Array Comparative Genomic Hybridization for Genetic Evaluation of Fetal Loss Between 10 and 20 Weeks of Gestation

Abstract

To estimate genomic copy number changes in fetal loss between 10 and 20 weeks of gestation using array comparative genomic hybridization. This was a prospective series of 35 women who experienced pregnancy loss between 10-20 weeks of gestation with either normal karyotype (n=9) or no conventional cytogenetic testing (n=26). DNA was isolated from fetal tissue and parental blood. Array comparative genomic hybridization was performed on DNA from fetal tissue using a whole genome BAC array chip. Copy number changes in fetal tissue were then compared against databases of benign copy number changes. Parental DNA was analyzed using the same BAC array in cases that contained suspected pathogenic copy number changes. In cases where de novo copy number changes were detected in fetal DNA, further characterization was performed using a 244K oligonucleotide microarray. DNA was successfully isolated in 30 of 35 (86%) of cases. Array comparative genomic hybridization was performed in all of these. De novo copy number changes were detected in six (20%) cases using the Spectral chip and confirmed in four (13%) cases using the Agilent chip. These ranged in size from 93-289 Kb and mapped on 5p, 13q and Xq22. In the cases with de novo copy number changes, the higher-density Agilent array detected additional changes (20-1,310 Kb). Array comparative genomic hybridization detected de novo copy number changes in 13% of cases where routine cytogenetic testing was normal or not performed. These involved large regions of DNA and may provide novel explanations for some cases of otherwise unexplained pregnancy loss. III.