Chromosomal microarray analysis as the first-tier clinical diagnostic test for miscarriage analysis

Abstract

Despite the high failure rate and inherent limitations of conventional cytogenetic/karyotype analysis for products of conception samples (POCs) and high success rate and diagnostic benefits of chromosomal microarray analysis (CMA), testing of this sample type by CMA remains low. This underutilization may be due to a lack of awareness of the technology's diagnostic power, and more importantly, lack of clear opinions or recommendations in support of this testing by professional committees, such as The American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal-Fetal Medicine (SMFM). We undertook a retrospective analysis of over 13 thousand consecutive POCs evaluated by CMA with the purpose of determining analytical success, failure rates, and frequency/rates of causative and non-causative abnormalities. In addition, potential challenges, either sample-related or test-related, were cataloged. Materials and Methods Of the 13,711 cases received for evaluation by CMA, 12,324 were successfully analyzed and reported (90%); 83% of samples were ascertained for recurrent pregnancy loss (RPL) or spontaneous abortion (SAB). About 78% of samples were fresh and 21% of samples were FFPE. The majority of samples (88%) were analyzed by whole-genome SNP-based CMA allowing detection of whole chromosome or segmental copy number changes (greater than 20kb; and greater than 5% mosaicism), triploidy, whole-genome uniparental isodisomy (molar pregnancy), and maternal cell contamination. In 54% (6665/12324) of cases, a clinically significant abnormality was identified, and over 96% of those abnormalities were deemed causative of the pregnancy loss. Normal results were obtained in 44% of cases, and variants of uncertain significance (VOUS) were detected in the remaining2% of cases. The most common abnormalities detected were autosomal trisomies (single trisomy, 62%; multiple trisomies, 4%), triploidy (12%), molar pregnancy (1%) and monosomy X (11%). Autosomal monosomies were rare (<1% of cases). Clinically significant segmental deletions and duplications were detected in 4.6% cases. This data shows the continued diagnostic value of CMA for the evaluation of POCs and further supports its use for miscarriage analysis. The success rates and diagnostic power in providing a high resolution genome-wide evaluation of POCs for causative abnormalities should be the primary determining factors for the establishment of recommendations or guidelines for routine genetic evaluation of RPL and SAB. Unfortunately, recommendations for miscarriage analysis by CMA remain unclear. As seen in this large, retrospective study, the high success rate (90%) and the ability to provide a causative genetic diagnosis for over 50% of samples make CMA the best testing option for POCs and support its use as the first-tier diagnostic test for evaluation of all miscarriages.