Low-level X chromosome mosaicism and its clinical relevance are still under debate. It could be interpreted as a technical artefact, genuine mosaicism or as being age-related. This study evaluated the contribution of X chromosome mosaicism in phenotypically normal women with sporadic premature ovarian failure (POF). During 1999-2008, 114 patients with POF and 64 age matched controls were karyotyped. Thirteen patients (11.4%) had true X chromosome mosaicism (>10% of aneuploid cells) and 12 had (10.5%) low-level X-mosaicism (between 6-10% of aneuploid cells). The mean age of women with true and low-level mosaicism was 26.0 ± 5.65 years and 35.92 ± 3.87 years, respectively (P < 0.001). In the control group the incidence of cells with an abnormal number of X chromosomes was 1-3%. The results have practical implications for genetic counselling and fertility treatment. To search and confirm the low-level mosaicism, a higher number of metaphases should be analysed or additional fluorescence in-situ hybridization analysis must be performed. Although peripheral blood does not reflect the situation in ovarian tissue well, it is presumed that there are different aetiological causes for true and low-level X chromosome mosaicism. The possible causes and reproductive significance of low-level X chromosome mosaicism are discussed.

Our data indicate that enlarged yolk sac may also be visualized in viable pregnancies. Patients with an enlarged yolk sac and normal karyotype require detailed ultrasound evaluation in the second and third trimester.

Purpose Estrogens are known to selectively influence cell proliferation. Physiological variations of blood hormone concentration might play a role in regulating the level of X chromosome aneuploidy. In this study we observed the percentages of X aneuploid cells in standard lymphocyte cultures from blood samples obtained in relation to the menstrual cycle, noting whether collection occurred during either the follicular or the luteal phase. Methods A study consisting of 28 women with X mosaicism and recurrent pregnancy loss, and 28 age-matched healthy controls. Cytogenetic studies were carried out on peripheral blood samples according to standard procedures. Results A significant difference in the percentage of X aneuploidy was found in blood samples obtained during different phases of the menstrual cycle. In the case group, the mean value of aneuploid cells in the follicular and luteal phase samples was 10.0 and 6.3 % respectively and in the control group, it was 2.8 and 1.0 % (P<0.0001). The difference in the case group varied between 0 and 8 % (3.6±2.1 %) and in the control group between 0 and 4 % (1.7±1.1 %). The specificity for detecting true X mosaicism was 0.875. We estimate that the initial diagnosis of X mosaicism could be correct in 68 % of patients with recurrent pregnancy loss. Conclusions This observational study establishes that the time of blood sampling in relation to the menstrual cycle can influence lymphocyte X chromosome mosaicism. The results, further proven by additional controlled studies, would have practical implications for genetic counselling and fertility treatment.

AbstractWe present the case of a 20-year-old man referred to the clinical geneticist because of mental retardation and dysmorphic features because of concerns about hereditability when his older, healthy brother was expecting a child. Deletion of proximal 3q arm was found with standard G-banding, and array comparative genomic hybridisation (array-CGH) was used to further locate the breakpoints. A unique interstitial deletion del 3q13.11q13.33 was confirmed. The first clinical symptoms in the 20-year-old were described at the age of 4 months when the pediatrician reported muscle hypertonia of the lower limbs, which later evolved into hypotonia. Later clinical observations revealed that the patient’s psychomotor development was delayed: he exhibited craniofacial abnormalities, cryptorchidism, thoracic kyphosis, and tapering fingers. Interstitial deletions of the proximal long arm of chromosome 3 have rarely been reported:; there are only 12 previously reported cases. The breakpoints and sizes of described deletions vary greatly, which makes definite genotype-phenotype conclusions impossible at this time. Developmental delay is one of the common features described in the majority of reported cases. The BTB-zinc finger gene ZBTB20 might be a potential candidate gene: it was shown in the mouse hippocampus to be expressed during the important period of neurogenesis of pyramidal neurons. Also, four of patients reported to date had agenesis of the corpus callosum and one, holoprosencephaly. We suggest that the GAP43 gene is involved in the development of structural neurological abnormalities in patients with 3q deletion.

Genetic causes of premature ovarian failure (POF) comprise less than one-third of all cases, among them X chromosome abnormalities, mutations and polymorphisms in some genes. The frequency of X-chromosome mosaicism in women with sporadic POF has been found to range between 3 and 10%, whereas the prevalence of POF in carriers of the FMR1 premutation is estimated to range between 13 and 25%. We report two successful pregnancy outcomes after in vitro fertilization-embryo transfer with donated oocytes in a woman with severe POF of a complex genetic origin. Chromosome analysis, fluorescence in situ hybridization on cultured peripheral blood lymphocytes and buccal mucosal cells, and molecular genetic studies, using autosomal, Y-chromosomal polymorphic microsatellite or short tandem repeat markers and CGG repeats in the FMR1 gene, were performed. FMR1 premutation, sex chromosome mosaicism and blood lymphocyte microchimerism were found. Assisted reproduction techniques can be safely used in POF women after a thorough clinical evaluation and genetic counselling.