| Human Molecular Genetics | Pages |
High level of unequal meiotic crossovers at the origin of the 22q11.2 and 7q11.23 deletions
Introduction
Results
Parental origin of the deletions
Haplotype determination at positions flanking the deletions
A high incidence of meiotic crossovers at 22q11.2 in patients with CATCH 22
A high incidence of meiotic crossovers at 7q11.23 in patients with WBS
No apparent correlation between the sizes of the deletions and the occurrence of unequal meiotic recombinations in patients with CATCH 22 and WBS
Discussion
Recurrence risk of the 22q11 and 7q11.23 deletions
Parent-of-origin bias in the occurrence of deletions and their mode of formation
Materials And Methods
Clinical evaluation of the patients
Molecular analyses
Acknowledgements
References
High level of unequal meiotic crossovers at the origin of the 22q11.2 and 7q11.23 deletions
Interstitial chromosomal deletions at 22q11.2 and 7q11.23 are detected in the vast majority of patients affected by CATCH 22 syndromes and the Williams-Beuren syndrome, respectively. In a group of 15 Williams-Beuren patients, we have shown previously that a large number of 7q11.23 deletions occur in association with an interchromosomal rearrangement, indicative of an unequal crossing-over event between the two homologous chromosomes 7. In this study, we show that a similar mechanism also underlies the formation of the 22q11.2 deletions associated with CATCH 22. In eight out of 10 families with a proband affected by CATCH 22, we were able to show that a meiotic recombination had occurred at the critical deleted region based on segregation analysis of grandparental haplotypes. The incidences of crossovers observed between the closest informative markers, proximal and distal to the deletion, were compared with the expected recombination frequencies between the markers. A significant number of recombination events occur at the breakpoint of deletions in CATCH 22 patients (P = 2.99×10-7). The segregation analysis of haplotypes in three-generation families was also performed on an extended number of Williams-Beuren cases (22 cases in all). The statistically significant occurrence of meiotic crossovers (P = 4.45×10-9) further supports the previous findings. Thus, unequal meiotic crossover events appear to play a relevant role in the formation of the two interstitial deletions. The recurrence risk for healthy parents in cases where such meiotic recombinations can be demonstrated is probably negligible. Such a finding is in agreement with the predominantly sporadic occurrence of the 22q11.2 and 7q11.23 deletions. No parent-of-origin bias was observed in the two groups of patients with regard to the origin of the deletion and to the occurrence of inter- versus intrachromosomal rearrangements.
INTRODUCTION
A number of human diseases are characterized by non-random interstitial deletions, the breakpoints of which appear to occur at `hot-spot' regions (1). This study deals with two diseases usually associated with deletions occurring in proximity to the centromere: the CATCH 22 syndromes (2) associated with a deletion affecting chromosome band 22q11.2 and the Williams-Beuren syndrome (WBS) (3,4) associated with a deletion affecting 7q11.23.
CATCH 22 encompasses a group of related syndromes; the acronym summarizes the major clinical manifestations characteristically detected in the patients, namely cardiac defects, abnormal facies, cleft palate and hypocalcaemia in early infancy due to hypoplasia or aplasia of the parathyroid glands. The group of disorders include the DiGeorge syndrome, the velo-cardio-facial syndrome, and some forms of conotruncal cardiac defects. The vast majority of patients have a common 1.5 Mb deletion on chromosome 22q11.2 (5,6). WBS is a neurodevelopmental disorder characterized by distinctive facial features, growth and mental retardation, hypercalcaemia in infancy and a very friendly outgoing personality. The syndrome is usually associated with a deletion spanning ~2 Mb of chromosome band 7q11.23 (7,8).
A high phenotypic variability is observed in CATCH 22 and WBS. The variability in both the clinical manifestations of certain features and their severity is not easily correlated with the length of the deletions. Illustrative of this phenomenon are discordant phenotypes manifested at times in monozygotic twins (9-12) and in familial cases (6,13). The variability in expression of the two diseases, together with the prevalence of consistent deletions, are indicative of contiguous gene defects. The rare cases where much smaller deletions or translocations have been detected have provided valuable information regarding the minimal critical regions within the `common' deletions. Critical regions have been defined in CATCH 22: a 250 kb region in the proximal region of the `common' deletion and the recently described critical regions at distal positions (5,14-16). The minimal critical region in WBS is ~300 kb in length (17). The characterization of a number of genes mapping to the critical regions has been reported recently (17-25). Strong candidate genes in the CATCH 22 diseases are, for example, the DGSI gene (20), the GSCL gene (21), the UFD1L gene (25) and the TBX1 gene (19), to name just a few of the >12 genes shown to map to the DiGeorge critical regions. Regarding WBS, many features of the disease can be explained by haploinsufficiency of the elastin gene. Other features, such as mental retardation, can be explained by further genes mapping to the common deletion, including the recently described LIM-kinase 1 gene (18), the WSCR1 gene, the RFC2 gene and the STX1A gene (26,27).
The 22q11 and 7q11.23 deletions usually occur sporadically, with an incidence of ~1/10 000 and 1/20 000 live births, respectively (28,29). Familial cases are inherited in an autosomal dominant manner. The 22q11.2 deletion is detected in ~85-90% of clinically diagnosed CATCH 22 patients (5). In ~75% of cases, the maternal allele is affected (30). Regarding WBS, the vast majority of clinically diagnosed patients, and probably all typical WBS cases, have a deletion affecting 7q11.23 (27). No significant statistical difference is detected in the parental origin of the deletion, which has been reported to be only slightly biased in favour of maternally derived deletions (7,31). Possible parent-of-origin effects on the phenotype have been proposed in a recent study by Pérez Jurado et al. (7). In their group of patients, the authors observed more severe forms of growth retardation and microcephaly in association with maternal deletions (7).
The aim of this work was to gain information on the mechanisms of formation of interstitial deletions. In recent publications (31,32), it was shown that unequal meiotic crossover events occur frequently in WBS. Dutly and Schinzel (32) showed that an unequal meiotic recombination occurred at the deletion site in 10 out of 15 probands affected by WBS. The group of WBS cases was extended to 22 families in this study; significant statistical values are obtained for increased levels of recombination at the critical region, thus consolidating the results of the previous report. A high level of meiotic recombinations was also reported to occur at the critical Prader-Willi (PWS)/Angelman syndrome (AS) deletion region (33).
In this study, we are able to show that a high level of interchromosomal rearrangements also occurs in patients with the 22q11.2 deletion associated with CATCH 22. Of the 10 families included in this study, eight showed a meiotic crossover at the critical region. Furthermore, no correlation could be found in either CATCH 22 or WBS between the size of the deletions and the inter- versus intrachromosomal recombinations.
Table 1
Table 2 Table 3
RESULTS
Parental origin of the deletions
Microsatellite markers mapping to the deleted regions were used in order to determine the parental origin of the affected chromosome. Tables 01 and
Haplotype determination at positions flanking the deletions
The occurrence of a meiotic crossover at the critical region was investigated by analysing the segregation of grandparental haplotypes at positions flanking the deletion breakpoints. Grandparental blood samples were collected according to the parental origin of the deletions. Several markers mapping to either side of the deletions were analysed in the three-generation families. Markers located at positions possibly included in the deletions were considered only if two distinguishable alleles were detected in the proband. The markers closest to the deletion breakpoints which were informative as to the grandparental origin of the allele transmitted to the proband are summarized in Tables 3. and
Table 4
A high incidence of meiotic crossovers at 22q11.2 in patients with CATCH 22
As shown in Table 3. , a significant number of 22q11.2 deletions appear to be associated with a meiotic crossover event. Figure 1. shows representative microsatellite results obtained for family 8. The proximal chromosome region is, in this case, of grandmaternal origin and the distal region of grandpaternal origin. For illustrative purposes, the marker D22S258 is depicted in the figure because of a better electrophoretic resolution of the different sized alleles than of the marker reported in Table 3. (i.e. D22S343). On the basis of the average genetic distance between proximal and distal markers, the number of meiotic crossovers expected by randomly analysing 10 individuals would be 0.98. The probability of detecting, by chance, eight or more crossovers in 10 meioses is P = 2.99×10-7 (calculated considering the interference value). In this group of patients, there is no evidence for a parent-of-origin bias in the occurrence of meiotic crossovers: three crossovers were detected in the maternally derived deleted chromosomes, and five in those of paternal origin.
Figure 1. Representative examples of microsatellite analysis at 22q11.2 carried out for family 8. The deleted region of chromosome 22 is indicated with a black bar beside the chromosome 22 ideogram. Marker D22S941, located within the deleted region, illustrates the paternal origin of the deletion. Grandparental origins of the regions flanking the deletion are shown with markers D22S420 (proximal region) and D22S258 (distal region). Figure 2. Representative examples of microsatellite analysis at 7q11.2 carried out for family 25. The deleted region of chromosome 7 is indicated with a black bar beside the chromosome 7 ideogram. Marker D7S1870, located within the deleted region, illustrates the maternal origin of the deletion. Grandparental origins of the regions flanking the deletion are shown with markers D7S672 (proximal region) and D7S524 (distal region).
A high incidence of meiotic crossovers at 7q11.23 in patients with WBS
In this study, we have increased the number of families with a proband affected by WBS from the 15 cases reported by Dutly and Schinzel (32) to 22 families. In the earlier publication, we reported a high incidence of meiotic recombinations associated with WBS. In the group of 15 WBS patients, 10 were shown to have an interchromosomal recombination at the critical 7q11.23 region. The extra patients reported here corroborate this observation further: 13 cases are associated with a meiotic crossover (Table 4. ). Figure 2. shows representative results obtained for family 25. The expected number of meiotic recombinations in 22 individuals would be ~2, based on the average genetic distance between the proximal and the distal markers. The probability of detecting 13 or more recombinations by chance in 22 meioses is P = 4.45×10-9 (calculated considering the interference value). No parent-of-origin bias in the occurrence of crossovers could be detected in the group of patients.
No apparent correlation between the sizes of the deletions and the occurrence of unequal meiotic recombinations in patients with CATCH 22 and WBS
The possibility was investigated of a correlation between the sizes of the 7q11.23 and 22q11 deletions and the occurrence of an unequal meiotic recombination. The approximate breakpoints of the deletions were analysed based on microsatellite markers mapping to the deleted regions. The common deletion usually includes markers D22S941 and D22S944 (34). Markers D22S264 and D22S311 have been reported to be deleted in almost all cases, and markers D22S306 and D22S308 possibly deleted in a much smaller percentage of patients (34). Table 5 summarizes the results obtained for the 10 cases with CATCH 22. No detectable difference was observed regarding the length of the deletions. For all patients, markers D22S941 and D22S311 showed only one allele, indicative of either deletion or homozygosity, and markers D22S427 and D22S306 showed either one or two alleles, placing these markers outside the `common' deletion. The distal breakpoints of the deletions in patient 7 (no meiotic crossover) and patients 1, 2, 3 and 9 (with meiotic crossovers) are all clearly located between markers D22S311 and D22S306.
Table 5
A largely homogeneous size of deletions associated with inter- and intrachromosomal recombinations was also seen in the patients with WBS (Table 6. ). Markers D7S653 and D7S489A usually flanked the deletions and markers D7S489B and D7S1870 showed homozygosity in almost all cases. One exception was detected; patient 13 had a larger deletion which included marker D7S489A. The deletion in this case was associated with a meiotic crossover event. Table 6
DISCUSSION
We show here that a significant number of 22q11.2 deletions in CATCH 22 syndromes are associated with interchromosomal rearrangements indicative of meiotic unequal crossing-over events between sister chromatids. The increase in number of patients with WBS further consolidates the previous finding that unequal meiotic recombinations underlie the formation of a high proportion of 7q11.23 deletions (32; this study).
Divergent reports have been published recently regarding the mode of formation of the deletions affecting the highly imprinted 15q11-13 region involved in PWS and AS (33,35). In one report (33), the authors demonstrated a significantly higher than random incidence of meiotic recombinations in PWS patients: five out of seven deletions were shown to be associated with unequal crossover events. The other report (35) suggests a difference in frequency of interchromosomal crossovers between AS and PWS. The incidence of meiotic crossover events detected in the PWS patients was not higher than that expected randomly, whilst all three AS patients showed an interchromosomal rearrangement at the critical region. A difference in the mode of formation of the paternal (PWS) versus maternal (AS) 15q11-13 deletion would be very interesting; however, the number of patients analysed should be increased in order to confirm this finding.
The seemingly identical size of the deletions involving either inter- or intrachromosomal rearrangements would indicate that the same `hot-spot' regions are involved preferentially in both events. Rare variants in deletion size, such as in patient 13, would suggest that other repeats in the critical region could also be involved in misalignments, but that the intermediate structures may be less stable. Alu sequences and highly homologous sequences have been found to flank the majority of deletion and recombination sites. It can be envisaged that similar sequences are also involved in the formation of the CATCH 22 and WBS deletions. Indeed, the 3[prime] region of the elastin gene has been found to be very rich in Alu sequences (36), and a number of low copy repeats were shown recently to be contained in chromosome 22q11 (37). Repeat sequences and highly homologous sequences are likely to stabilize chromosomal pairings and facilitate crossover events. The mechanism leading to the deletions probably involves mispairing of such elements either in sister chromatids (in the case of interchromosomal recombinations) or the creation of a loop within individual chromatids (in the case of intrachromosomal recombinations), followed by excision of the extruding loop (1).
Recurrence risk of the 22q11 and 7q11.23 deletions
The recurrence risk for healthy parents in cases where a meiotic recombination can be demonstrated is probably not higher than that for the normal population. However, it cannot be excluded that variations in the number and position of repeat sequences may result in a higher rate of unequal crossing-overs. The implications of similar mechanisms underlying both inter- and intrachromosomal deletions are that the recurrence risk for healthy parents would also be minimal in cases of intrachromosomal recombinations considering that the contribution of further endogenous or genetic factors, if at all, appears to be minimal. A slightly higher recurrence risk in these cases must, however, be taken into account due to the possibility of gonadal mosaicism in one of the parents. Indeed, recurrence of deletions has been shown not only in familial cases where one parent is a carrier for the deletion, but also in a familial case described by Eydoux et al. (38) with phenotypically normal parents. In this family, two siblings were shown to have a deletion on 22q11.2 by fluorescence in situ hybridization analysis. It would obviously be very interesting to analyse such cases at the molecular level.
Parent-of-origin bias in the occurrence of deletions and their mode of formation
A parent-of-origin bias is reported in the literature regarding the CATCH 22 deletions. The proportion of deletions affecting the maternal chromosome is estimated at ~75% (30). A slightly higher incidence of maternal deletions has also been reported in WBS (31). In the group of 32 CATCH 22 patients analysed in our Institute for parental origin of the 22q11.2 deletion, a maternal bias was not evident. The deletions affecting the maternal chromosomes (17 cases, 53%) were only marginally more frequent than those affecting the paternal chromosomes (15 cases). The percentage of maternally derived deletions (58%) in the 67 patients with WBS diagnosed at the molecular level in our institute is in agreement with the slightly higher incidence of maternal deletions reported in the literature. Taken together, the data would indicate the lack of imprinted genes in the critical CATCH 22 and WBS regions. This is also evidenced by the apparent absence of abnormal phenotypes in cases with uniparental inheritance of chromosome 22 (39). However, an interesting parent-of-origin repercussion on the WBS phenotype was reported by Pérez Jurado et al. (7). The authors have observed more severe forms of developmental delay in patients with maternally derived 7q11.23 deletions. This study raises the possibility that the 7q11.23 deletions may alter an adjacent imprinting centre (7).
Regarding the mode of formation, no sex-specific occurrence of inter- versus intrachromosomal rearrangements were detected. We observed, however, a high incidence (eight out of 10) of grandmaternal alleles at the proximal positions in the CATCH 22 deletions, whereas an even distribution of grandmaternal and grandpaternal alleles was detected in WBS. A larger group of CATCH 22 patients will be needed in order to support this observation at the statistical level.
MATERIALS AND METHODS
Clinical evaluation of the patients
The patients included in this study were ascertained by clinical geneticists at our institutes or referred to us by general practitioners for molecular diagnosis.
All patients had de novo interstitial deletions. The major clinical findings in the 11 probands with CATCH 22 are summarized in Table 1. . In the first family, the affected children are monozygous twins. The major clinical findings in the 22 patients affected by WBS are listed in Table 2. .
Molecular analyses
Lymphocyte DNA was extracted by standard procedures from blood samples of the probands, their parents and, after determining the parental origin of the deletions, also from the relevant grandparents. Determination of parental origin of the deletions and haplotype analysis was carried out using microsatellite primers purchased from Research Genetics. The localization and genetic distances of the markers reported in the tables are derived from Généthon and GDB linkage maps. The microsatellite markers were used in polymerase chain reactions (PCR) consisting of 35 cycles of: denaturation for 30 s (3 min in the first cycle) at 94°C, primer annealing at 52-60°C for 45 s and primer extension at 72°C for 1 min. The reactions were carried out using a Perkin Elmer PCR cycler. The PCR products were separated on 6% denaturing polyacrylamide gels and visualized by silver staining using standard procedures.
ACKNOWLEDGEMENTS
We are grateful to the patients, their families and physicians for their valuable co-operation. In particular, we would like to thank Dr S. Basaran (Istanbul, Turkey), Dr E. Irnberger (Salzburg, Austria), Dr E. Troy (Hohenems, Austria), Dr T. Felix (Porto Alegre, Brazil), Dr A. Frank (Winterthur, Switzerland) and Professor K. Baerlocher (St Gallen, Switzerland) for referring patients to us. This study was supported by the Swiss National Foundation (grant no. 32-37798.93).
REFERENCES
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