Detection of a New Unbalanced Rearrangement leading to a partial Monosomy Xq and a partial 18q Trisomy associated with Diminished Ovarian Reserve (DOR)"

Diminished Ovarian Reserve (DOR) is a heterogeneous disorder belonging to the gonad failure spectrum, characterized by low numbers of remaining oocytes in the ovaries, usually accompanied by high follicle stimulating hormone (FSH) level. Such diminished ovarian reserve is thought to reflect both a decreased number of eggs and a decrease in egg quality. DOR aetiology factors are multiple and different, such as genetic factors, aging, autoimmune disorders, adrenal gland impairment, iatrogenic, e.g., due to radiation or chemotherapy. At present the exact genetic cause of DOR is still unknown, although DOR with a severe reduction of reproductive performance was reported with a significant high incidence (44.4%) in females carrying X chromosome mosaicisms (45,X/46,XX; 46,XX/47,XXX) without balanced autosomal rearrangements. We report the first unbalanced translocation with segmental loss and gain of genomic fragments associated with DOR. Array CGH and FISH studies revealed a partial Xq monosomy and a partial 18q trisomy resulting from an unbalanced t(X;18) translocation. Real time experiments showed a Xq27 monosomy starting at position 141.2 Mb and a 18q22 duplication starting at position 64.5 Mb. Sequence inspection revealed the presence of a genomic context of LINE-1 (L1) clusters, at both the Xq27 and the 18q22 breakpoints. This structure might increase the likelihood of mispairing, unusual crossover and therefore, gain or loss of genomic materials. To further characterize the outcome of DOR rearrangement, the status of X chromosome inactivation was investigated. Androgen Receptor assay and late-replication DNA analysis revealed a preferential inactivation of rearranged X:18 chromosome, therefore completely skewed inactivation and late replication might mask the outcome of the 18 trisomy as well as of the X monosomy. Our patient has only DOR and no other unusual clinical features. This finding is in agreement with other reports that demonstrated that in X:autosome unbalanced translocation, inactivation signals of X-inactivation centre spread across the X:autosome boundary therefore, resulting in various attenuated phenotypes. Our data include DOR condition among the gonad failure spectrum of diseases linked to X-chromosome abnormalities, and confirm the feature of the Xq27-28 as a region of high genome instability. The hypothesis that the DOR phenotype occurs as a result of faulty meiotic pairing and recombination will be discussed.