Whole genome sequencing vs chromosomal microarray analysis in prenatal diagnosis

Abstract

Emerging studies suggest that whole genome sequencing provides an additional diagnostic yield of genomic variants compared with chromosomal microarray analysis in the etiologic diagnosis of infants and children with suspected genetic diseases. However, the application and evaluation of whole genome sequencing in prenatal diagnosis remains limited. This study aimed to evaluate the accuracy, efficacy, and incremental yield of whole genome sequencing compared with chromosomal microarray analysis for routine prenatal diagnosis. In this prospective study, a total of 185 unselected singleton fetuses with ultrasound structural anomalies were enrolled. In parallel, each sample was subjected to whole genome sequencing and chromosomal microarray analysis. Aneuploidies and copy number variations were detected and analyzed in a blinded fashion. Single nucleotide variations, and insertions and deletions were confirmed by Sanger sequencing, and trinucleotide repeats expansion variants were verified using PCR plus fragment-length analysis. Overall, genetic diagnosis of whole genome sequencing was encountered in 28 (15.1%) cases. Whole genome sequencing not only detected all these aneuploidies and copy number variations in 20 (10.8%) diagnosed cases identified by chromosomal microarray analysis, but also detected one case with an exonic deletion of COL4A2, and seven (3.8%) cases with single nucleotide variations/insertions and deletions. Additionally, three incidental findings were detected including an expansion of the trinucleotide repeat in ATXN3, a splice-sites variant in ATRX, and a ANXA11 missense mutation in a case of trisomy 21. Compared with chromosomal microarray analysis, whole genome sequencing increased the additional detection rate by 5.9% (11/185). Using whole genome sequencing, we detected not only aneuploidies and copy number variations, but also single nucleotide variations/insertions and deletions, trinucleotide repeat expansions, and exonic copy number variations with high accuracy in an acceptable turnaround time (3-4 weeks). Our results suggest that whole genome sequencing has the potential to be a new promising prenatal diagnostic test for fetal structural anomalies.