Evidence for the Oocyte Mosaicism Selection model on the origin of Patau syndrome (trisomy 13)

Abstract

In 2008, Hultén etal hypothesized that maternal ovarian trisomy 21 mosaicism might be the primary causative factor for fetal Down syndrome. We hypothesize that this theory can be extended to trisomy 13. We collected fetal ovarian tissue from seven female fetuses between 16 and 23 gestational weeks, following the termination of the pregnancy for non-genetic reasons. All procedures were performed with informed consent and ethical approval from the local ethics committee. We used touch preparation techniques from fetal ovarian tissues and an anti-stromal antigen 3 antibody against the meiosis-specific stromal antigen 3 protein to differentiate between germ cells, ovarian stromal cells and the cells entering their first meiotic prophase. We used fluorescence in situ hybridization analysis to determine chromosome 13 numbers in each cell. We were able to detect a proportion of trisomy 13 cells in all cases. The average incidence of trisomy 13 cells was 2.04% in stromal antigen 3-positive and 0.91% in the stromal antigen 3-negative cells. The number of the trisomic cells increased significantly with gestational age (for stromal antigen 3-positive cells r=0.93, P=0.0038, for stromal antigen 3-negative cells r=0.85, P=0.0071). This study indicates that besides trisomy 21, the Oocyte Mosaicism Selection model could be extended to trisomy 13 as well. The crucial factor for trisomy 13 seems to be the pre-meiotic/mitotic trisomy 13 mosaicism, leading to a so-called secondary meiotic nondisjunction of those oocytes having three copies of chromosome 13.