Aneuploidy Patterns in 3143 day-3 Embryos Analyzed by Array CGH

Abstract

BACKGROUND: Previous FISH studies with day-3 biopsy showed an excess of monosomies, a correlation between maternal age and percentage of normal embryos (lower maternal age = higher percentage of normal embryos), and no correlation between maternal age and mosaicism. These studies were performed with 9-12 chromosome probes and thus did not include more than half of the chromosome complement. OBJECTIVE(S): To assess the types of chromosome abnormalities observed by array CGH and their relationship to maternal age. MATERIAL AND METHOD(S): Single blastomeres from day-3 embryos were analyzed by aCGH (24Sure, BlueGnome, UK). This technique can analyze all chromosomes with a very low error rate, including errors caused by mosaicism, (2%, Gutierrez-Mateo et al. 2010) and thus we assume that day-3 PGD results are mostly representative of the rest of the embryo. An embryo with 3 or more chromosomes out of the 24 being abnormal was considered “complex abnormal”. RESULT(S): Complex abnormal embryos and double aneuploidies significantly increased with advancing maternal age, while trisomies and monosomies did not. Normal embryos significantly decreased with advancing maternal age (48% in the <35 years of age group to 21% in the >39 years). We observed an excess of monosomy events (n=1006) compared to trisomy events (n=695) with one third of that excess being caused by monosomy X. There was a slightly higher average maternal age for aneuploidy events on chromosomes 13 to 22 (av. Age 38.4) than 1 to 12 (37.7), while monosomy X results showed an average maternal age of 36.4 years. Normal embryo results had an average maternal age of 35.9 years, compared to complex abnormal embryo results of 38.7 years. The most common aneuploidies were for chromosomes 16 (n=204), 22 (157), X (125), 15 (119), 21 (107), and 19 (91). CONCLUSION(S): Large studies using FISH (Munne et al. 2007) considered complex abnormalities akin to chaotic mosaics. However, by analyzing all chromosomes with aCGH, many embryos classified by aCGH as complex abnormal must be true aneuploid, as seen by their increased maternal age. The percentage of abnormal embryos does increase significantly with maternal age, as does the percentage of double aneuploids and complex abnormals. The excess of monosomies observed is not an artifact, as described in a separate abstract by Colls et al. SUPPORT: Departmental funds