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Clinical application of targeted next-generation sequencing on fetuses with congenital heart defects Fengchang Qiao1, Ping Hu2, Wang Yan3, Zhengfeng Xu3
1Department of Prenatal Diagnosis, the Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China 2Department of Prental Diagnosis, The Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital., Nanjing, China 3Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, China Objectives This study aimed to determine the diagnostic yield of targeted next-generation sequencing (NGS) in prenatal diagnosis of congenital heart defects (CHDs) and for investigating the possible genetic etiology of prenatal CHD cases. Methods Forty-four fetuses with CHDs and normal molecular karyotypes underwent targeted NGS using DNA obtained via amniocentesis, were recruited in this study. Fetal genomic DNA was directly extracted from amniotic fluid cells in each prenatal case. A customized targeted NGS panel containing 77 CHD-associated genes was designed to detect variants in the coding regions and the splicing sites of these genes. The detected variants were then interpreted following the guidelines recommended by American College of Medical Genetics and Genomics. Results In the 44 fetuses, the detection rates of pathogenic and likely pathogenic variations were 13.6% (6/44) and 2.27% (1/44), respectively. The 6 pathogenic variations were identified on genes of CHD7 (associated with CHARGE syndrome), CITED2 (associated with Tetralogy of Fallot, Ventricular Septal Defect and Atrial Septal Defect), ZFPM2 (associated with Tetralogy of Fallot), MYH6 (associated with Atrial Septal Defect, Familial Isolated Dilated Cardiomyopathy), KMT2D (associated with Kabuki syndrome). One likely pathogenic variation was on JAG1, associated with Tetralogy of Fallot and Alagille syndrome. Conclusions Targeted NGS of fetuses with isolated and non-isolated CHDs achieved a high diagnostic yield in our cohort, with an acceptable turnaround time for the prenatal setting. Our results have important implications for clinical management and genetic counseling.
