Expanded chromosomal microarray comprising screening for spinal muscular atrophy and monogenic diseases

BackgroundCopy number variants platforms, as critical supports for genetic diagnosis, have been well implemented in prenatal diagnosis. However, numerous severe conditions with underlying single-gene defects are not included in current invasive prenatal screening. To bridge this gap, an expanded chromosomal microarray analysis was developed, employing a meticulous designed single nucleotide polymorphism chip. This chip incorporated additional probes to augment its efficacy in screening for spinal muscular atrophy and diagnosing monogenic disorders. Objective(s)This study aimed to evaluate the accuracy, efficacy, and incremental yield of expanded chromosomal microarray, compared with karyotype analysis and low-depth genome sequencing for routine prenatal diagnosis. Study DesignIn this prospective study, total of 512 fetuses were included in this study. In this study three distinct diagnostic techniques-karyotype analysis, low-depth genome sequencing, and expanded chromosomal microarray-were processed to evaluate each sample. Aneuploidies and multigene copy number variations were detected and analyzed in a blinded fashion. SMN1 exonic copy number variations were confirmed by multiplex ligation-dependent probe amplification and single nucleotide variations were confirmed by sanger sequencing. ResultsOverall, expanded chromosomal microarray identified genetic abnormalities in 91 out of 512 cases (17.6%). The encountered rate was significantly higher than the rates observed with low-depth genome sequencing (66 out of 512 cases, 12.9%) and conventional chromosome karyotyping (42 out of 512 cases, 8.2%). Expanded chromosomal microarray not only detected all these non-mosaic aneuploidies and copy number variations in 62(12.1%) diagnosed cases identified by low-depth genome sequencing (low-depth genome sequencing), but also detected 9 cases with regions of homozygosity, 10(2.0%) cases with exonic deletions (SMN1 and DMD), and 13(2.5%) cases with single nucleotide variations. ConclusionsCompared with low-depth GS, expanded chromosomal microarray increased the additional detection rate by 4.7% (24/512). Compared with traditional chromosomal microarray, expanded chromosomal microarray increased the additional detection rate by 3.9% (20/512) in 512 fetuses. Although the expanded chromosomal microarray (ECMA) has limited accuracy for detecting single nucleotide variations, its screening capacity is significantly enhanced when complemented with Sanger sequencing validation. Using expanded chromosomal microarray, we detected not only copy number variations, but also exonic deletions, regions of homozygosity with high accuracy in an acceptable turnaround time (2-3 weeks). Our results suggest that expanded chromosomal microarray has the potential to be a promising prenatal diagnostic tool with incremental yield of screening exonic copy number variations in SMN1.