Background: Mosaicism for chromosomal structural rearrangements (Rea) is rare and the timing and mechanisms of mosaic Rea formation, maintenance, and clinical manifestation are poorly understood. To date, there are no published data on the cytogenetic profile of mosaic Reas. The question as to whether the proportion of abnormal cells in the carrier's cultured blood is clinically significant remains unanswered. A previous study showed a strong female preponderance among carriers of mosaicism for Rea with pericentromeric breaks, indicating female-specific instability in early embryos. However, there is no corresponding study on male to female sex ratio (SR) among carriers of somatic and/or gonadal mosaicism for non-centromeric Rea. Population rates of mosaic Rea carriers calculated from consecutive series of patients referred for various reasons and from prenatal samples have not been established. Therefore the objectives of the present study were several-fold: (1) a study on profiles of Rea involved, (2) comparative analysis of the proportion of cells with unbalanced Rea in blood cultures from asymptomatic and affected carriers, (3) comparative analysis of SR in carriers of mosaicism for balanced and unbalanced Rea, and (4) determination of the population frequency of mosaicism for autosomal Rea.
Results: One hundred and three cases of mosaicism for autosomal non-centromeric Rea (N/Rea; normal line/structural rearrangement) in which the sex of the carrier had been specified were identified in the literature. Among balanced Rea, there was a prevalence of reciprocal translocations (89 %) over inversions (11 %). Among unbalanced Rea, deletions were the most frequent (40 %), followed by duplications (25 %) and rings (16 %). Derivatives and other chromosome abnormalities were less frequent (9 and 10 %). Eight of eleven (73 %) affected carriers of unbalanced Rea displayed a high proportion (>50 %) of abnormal cells compared to 4/37 (11 %) in asymptomatic carriers, p < 0.0001. Among carriers of mosaicism for balanced Rea there was a slight male predominance, 24 M/22 F, unlike the strong female predominance among carriers of mosaicism for unbalanced Rea, 11 M/46 F, p < 0.0001. Among ten carriers of unbalanced Rea with reproductive failure, only one was a male with infertility, and one was a partner of a woman experiencing recurrent spontaneous abortion. Population rates of mosaics for reciprocal translocaton (N/rcp), inversion (N/inv), and unbalanced Rea (N/unbal Rea) calculated from published data on consecutive series of patients with reproductive failures were 0.02 ‰, 0.005 ‰, and 0.002 ‰, correspondingly. Among 30,376 infertile patients three carriers of mosaicism for balanced Rea were identified (two cases of N/rcp and one case of N/inv), whereas among 26,384 patients with habitual abortion seven carriers were detected (five N/rcp and two N/inv). Among all 56,760 tested patients with reproductive failures only one was found to be a carrier of mosaicism for an unbalanced Rea (N/del, mosaicism for deletion).
Conclusions: A high proportion of Rea cells (>50 %) detected in cultured T-lymphocytes is associated with clinical manifestation of chromosomal imbalance. A strong female prevalence among carriers of mosaicism for unbalanced Rea suggests male-specific selection against abnormal cells rather than impairment of male gametogenesis, as the latter suggests a better prognosis for male fetuses. These findings should be taken into consideration when genetic counseling of patients referred after a diagnosis of mosaicism for an unbalanced rearrangement in a fetus.