Comprehensive genetic analysis of pregnancy loss by chromosomal microarrays: outcomes, benefits and challenges. T. Sahoo, M. Strecker, A. Mehta, N. Dzidic, R. W. Tyson, K. Hovanes Combimatrix, Irvine, CA.

   INTRODUCTION: Chromosomal aneuploidies, polyploidies and unbalanced structural rearrangements account for >50% of all first trimester pregnancy losses. Determining the cause of pregnancy loss can assist in providing appropriate medical management and recurrence risk counseling. However, the limited success of classical cytogenetic analysis of products of conception (POC) has led to implementation of alternative methods of evaluation; in particular, chromosomal microarray analysis (CMA). Utilizing genomic DNA, CMA allows for direct cytogenomic analysis of both fresh POC tissue and archived formalin-fixed, paraffin-embedded (FFPE) samples. METHODS: At CombiMatrix we undertook a comprehensive, multi-year analysis of over 3400 POC specimens analyzed by various types of CMA: BAC-aCGH (N=678), oligo-aCGH (N=754), and single nucleotide polymorphism (SNP) array (N=1976). RESULTS: Of the 3408 consecutive specimens (fresh POC: 2712, FFPE: 564, other: 132) referred for analysis, 2345/2712 (86.5%) of fresh POC samples and 492/564 (87.2%) of FFPE samples provided a successful result. Common reasons for test failure included insufficient sample size and poor DNA quality. Of the 2930 samples resulted, 1533 (52%) were abnormal, 1330 (46%) were normal, and 67 (2%) revealed a variant of uncertain significance. As expected, CMA identified a broad spectrum of abnormalities: 1056 single or multiple trisomies, 187 triploidies, 161 monosomy X, and 129 with other gross genomic imbalances. Of the three platforms, the SNP array had the highest abnormality detection rate (53.8%), and in addition to chromosomal imbalances, also identified cases with whole genome or multiple regions of allelic homozygosity. CONCLUSIONS: The exacting nature of POC specimens precludes successful culture and cytogenetic analysis in 20-40% of cases, which underscores the value of CMA in successfully enabling analysis of a great majority of these specimens. In particular, SNP-based CMA allows for the identification of polyploidy, aneuploidy, allelic homozygosity, genomic imbalances, and maternal cell contamination in both fresh and FFPE tissue samples. This comprehensive study confirms and significantly extends the value of CMA in POC analysis, and highlights the spectrum of abnormalities identifiable using genome-wide, high resolution CMA. This expands our understanding of the causes, clarifies the risk of future loss(s) and helps counsel families on the need for potential genetic counseling.

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