Chromosomal rearrangements in Xq and premature ovarian failure: Mapping of 25 new cases and review of the literature

Background: Chromosomal rearrangements in Xq are frequently associated with premature ovarian failure (POF) and have defined a POF 'critical region'. Search for genes responsible for the disorder has been elusive. Methods: We report mapping of novel breakpoints of X;autosome-balanced translocations and interstitial deletions and a review of published X chromosome rearrangements. Results: All the novel POF-associated rearrangements were mapped outside and often very distant from genes. The majority mapped to a gene-poor region in Xq21. In the same region, deletions were reported in women who apparently did not have problems conceiving. Expression analysis of genes flanking breakpoints clustered in a 2-Mb region of Xq21 failed to demonstrate ovary-specific genes. Conclusions: Our results excluded most of the possible explanations for the POF phenotype and suggested that POF should be ascribed to a position effect of the breakpoints on flanking genes. We also showed that while the X breakpoint may affect X-linked genes in the distal part of Xq, from Xq23 to Xq28, interruption of the critical region in Xq21 could be explained by a position effect of the Xq critical region on genes flanking the autosomal breakpoints.