1 Cytogenetic Laboratory, General Hospital, BP 1125, 73011 Chambéry cedex, 2 Cytogenetic Laboratory, Cochin-Saint Vincent de Paul Hospital, Paris, 3 Department of Medical Genetics, Hopital dEnfants de la Timone, Marseille, France and 4 Division of Medical Genetics, University of Geneva Medical School, and University Hospitals, 1211 Geneva 4, Switzerland
5 To whom correspondence should be addressed at: e-mail: james.lespinasse{at}ch-chambery.rss.fr
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Abstract |
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Key words: chromosomes 13, 14 and 22/familial balanced complex chromosomal rearrangement/genetic counselling/infertility/meiosis
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Introduction |
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Family report |
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Results |
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The analysis of these 12 markers did not show any evidence of DNA duplication or deletion in the four children analysed. In addition, all informative markers in the three chromosomes do not provide any evidence of uniparental disomy.
Further analysis of genotypes suggests that the children displaying the same rearrangements preferentially share specific haplotypes. For example, the three children having a translocation between chromosomes 13 and 14 show the same alleles on proximal markers of chromosome 13. Moreover, genotypes of chromosome 14 markers are compatible with a common paternal haplotype but not with the maternal haplotype. A compatibility with a common paternal haplotype is also seen with the three most proximal markers of chromosome 22 in the sibs sharing the same chromosomal pattern, whereas sib II4-A does not share.
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Discussion |
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The result of the microsatellite analysis is not easily interpretable. The molecular analysis of the genotypes shows that the proximal part of chromosome 22 is non-informative. We might surmise the existence of a common haplotype in subjects with a translocation (14;22). However, confirmation of this is impossible, the mother (I1-M) being homozygote for marker D22S446, the fathers (I2-A) deduced haplotype being non-informative for D22S420. The data for the three sisters (II2-D, II3-B, II4-A) with the Robertsonian translocation t(13;14) is less ambiguous.
Another hypothesis is possible. I2-A could be a carrier of two translocations: a Robertsonian translocation der(13;14) (p11;p11) and a reciprocal translocation t(14;22) (q32.3;q11.2). During meiosis, a crossing-over would have occurred between the two chromosomes 14 giving rise to a derivative der(13;14)t(14;22) and another der(22)t(14;22); II3-B would have received only the translocation t(13q;14q) whereas II1-C would have received the derivative 14 of translocation t(14;22) without the derivative 22. The other question is the probability of a second crossing-over identical to the index case (II2-D). However, such a relatively simple mechanism is insufficient to explain the identical rearrangement in the sib of the proband, which would seem to suggest that the same crossing-over occurred twice in succession.
Review of the literature suggests that severely unbalanced configurations often occur in female gametogenesis. Paternal origin was, however, very frequently shown in de-novo CCR informative reports. The probability of such uniparental origin occurring by chance alone is 1/256 (Batista et al., 1993). This low probability leads us to speculate that mechanisms resulting in BCCR occur preferentially during spermatogenesis.
BCCR and fertility
BCCR rarely occur in phenotypically normal persons (Fukushima et al., 1986). The impact of CCR on fertility is important. Anomalies of the acrocentric chromosomes increase the risk of sterility (Gabriel-Rodez et al., 1986
). The fact that individual I1-M had six children is surprising. The possibility of a germinal parental mosaicism should be considered. In the female, gametogenesis can accommodate the complexity of CCR. The female may be fertile and have pregnancies that produce phenotypically normal children. In the fathers case (I2-A), we suspect that spermatogenesis produces phenotypically normal children. In contrast, in the literature, male carriers are often subfertile (Johannisson et al., 1985
; Saadallah and Hulten, 1985
) or sterile due to spermatogenic arrest (Rodriguez et al., 1985
).
Studies of the pachytene stage of meiosis have provided clues to the underlying mechanisms responsible for male sterility associated with some autosomal translocations. Three features are regularly observed in such male-sterilizing rearrangements: (i) synaptic failure around breakpoints, (ii) association of the translocation figure with the sex chromosomes, (iii) frequent occurrence of an acrocentric chromosome in the translocation.
Two main models have been proposed to explain gametogenic failure in the male. Burgoyne and Baker (1994) have argued that impairment of spermatogenesis might be attributed to generalized pairing disruption along the genome, an extension of the earlier hypothesis of Miklos (1974
) in which XY-pairing failure was suggested as a primary cause of germ cell failure. Alternatively, the defect could result from XYmultivalent interaction, as originally proposed for the mouse by Forejt (1974
) and later suggested by Chandey (1979
) to explain human spermatogenic failure. Each mechanism in itself may be sufficient to cause spermatogenic failure, but the two could interact, where partial asynapsis between normal and translocated chromosomes would favour attraction between the translocation figure and the differential segment of the X-autosome (Rosenmann et al., 1985
).
Studies of three-way translocation (Johannisson et al., 1985; Saadallah and Hulten, 1985
) gave few indications of XY association, all arms of the hexavalents being fully paired during the pachytene stage. Extensive asynapsis around the breakpoints was a feature, but there was very little evidence of spermatogenic depression or arrest, with the sperm count being within normal limits. Our case presents a hexavalent formed by three acrocentric chromosomes (one Robertsonian translocation and one reciprocal translocation). Meiotic studies on human infertile male carriers of Robertsonian translocation have shown that X-autosome association was attained by the central asynapsis and/or by the terminal chromomere of the acrocentric chromosome involved in the translocation. It was proposed that the acrocentric chromosome favours the contact between the quadrivalent and the sex vesicle, and increases the risk of sterility in male carriers of Robertsonian translocations and of reciprocal translocation involving almost one acrocentric chromosome.
In women, without sex vesicle, an involved cause of infertility does not exist and by itself could explain the different effect on fertility between male and female. Moreover, all the studies on infertile males with a balanced Robertsonian translocation show a slightly reduced number of chiasma. Variations in pattern of maternal recombination have been identified as a risk factor for meiotic chromosome non-disjunction. Recent studies have confirmed the large difference in recombination frequency between human oocytes and spermatocytes and demonstrate a clear between-sex variation in distribution of crossing-over (Tease et al., 2002). They observed an abnormal pattern of meiotic recombination in abnormal oocytes that showed chromosome-pairing errors. These facts could explain the high rate of conceptuses with presumed severely unbalanced karyotypes (spontaneous miscarriages) present in women of this family.
BCCR and genetic counselling
The nature of CCR implies that different unbalanced combinations might be expected to be viable. By attachment to centromeres, the meiotic spindle ensures attachment at the two poles and thus successful segregation of homologous chromosomes to opposite poles (Kallio et al., 1998). Therefore, the complex meiotic configuration disturbs the chromosome orientation and causes abnormal spindle attachment leading to chromosome malsegregation. Moreover, normal meiosis requires crossing-over during homologous chromosome pairing at the pachytene stage: these chromatid exchanges, in the case of complex meiotic configurations, increase the risk of chromosome rearrangement, as for patient II4-A, and of segmental aneuploidy, as for III9-SA. A theoretical prediction of chromosomal segregation in gametes is possible, giving 30 different karyotypes. The empirical estimated risk for spontaneous abortion is 75100% for some BCCR (Creasy, 1989
). The chance of carrying a pregnancy to term with an abnormal and developmentally delayed child is possible and has been estimated at 50% (Wang et al., 1993
). We think that this risk can be higher depending of the type of BCCR (Ruiz et al., 1996
). Viability thresholds for chromosomal imbalances have been estimated at 5% of haploid autosomal length for pure trisomies and 3% for pure monosomies. In a monosomytrisomy combination, the haploid autosomal length represented by the trisomy should not be >3.6% and should not be >0.6% for the monosomy (Cohen et al., 1994
). The resulting viability area has a step shape out of which every chromosomal imbalance is considered as lethal. The risk of serious congenital malformation with de-novo balanced reciprocal translocation between two chromosomes was estimated at
7% (3.5% per each break) on the basis of published data (Warburton, 1991
). For apparently balanced CCR arising de novo, an empirical risk of up to 90% has been proposed for phenotypic abnormality and mental retardation (Gardner and Sutherland, 1989
), although the exact prevalence is impossible to establish. The risk is undoubtedly much smaller. We can speculate on 3.5% per break whatever the number of breakpoints. These values vary slightly with the segregation mode, the sex of the carrier parent and the genomic content of unbalanced chromosomal segments. An international registry of minimal chromosomal imbalances should be considered in order to assist in the counselling of these patients. Preimplantation genetic diagnosis (PGD) has been used for couples with normal fertility but at high risk of having a child with chromosomal abnormalities. PGD increases the implantation rate in human IVF by avoiding the transfer of chromosomally abnormal embryos. Here, the complexity of these BCCR makes the preimplantation diagnosis impossible.
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Conclusion |
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Acknowledgements |
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References |
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Submitted on May 7, 2003; accepted on July 9, 2003.