Balanced structural changes involving the human X: Effect on sexual phenotype

Abstract

Reports of 107 cases (89 females and 18 males) with balanced X-autosome translocations and 11 cases with pericentric inversions (and their families) have been reviewed. Of the 78 informative females, 36 were infertile and had an X-breakpoint in the segment Xq13-26. Thus the existence of the critical segment has been amply confirmed by this review. However the finding of three normal fertile females with deletion of a part or the whole of this segment suggests that it is not the break in the critical segment, as was first thought, but rather the contact between loci in the critical segment and loci external to it that is responsible for the abnormal sexual phenotype. Six females were exceptions to the critical region hypothesis. The X-breakpoints in these were in the critical region and yet each had had one or more children. Three of the six women (two inversions and one translocation carriers) were not wholly normal as they suffered from menstrual cycle disorder, secondary sterility and/or early menopause. Four of the six (including the three true exceptions) had a breakpoint in band Xq22. It is possible that there are two critical segments within Xq13-26 separated by a small segment in band Xq22. Seven of the nine adult male carriers of the balanced X-autosome translocations were infertile. Even from this limited number of cases it appears that male carriers of X-autosome translocations are likely to suffer from a disturbance of spermatogenesis as is the case in mouse and drosophila. Male carriers of X-inversions do not necessarily suffer from infertility. Results from one family with X-inversion suggest that some sort of a position effect in the X affecting the sexual phenotype may also be operating in the male.

Physical mapping of nine Xq translocation breakpoints and identification of XPNPEP2 as a premature ovarian failure candidate gene

“…We found similar phenotypic variability associated with two closely spaced breakpoints in Xq25, SW179 and SW181. Another difficulty with the pairing model is the fact that translocations involving Xp or regions of Xq outside of the critical region impair meiosis in males (Madan, 1983) but not females (Therman et al, 1990), implying that different chromosome regions are important for meiotic chromosome pairing in the two sexes.…”

Somatic chromosomal abnormalities in infertile men and women

“…De novo balanced X-autosome translocations studied thus far have been of paternal origin. Phenotype or fertility effects of a balanced X-autosomal translocation vary depending on the sex of the carrier, the position of the breakpoints and the pattern of X inactivation (Madan, 1983;Schmidt and Du Sart, 1992;Kalz-Füller et al, 1999). Most carriers are phenotypically normal.…”

“…Gonadal dysgenesis in females may occur (Hens et al, 1989) but several female carriers obviously remain fertile. In males usually azoospermia is present (Madan, 1983;Quack et al, 1988;Lee et al, 2003). Some females have multiple anomalies and/or mental retardation.…”

Most X;autosome translocations associated with premature ovarian failure do not interrupt X-linked genes

“…A genetic basis for the disorder is suggested by the occurrence of families with multiple affected women and by an association with X chromosome abnormalities. These include deletions of either Xp or Xq, as well as balanced X;autosome translocations involving the Xq "critical region," an interval from Xq13 to Xq26, excluding part of Xq22 (Sarto et al, 1973;Madan, 1983).…”