined use of CNV-seq and WES provides a comprehensive approach to prenatal genetic testing for CHDs, unveiling significant genetic cause that could impact clinical management and parental decision-making. This study supports the integration of these advanced genomic technologies in routine prenatal diagnostics to increase detection diagnostic yields of causal genetic variants associated with CHDs.
本研究旨在评估CNV-seq和全外显子测序（WES）在产前诊断中检测先天性心脏病（CHD）遗传病因的效率，并比较孤立性和非孤立性CHD病例之间的拷贝数变异（CNV）检测率。我们对118例经产前超声诊断为CHD的中国胎儿进行了一项回顾性研究。参与者接受了CNV-seq检测，必要时还接受了WES检测，以检测染色体和单核苷酸变异。致病性或可能致病性染色体异常的总体检测率为16.9%，包括7.6%的非整倍体和9.3%的致病性/可能致病性拷贝数变异（CNV），主要是22q11.2缺失综合征（54.4%）。CNV-Seq检测致病性/可能致病性CNV的灵敏度和特异性分别为95%和100%。与核型分析相比，CNV-Seq在检测染色体异常方面提高了6.7%。WES进一步鉴定出TMEM67、PLD1、ANKRD11和PNKP等基因中导致CHD的显著单核苷酸和小插入/缺失变异，在CNV检测为阴性的病例中，诊断率提高了14.8%。与孤立性病例相比，非孤立性CHD病例的可检测染色体异常率更高（32.4%对9.9%，P = 0.005），这突出了这些疾病的遗传复杂性。CNV-seq和WES的联合使用为CHD的产前基因检测提供了一种全面的方法，揭示了可能影响临床管理和父母决策的重要遗传病因。本研究支持将这些先进的基因组技术整合到常规产前诊断中，以提高与CHD相关的因果基因变异的检测诊断率。
