Hum. Reprod. Advance Access originally published online on April 3, 2006
Human Reproduction 2006 21(8):2052-2056; doi:10.1093/humrep/del090
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Chromosome segregation in an infertile man carrying a unique pericentric inversion, inv(21)(p12q22.3), analysed using fluorescence in situ hybridization on sperm nuclei: significance for clinical genetics. A case report
1 Service d’Histologie-Embryologie et Cytogénétique, Biologie de la Reproduction, Hôpital Jean Verdier(AP-HP), UFR-SMBH, Bondy, France and 2 Service d’Aide Médicale à la Procréation, Hôpital Jean Verdier, Laboratoire de Cytogénétique (AP-HP), Bondy, France
3 To whom correspondence should be addressed at: Hôpital Jean Verdier, Laboratoire de Cytogénétique (AP-HP), Avenue du 14 juillet, 93143 Bondy Cedex, France. E-mail: brigitte.benzacken{at}jvr.ap-hop-paris.fr
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Abstract |
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We report the case of a 40-year-old patient referred to our centre after 3 years of infertility. Karyotyping with the aid of fluorescence in situ hybridization (FISH) analysis showed a unique pericentric inversion of chromosome 21:46,XY,inv(21)(p12q22.3). This type of intrachromosomal structural rearrangement can lead to chromosome imbalance in offspring by producing unbalanced gametes if an odd number of crossover events occur within the inverted segment. Therefore, partial trisomy/monosomy with clinical consequences can be observed in the progeny of carriers. Semen samples from the inversion carrier were analysed by FISH using a combination of probes [a subtelomeric 21q probe and a locus-specific Down’s syndrome critical region (DSCR) probe] to evaluate the proportion of recombinant chromosomes. Sperm-FISH analysis of 3400 spermatozoa revealed a 67.4% rate of balanced chromosomes (normal or inverted). The frequencies of recombinant chromosomes with duplication of the long arm and deletion of the short arm, and vice versa, were 11.2 and 21.4%, respectively. The risk for the couple of conceiving a child with an unbalanced chromosome 21 is estimated to be around 32%. This case study shows the utility of sperm-FISH analysis in the genetic counselling of a pericentric inversion in a male carrier to assess the frequency of recombinant chromosomes and therefore evaluate the probability of having a normal conception.
Key words: chromosome 21/human sperm-FISH/pericentric inversion/primary infertility/recombinant chromosome
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Introduction |
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TopAbstractIntroductionCase reportMaterials and methodsResultsDiscussionReferences |
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Pericentric inversions are among the most frequent chromosomal rearrangements with a frequency of 1–2% (de la Chapelle et al., 1974
; Kaiser, 1984). Pericentric inversions result from a two-break event which occurs between the short (p) and the long arms (q) within the chromosome followed by a 180° rotation of the intercalary segment. There is no phenotypic effect in the majority of pericentric inversion heterozygote carriers, when it is a balanced rearrangement. However, infertility, miscarriages and/or chromosomally unbalanced offspring can be observed in carriers of a pericentric inversion (Gardner and Sutherland, 2004). Carriers of such rearrangements are at risk, during meiosis, to produce a percentage of abnormal gametes with duplication of the region outside the inversion segment on one arm of the inverted chromosome and deletion of the terminal segment on the other arm, and vice versa, ending up with duplicated/deficient recombinant chromosomes distal to the breakpoints. Here, we report the case of an infertile patient who carries a unique pericentric inversion of one chromosome 21: inv(21)(p12q22.3). In this study, sperm-fluorescence in-situ hybridization (sperm-FISH) analysis was performed to estimate the proportion of recombinant chromosomes to assess the patient’s opportunity to conceive a normal child.
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Case report |
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TopAbstractIntroductionCase reportMaterials and methodsResultsDiscussionReferences |
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A 40-year-old healthy male of Asian origin was referred to our centre after 3 years of primary infertility. His wife was a 34-year-old woman with normal fertility evaluation (ovulatory cycles with normal ovarian reserve, normal hysterosalpingography and normal karyotype). Male factor infertility was revealed by sperm analysis (World Health Organization, 1999
): sperm count between 2.1 and 3.8 x 106/ml, motile spermatozoa lower than 10% with grade ‘a’ motility equal to 0 and about 90% of spermatozoa with morphologic abnormalities, including mainly head defects (absent or malformed acrosomal cap) and flagellum defects. His medical history was unremarkable, and the physical examination showed normal size testes. Basal hormonal levels of FSH and testosterone were normal. There was no sign of partial seminal tract obstruction (normal carnitine level in the seminal fluid). The patient’s karyotype showed a pericentric inversion of one chromosome 21 never previously described in literature, with breakpoints in the short arm at 21p12 and in the distal region of the long arm at 21q22.3 [between the Down’s syndrome critical region (DSCR) and the subtelomeric 21q region]: 46,XY,inv(21) (p12q22.3) as shown in Figure 1. Unfortunately, the parents’ karyotypes were not available. A microdeletion of chromosome Y was not found for the AZF a, b or c genes (Vogt et al., 1996).
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Materials and methods |
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Semen preparation for FISH
Three ejaculates were washed three times in phosphate-buffered saline (PBS: 150 mmol/l NaCl, 10 mmol/l sodium phosphate, pH 7.2) and centrifuged at 280 g for 10 min (Martini et al., 1998
). The pellet was resuspended carefully in 1 ml of fresh cold fixative solution (methanol:acetic acid, 3:1) and stored at –20°C for 1 h. The samples were then dropped onto clean microscope slides and air-dried (Chevret et al., 1995). The slides were washed twice in standard saline citrate (SSC) for 10 min and then dehydrated in ethanol and air-dried. Sperm heads were decondensed for FISH in 1 mol/l NaOH for 3 min. After washing in cold water, the slides were air-dried.
DNA probes for FISH
From the sperm samples, FISH was performed with a simultaneous locus-specific DSCR probe (21q22.13q22.2) (LSI21) (Abott®, Vysis-Abbott, Downers Grove, IL, USA), a subtelomeric 21q probe (21qtel) (Cytocell®, Cambridge, UK) and an 18 alpha-satellite probe (Abott®), respectively labelled in red (spectrum red), green [fluorescein isothiocyanate (FITC)] and blue (spectrum aqua) (Figure 1). We used the CEP 18 probe as a control of the FISH procedure.
FISH studies
Three microlitres of the probe solutions, denatured at 80°C for 2 min, was deposited onto the slides that were covered with a coverslip and were incubated overnight at 37°C for hybridization. After post-hybridization washes in 0.4 x SSC containing 0.3% Tween 20 at 72°C for 2 min, slides were transferred to 1 x SCC containing 0.1% Tween 20 and then counterstained with 4,6-diamidino-2-phenylindole (DAPI).
Slides were analysed using a Zeiss Axiophot microscope equipped with a camera and were connected to an imaging system software (Applied Imaging, Newcastle-upon-Tyne, UK). Appropriate fluorescence filters for FITC, Texas Red, aqua and DAPI were used to visualize the spots. From the sperm sample, hybridization signals were scored on approximately 1100 spermatozoa per slide (one slide per ejaculate). Only spermatozoa with well-defined boundaries were scored, and signals in specific colour were considered to be multiple when separated by at least one signal diameter (Spriggs et al., 1995; Egozcue et al., 2000; Soares et al., 2001). DAPI-stained spermatozoa with no FISH signals were eliminated. The occasional diploid/disomic spermatozoa detected were not included in the counting. Only spermatozoa with one blue signal (haploid cells) were considered.
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Results |
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Chromosome segregation in spermatozoa from the patient was studied by FISH using the subtelomeric 21q probe and the locus-specific DSCR probe to assess the frequency of recombinant chromosomes. At least 3400 spermatozoa were analysed. The proportions of recombinant chromosomes and balanced chromosomes (normal or inverted) in the patient’s sperm are summarized in Table I. The rate of balanced gametes was 67.4%. The two types of recombinant chromosomes were observed. The frequency of the first recombinant duplication of the subtelomeric region (21q22.3-qter) with deletion of the short arm (21p12-pter) was 11.2%, whereas the frequency of the second recombinant deletion of the subtelomeric region (21q22.3-qter) with duplication of the short arm (21p12-pter) was 21.4%. FISH is shown in Figure 2. The two potential viable recombinants of chromosome 21, with the location of the different probes, are shown in Figure 3.
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Discussion |
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In this study, we report the case of an infertile patient with a unique pericentric inversion of one chromosome 21. The first case of pericentric inversion of one chromosome 21 was reported by Gray et al. (1962)
. Since then, at least 14 cases (Fraisse, 1975; Fraisse et al., 1986; Groupe de Cytogénéticiens Français, 1986; Leonard et al., 1986; Miyazaki et al., 1987; Gabriel-Robez et al., 1988; Tardy et al., 1997; Ilgin Ruhi et al., 2001; Lazzaro et al., 2001) have been reported. The low frequency of inverted chromosome 21 described in the literature is probably because of the small size of this chromosome (Kaiser, 1984). In all cases previously reported except for one (Gabriel-Robez et al., 1988), ascertained after four miscarriages, and for our patient, ascertained by infertility, individuals were referred for Down’s syndrome in offspring resulting from meiotic recombination in the inverted segment. These patients had inherited the rec(21)dup(21q), leading to a partial trisomy of chromosome 21 (including the DSCR). In fact, pairing in meiosis constitutes the main problem in inversion heterozygosis. An odd number of crossover events (during the pachytene stage of meiosis I) within the inversion segment can lead to two monocentric recombinants with reciprocal duplications/deficiencies in the gametes, ending up in a risk of inheriting such an imbalance when conception occurs.
Hence, the offspring of our patient carries such risk of imbalance in the inverted chromosome 21. It has been shown that the risk of recombination depends on the location of breakpoints and on the rearranged chromosomes. Several studies (Dutrillaux et al., 1973, 1980) demonstrated that the more distal the breakpoints, the higher is the risk. This is because of the fact that the imbalance is smaller, thus more compatible with life, and that the probability of crossover will be higher in the inverted segment. Moreover, the risk of a liveborn child with a recombinant is higher when the carrier is ascertained through the birth of an affected individual than through miscarriage or infertility. In a study (Groupe de Cytogénéticiens Français, 1986), the authors estimated that the risk of recombination in patients with an inversion of one chromosome 21 is close to 10%. However, in all previously reported cases, the breakpoints were not similar to our case. In our patient, the breakpoint on the long arm is more distal than those reported in the literature. It is located between the subtelomeric region 21qtel and the DSCR, whereas it is above the DSCR region in all the cases described. Hence, the inverted segment is larger in our patient, leading to a higher risk of recombination.
However, it has been shown that the classical assumption that loops are invariably present at meiotic prophase to realize a homologous pairing in inversion heterozygotes is not true (Gabriel-Robez et al., 1986, 1987; Guichaoua et al., 1986; Saadallah and Hulten, 1986; Batanian and Hulten, 1987; Chandley et al., 1987). Synaptonemal complexes in a subfertile man with a pericentric inversion in chromosome 21 were studied by Gabriel-Robez et al. (1988). In this case, during meiosis, early heterosynapsis was observed. This meiotic process that leads to a failure of crossover reduces the recombination rate. So, bivalents with inv(21) can behave in a different manner to bivalents with another. The authors suggested that there could be different types of inv(21). In one type, the occurrence of homosynapsis would permit the formation of duplications and deficiencies, as the cases described by Fraisse et al. (1986) and Leonard et al. (1986). In the other type (Gabriel-Robez et al., 1988), the absence of homosynaspsis would not permit such duplication/deficiency products to occur. In our case, we have no information regarding the formation of homosynaspis or heterosynapsis during meiosis to predict the opportunity for crossover and consequently the occurrence of recombinant offspring.
In all previous cases, except for only one case of rec(21) which derived from paternal inv(21) (Ilgin Ruhi et al., 2001), the recombinant chromosome originated from inversion carrier mothers. None of the male carriers reported (Fraisse et al., 1986; Daniel et al., 1989), except for one patient described by Ilgin Ruhi et al. (2001), had a child with rec dup(21q), suggesting that the risk of live born child with recombinant chromosome 21 might be very small for a male carrier compared to a female carrier. However, the number of male carriers is limited. This is probably because of the fact that male carriers are infertile. To achieve a better characterization of the meiotic behaviour of this inversion, we used FISH on decondensed sperm nuclei to analyse the segregation. This method has been used in several studies to score recombination frequency within pericentric inversions (Jaarola et al., 1998; Anton et al., 2002; Yakut et al., 2003; Mikhaail-Philips et al., 2004). The results of FISH investigation in our patient showed 67.4% balanced chromosomes (normal or inverted) and 32.6% recombinant chromosomes: 11.2% with dup21q and del21p and 21.4% with del21q and dup21p. Our results agree with the assumption that production of unbalanced gametes depends on the size of the inverted segment with significant risk when the inverted segment is large (Anton et al., 2005).
So in our study, for our patient, the risk of imbalance during conception associated with this inversion after assisted reproductive technologies (ARTs) would be around 32%. We compared our results to the ones of Olivier Cohen, in which the risk was 30.41% as given by Reci-Conseil Data Bank [HC Forum (http://www.hcforum.fr)]. In addition, he suggests that the two imbalanced gametes are potentially viable.
Data of different authors who have performed sperm segregation studies showed a great heterogeneity in the percentage of recombinant gametes (0–37.85%) (Anton et al., 2005). Anton et al. who have compiled their results suggested that the production of a significant level of unbalanced recombinant gametes requires a minimum size inversion of 100 Mbp. Our results showed a high percentage of recombinant gametes (32.56%), despite the small size of the chromosome 21 (approximatively 47 Mbp). This assumption proposed by Anton et al. could be true for long chromosomes but not necessarily for the smaller ones.
Furthermore, the frequency of the two types of recombinants rec(21)dup(21q)/rec(21)dup(21p) was statistically different from the expected ratio 1:1 (
2 = 107.5, P < 0.0001). This could be explained by a selection against the recombinant with the duplication of the long arm, rec(21)dup(21q), during spermatogenesis.
For genetic counselling, the main concerns relate to the phenotypical repercussions of a child inheriting one of these recombinants. It is known that a deletion or a duplication of the region distal to p12 in an acrocentric chromosome does not lead to any phenotypic effect. On the other hand, the presence of an abnormal phenotype (mental retardation and/or malformations) is not always present in patients with partial trisomy or monosomy of the distal region of the long arm of chromosome 21 (21q22.3-qter). (Mattei et al., 1981; Dallapiccola et al., 1986; Pellissier et al., 1988; Estabrooks et al., 1990; Korenberg et al., 1990; Krasikov et al., 1992; McGinniss et al., 1992; Chen et al., 2004). Further molecular characterization with phenotype–genotype correlations in individuals with partial monosomy or trisomy of region 21q22.3-qter might be useful.
For any possible future progeny of our patient, the clinical phenotype of a child carrying one of these recombinants is very difficult to predict. Thus, for ethical reasons, PGD was proposed for the patient, after ICSI, to select balanced embryos for re-implantation. The couple already had two failed ICSI cycles.
In humans, the problem of genetic counselling of inversion carriers and risk estimation is very difficult to resolve. The risk certainly varies according to the inversion itself, depending on several parameters. We suggest that sperm-FISH is essential for better genetic counselling in male carriers of pericentric inversion to assess the risk of producing recombinant chromosomes, especially before ART.
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Submitted on September 2, 2005; resubmitted on December 20, 2005; resubmitted on January 26, 2006; resubmitted on February 8, 2006; accepted on March 1, 2006.
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