Shiyu Sun ¹ Yizhen Ji ¹ Di Shao ² Yasong Xu ¹ Xiaomei Yang ¹ Sun Li ¹ Nan Li ² Hui Huang ² Qichang Wu ^1*

• ¹ Prenatal Diagnosis Center, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China
• ² BGI Genomics, Shenzhen, China

This study aimed to assess the efficiency of CNV-seq and WES in detecting genetic cause of congenital heart defects (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/LP 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%, p = 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.