Correlation of intercentromeric distance, mosaicism, and sexual phenotype: Molecular localization of breakpoints in isodicentric Y chromosomes

Abstract

Isodicentric chromosomes are among the structural abnormalities of the Y chromosome that are commonly identified in patients. The simultaneous 45,X cell line that is generated in cell division due to instability of the isodicentric Y chromosome [idic(Y)] has long been hypothesized to explain the variable sexual development of these patients, although gonads have been studied in only a subset of cases. We report here on the molecular localization of breakpoints in ten patients with an idic(Y). Breakpoints were mapped by FISH using BACs; gonads and fibroblasts were also analyzed when possible to evaluate the level of mosaicism. First, we demonstrate great tissue variability in the distribution of idic(Y). Second, palindromes and direct repeats were near the breakpoint of several idic(Y), suggesting that these sequences play a role in the formation of idic(Y). Finally, our data suggest that intercentromeric distance has a negative influence on the stability of idic(Y), as a greater proportion of cells with breakage or loss of the idic(Y) were found in idic(Y) with a greater intercentromeric distance. Females had a significantly greater intercentromeric distance on their idic(Y) than did males. In conclusion, our study indicates that the Y chromosome contains sequences that are more prone to formation of isodicentric chromosomes. We also demonstrate that patients with an intercentromeric distance greater than 20 Mb on their idic(Y) are at increased risk of having a female sexual phenotype.

Screening of Y chromosome microdeletions in 46,XY partial gonadal dysgenesis and in patients with a 45,X/46,XY karyotype or its variants

“…Three of our patients (cases 8, 10 and 11) had a breakpoint within regions consisting of palindromes [26,27], which may have contributed to the emergence of these deletions [26,27]. …”

The Role of Number of Copies, Structure, Behavior and Copy Number Variations (CNV) of the Y Chromosome in Male Infertility

“…A similar situation is described for buccal cells of ectodermic origin [32]. Relying on the formation of mosaics in patients with rearranged, dicentric Y chromosomes, some authors suggest that a greater instability of the aberrant Y chromosome might promote its loss during the cell divisions of the germline, thus, promoting the development of a female habitus [34].…”

Interstitial 4q Deletion and Isodicentric Y-Chromosome in a Patient with Dysmorphic Features

“…This idic(Y) was present in all 40 metaphases analyzed, indicating stability of the abnormal chromosome. Bergeron et al [2011] suggested that the intercentromeric distance has a negative influence on the stability of idic(Y), since a greater proportion of cells with breakage or loss of the idic(Y) were found in idic(Y) cases with a greater intercentromeric distance. In fact, our patient presents the smallest intercentromeric distance compared to the 10 idic(Y) patients reported by Bergeron et al [2011].…”