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

Abstract Purpose Genome sequencing (GS) is potentially the most suitable diagnostic tools for fetal CNS structural anomalies. However, its efficacy hasn’t 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.