Genome sequencing combining prenatal ultrasound in the evaluation of fetal CNS structural anomalies

Purpose: Genome sequencing (GS) is potentially the most suitable diagnostic tools for fetal CNS structural anomalies. However, its efficacy hasn9t been proved in large cohort of fetal CNS structural anomalies. Methods: Patients were enrolled by a multiple-level referral system when fetal CNS structure anomalies were found by ultrasonography. Samples from fetuses were subjected to GS. Results: Data of 162 fetuses with 11 frequent types of CNS anomalies was collected. The overall diagnosis yield of GS was 38.9%. 36(20.3%) fetuses were detected with chromosomal anomalies and pathogenic CNVs. Pathogenic or likely pathogenic single-gene variants and intragenic CNVs were found in 24 and three fetuses, contributing 14.8% and 1.9% diagnostic yield respectively. The diagnostic rate in 41 fetuses with CNS malformation combined with anomalies out of brain was as high as 73.3%. Malformations of the posterior cerebral fossa, abnormal neuronal proliferation and migration have the highest diagnostic rates. NTDs had the second lowest diagnostic rates of 14.7% and none pathogenic variants were found in ultrasound anomalies that suggested destructive cerebral lesions. Conclusion: GS is an efficient genetic testing tool with the diagnostic power compared to current CMA plus ES procedure in fetal CNS anomalies evaluation.