Abstract
As there is some evidence that individuals bearing supernumerary marker chromosomes (SMCs) might have an increased risk of being uniparentally disomic for the structurally normal homologues of the SMC, we made a systematic search for uniparental disomy of the autosomal homologues from which SMCs were derived. Of the 22 families studied, a biparental origin of the normal homologues was demonstrated in 21, and 1 case of paternal isodisomy of chromosome 6 was detected in the carrier of a supernumerary marker ring chromosome 6 which itself was of maternal origin. Our results confirm that uniparental disomy may be found in association with SMCs, but until more cases are studied we can only speculate on their frequency and the mechanism(s) which result in this phenomenon.
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Introduction
Supernumerary marker chromosomes (SMCs) are detected in <0.1% of the general population, but in 0.327% of the mentally retarded [1]. Ramos et al. [2] and Buckton et al. [1] have suggested that the presence of a SMC at meiosis may interfere with normal chromosome disjunction resulting in aneuploidy, and it has been shown that an increased incidence of aneuploidy is associated with an increased risk of uniparental disomy (UPD) by mechanisms of aneuploidy correction [3, 4].
The first hypothesis suggesting a link between a SMC and UPD was that of Robinson et al. [5], who proposed that, in some individuals with a small inv dup(15) SMC and Prader-Willi syndrome (PWS), the disease phenotype may be the result of maternal uniparental disomy of the two normal homologues of chromosome 15. The first evidence that a SMC may be ascertained in combination with UPD was reported by Robinson et al. [6] who described 2 individuals with small inv dup(15) chromosomes; one had paternal isodisomy for chromosome 15 and Angelman syndrome. The other had maternal UPD and PWS.
The prediction of phenotypic risks associated with the ascertainment of an SMC is highly problematic and, with the exception of chromosome 15 markers [7, 8], correlations between the chromosomal origin of markers and their associated phenotypes have not convincingly emerged [9–11]. This karyotype/phenotype correlation would be further complicated if the presence of a SMC predisposes the patient to an increased risk of a concomitant UPD for the normal homologues, as it has been shown that developmental and growth defects may be associated with UPD.
As the frequency of UPD in association with SMCs is unknown, we have carried out a systematic study to determine the parental origin of the normal homologues of the chromosomes from which the SMCs are derived. The SMCs originating from chromosome 15 are reported elsewhere [8], and in this communication we present our results on 22 patients with a SMC which is not of chromosome 15 origin.
Materials and Methods
Study Population
Details of the study population are found in table 1. The chromosomal origin of the SMCs was defined by fluorescence in situ hybridisation in 39 families where the mother, father and proband were available, and of these, 22 have an autosomal origin other than chromosome 15. Peripheral blood was obtained from the proband and both parents in these 22 families and used for the extraction of DNA, the establishment of permanent lymphoblastoid cell lines at the European Collection of Animal Cell Cultures (ECACC), and for conventional cytogenetic and molecular cytogenetic studies. In cases where it was impossible to differentiate between markers of 13 or 21 origin, or between 5 or 19 origin, the parental origin of the normal homologues of both autosomes was determined. The seventeen probands with SMCs of chromosome 15 origin from part of a separate study [8].
Methods
The chromosomal origin of the SMCs was determined using non-isotopic in situ methods as described by Crolla et al. [10]. DNA was extracted from whole blood by a salt precipitation technique [12]. The parental origin of the normal homologues of the chromosomes from which the SMCs originated was determined by polymerase chain reaction (PCR) amplification of chromosome-specific microsatellite repeat sequences [13]. Primers were chosen that amplified sequences located distal to the regions represented by the SMCs, and PCR conditions were those described by Hudson et al. [14]. Details of the primers have been previously published and can be obtained from the Genome Data Base or on request from the authors. PCR products were visualised using a 6% denaturing Polyacrylamide gel followed by autoradiography. Since the object of the study was to determine the frequency of UPD of whole chromosomes as opposed to chromosome regions, a single result indicating a biparental origin of the normal homologues was considered sufficient to exclude UPD.
Results
The results are shown in table 1 from which it can be seen that the normal homologues are biparental in origin in all the probands except case 5 which showed paternal uniparental isodisomy for chromosome 6 in association with a SMC(6) of maternal origin. The proband is a female with intrauterine growth retardation who developed transient neonatal diabetes and details of this case have been reported elsewhere [15].
Discussion
Uniparental disomy is recognised as a possible outcome of a number of mechanisms for aneuploidy correction including gamete complementation, monosomy duplication and trisomy correction [4]. In searching for examples of UPD in humans, efforts so far have been concentrated on those populations who, because of their abnormal chromosome constitutions, were thought to be at increased risk of non-disjunction involving specific chromosomes, and by definition at increased risk of producing UPD by aneuploidy correction [16]. In this context, it has been suggested that the presence of a SMC may interfere with normal disjunction during meiosis, resulting in aneuploidy [1]. Two cases of UPD in association with SMCs have been reported [6]: one was uniparental isodisomy and the other heterodisomy. In this study we have identified a case of paternal uniparental isodisomy in association with a SMC. There are a number of different mechanisms which could result in UPD in carriers of SMCs and some of the possibilities are shown in figure 1.
Postzygotic events resulting in marker formation or UPD might be associated with mosaicism for the SMC and/or UPD, in which case it is possible that the normal homologues may be biparental in a normal diploid line. In our case, the SMC was present in 80% of lymphocytes and although we have not formally ascertained the parental origin of the chromosomes 6 in those cells without the SMC, these techniques would be expected to detect biparental alleles present in 20% of cells.
Prior to this study, a systematic search for the frequency of UPD in association with SMCs had not been carried out. In 17 cases of SMCs of chromosome 15 origin, UPD for the normal homologues of chromosome 15 was excluded in all 10 cases where parental DNA was available [8]. We have shown that UPD of the normal homologues of the chromosome from which the SMC originated does occur, and there is therefore a case for determining the parental origin of the normal homologues in individuals where a SMC is detected prenatally.
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Acknowledgements
RSJ is supported by a grant from the Wellcome Trust, and JAC by a grant from Action Research. We are grateful to our colleagues in the Wessex Regional Genetics Laboratory, notably Professor Patricia Jacobs for her encouragement and constructive criticism.
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James, R.S., Temple, I.K., Dennis, N.R. et al. A Search for Uniparental Disomy in Carriers of Supernumerary Marker Chromosomes. Eur J Hum Genet 3, 21–26 (1995). https://doi.org/10.1159/000472270
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DOI: https://doi.org/10.1159/000472270
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