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We report on a 23-yr-old healthy female with repeated miscarriages and a de novo complex chromosomal rearrangement (CCR) involving chromosomes 1, 2, 5 and 11 with 5 breakpoints. A review of cases reported in the last five yr is provided.

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ABSTRACT. Distamycin A, netropsin and berenil are knownto cause undercondensation of heterochromatic regions of metaphase chromosomes. These ligands interfere with DNAcurvature by binding to the minor groove of the DNA.Whereas the effects of these ligands upon chromatin structure are well established, little is known about their possible interference with cell cycle progression. Weshow that the presence of these DNAligands causes protracted cell growth consisting of a prolongation of the Gl phase of the cell cycle along with arrest in the G2 compartment. Concomitant with these cell kinetic disturbances the DNAligands cause increased polyploidisation. These observations suggest that the DNA-minorgroove may play an important role in progression through the G2 phase and proper mitotic transit.Being situated between the phase of chromatin duplication (S phase) and the stage of chromatid separation (mitosis) the G2 phase is regarded as the period during which chromatin packaging and folding occurs. This proposition can be tested by perturbing chromosome condensation and subsequent analysis of the cell cycle kinetics of treated cells. Minor groove binding DNA ligands such as berenil (Ber), netropsin (Net) and distamycin A (Dis) induce chromosome undercondensation when added to a cell culture (2,24,25). Thus, these ligands mayserve as probes for chromatin packaging during the G2 phase of the cell cycle. To analyse the putative influence of these ligands on cell cycle traverse, we exposed human diploid fibroblasts to Net, Ber or Dis and analysed cell activation and cell cycle progression with a highly informative cell kinetic assay: bromodeoxyuridine/Hoechst flow cytometry (21 , 22 FBS and 65 juM of both bromodeoxyuridine (BrdU) and deoxycytidine (CdR) and varying concentrations of the agents to be analysed. They were plated into 80 cm2 cell culture flasks (Nunc, Intermed, Denmark) at a density of 2000 to 2500 cells per cm2. All experiments were carried out in incubators with sensor regulated CO2and oxygen supply (Heraeus, Hanau, F.R.G.). CO2was kept constant at 5%(vol/vol), and air was replaced by nitrogen to lower the oxygen concentration to 5% (vol/vol). At intervals from 24 to 96 hours after plating, cells were harvested by trypsinization and stored at -20°C in MEMsupplemented with 10% FBS and 10% dimethylsulfoxide. To avoid any exposure to light of short wavelengths all cell culture flasks were wrapped in aluminium foil and harvesting was under illumination with red light only. Cell staining and flow cytometry. After thawing, cell pellets were resuspended in staining buffer containing 1.2 jug Hoechst 33258 and 2.0jug ethidium bromide per ml of buffer (17, 21). Flow cytometric analysis was performed with an epiilumination flow system of conventional design (ICP 22,

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