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Case Report |
From the * Veterinary Research Institute and
Repromeda, Brno, Czech Republic.
| Correspondence to: Jiri Rubes, Department of Genetics and Reproduction, Veterinary Research Institute, Hudcova 70, 621 00 Brno, Czech Republic (e-mail: rubes{at}vri.cz). |
| Received for publication September 2, 2008; accepted for publication December 1, 2008. |
We identified a small, paternally inherited, supernumerary marker
chromosome, inv dup(15), in a phenotypically normal and normozoospermic male
from a couple with reproductive problems. Sperm analysis by fluorescence in
situ hybridization (FISH) showed that the marker was present in 26% of sperm
nuclei. The disomy 15 was 10 times higher than in normal control donors. FISH
analysis for aneuploidies of the other chromosomes showed an increase in
nondisjunction of chromosome 21. We also examined 24 embryos by
preimplantation genetic diagnosis, and 10 embryos (41.7%) contained the
marker. This report provides information about inheritance of inv dup(15) from
a male carrier.
Chromosomal aberrations play an important role in the etiology of male infertility, but the influence, if any, of sSMCs is uncertain. Older meiotic studies on sperm from sSMC carriers using human in vitro fertilization (IVF) with the hamster egg bioassay or fluorescence in situ hybridization (FISH) showed 1:1 segregation ofthe marker chromosome in sperm karyotypes, as expected (Martin et al, 1986; Mennicke et al, 1997). More recent FISH analysis ofsperm nuclei in sSMC carriers showed a lower proportion of spermatozoa with the marker (Cotter et al, 2000; Paetzold et al, 2006).
An influence of sSMCs on the occurrence of nondisjunction by the so-called interchromosomal effect (ICE) also could be hypothesized. The sSMCs might disrupt the normal pairing and disjunction ofother chromosomes during meiosis, as is observed in some carriers of chromosomal translocations. Sperm chromosome studies using FISH analysis provide a means ofexploring these possibilities in sSMC carriers (Mennicke et al, 1997).
Preimplantation genetic diagnosis (PGD) often is used for selection of normal and balanced embryos for embryo transfer during in vitro fertilization (Munne, 2002, 2005; Simopoulou et al, 2003; Otani et al, 2006). Using appropriate specific probes, PGD detects marker chromosomes in preimplantation embryos from sSMC carriers as well as aneuploidy in the embryos. One or two blastomeres have been examined by the FISH method, using probes for 5–9 chromosomes (Munne et al, 1993; Thornhill et al, 2005).
Here, we report a case study in a phenotypically normal male proband carrying sSMC. A small supernumerary marker chromosome was identified as a familial heterochromatic dicentric derivative ofchromosome 15. Investigations ofsomatic cells combined with sperm analysis informed genetic counseling of the couple. Multicolor FISH analysis ofsperm and blastomeres (PGD) was used to determine the segregation ratio ofthe supernumerary marker chromosome and aneuploidy ofchromosomes 13, 15, 16, 18, 21, 22, X, and Y. Although there are 3 case studies on sSMC(15) in sperm ofcarriers (Mennicke et al, 1997; Cotter et al, 2000; Paetzold et al, 2006), this is the first report on the frequency of this sSMC in both sperm and preimplantation embryos.
Case Report
The proband was a 29-year-old male with karyotype 46,XY,+mar. The marker
was ascertained during cytogenetic examination performed because of primary
sterility of the couple. Cytogenetic analysis of the proband's parents
confirmed the presence of sSMC in all investigated metaphase lymphocytes of
his father. The proband reported no health problems; his seminal parameters
(volume, concentration, percentages of motile and morphologically normal
sperm) were normal according to the World Health Organization guidelines
(1999). Sperm chromatin
integrity detected by the Sperm Chromatin Structure Assay
(Evenson et al, 2002) failed
to show either increased frequency of sperm DNA breaks or defects in sperm
chromatin condensation. His wife, a 30-year-old woman, reported no health
problems. Her karyotype was found to be normal. The couple underwent 2 IVF
cycles with PGD analysis for aneuploidy and detection of marker chromosome and
FISH analysis of sperm for the same chromosomes as the embryos. The patients
gave their informed consent to participate in the study. This study was
approved by the Institutional Review Board of the Repromeda center for
reproductive medicine.
Materials and Methods
Cytogenetic and FISH Analyses of Lymphocytes—
Reverse FISH was performed for identification of the marker. The DNA probe
was prepared from the whole marker chromosome using laser microdissection in
our laboratory (Kubickova et al,
2002). This probe, labeled with Spectrum Orange, was hybridized
with metaphase chromosomes prepared from the cultured lymphocytes of the
patient. Furthermore, the origin of the marker chromosome was investigated by
FISH analysis using 2 DNA probes specific for chromosome 15: a satellite III
probe D15Z1 (Spectrum Aqua; Abbott, Abbott Park, Illinois) and an
-satellite probe D15Z4 (red; Cytocell, Cambridge, United Kingdom).
Hybridization was performed according to the manufacturer's instructions.
Semen Sample— Semen was collected by masturbation after requested 2-day abstinence. The semen was stored frozen in liquid nitrogen without any cryoprotectives. For the FISH assay, the sample was thawed at room temperature, and semen was smeared onto clean microscopic slides and allowed to air dry. Slides were fixed in methanol–acetic acid (3:1). Sperm nuclei were decondensed by dithiothreitol as described by Robbins et al (1993) and hybridized immediately.
FISH Analysis of Sperm—
We carried out 4 different FISH experiments. The first FISH experiment was
performed for the assessment of the frequency of sperm with the sSMC and
disomy for chromosomes 15 and 18. A 3-color FISH assay was performed using
chromosome 18 -satellite probe (Spectrum Orange; Abbott), chromosome 15
satellite III probe (D15Z1, Spectrum Aqua; Abbott), and a subtelomeric probe
for chromosome 15q (green; Q-BIOgene, Illkirch, France). The next experiment
allowed determination of the ratio of X- to Y-bearing spermatozoa with sSMC
and frequency of sex chromosome disomy. The 4-color FISH assay was performed
using chromosome X -satellite probe (a 1:1 mixture of probes labeled
with Spectrum Orange and Spectrum Green to obtain a yellow signal; Abbott),
chromosome Y satellite III probe (Spectrum Orange; Abbott), chromosome 15
satellite III probe (Spectrum Aqua; Abbott), and a subtelomeric probe for
chromosome 15q (green; Q-BIOgene). The 2-color FISH was performed using a
satellite probe specific for chromosome 16 (green; Q-BIOgene) and a chromosome
21 locus-specific probe (Spectrum Orange; Abbott), for the detection of disomy
of chromosomes 16 and 21. Finally, the 2-color FISH was performed using
subtelomeric probes 13qter and 22qter (green and red; Q-BIOgene) for detection
of disomy of chromosomes 13 and 22. FISH was performed according to Rubes et
al (2005).
Sperm Scoring After FISH— The slides were examined using an Olympus BX60 fluorescence microscope equipped with fluorescein isothiocyanate–propidium iodide (FITC/PI) dual filter, a DAPI/FITC/Texas Red triple-bandpass filter, FITC, Texas Red, aqua single filters (Olympus, Melville, New York), and phase-contrast optics. Strict scoring criteria were used for the scoring (Rubes et al, 2005). More than 10 000 sperm nuclei after hybridization were scored in each FISH experiment.
IVF and PGD— The couple underwent 2 IVF cycles that were combined with intracytoplasmic sperm injection (ICSI) and PGD. For ICSI (Palermo et al, 1992), the ejaculate was immediately processed by sperm washing, centrifugation, and swim-up techniques. The embryos were biopsied on developmental day 3, and 1 or 2 blastomeres from each embryo were fixed on a glass slide using the Tween-HCl method (Coonen et al, 1994).
FISH Analysis of Blastomeres— PGD was performed by sequential FISH with probes for 8 chromosomes: MultiVysion PB probe (Abbott) specific for chromosomes 13, 16, 18, 21, and 22 was used in the first round; chromosome 15 satellite III probe (D15Z1, Spectrum Aqua; Abbott) and a subtelomeric probe for chromosome 15q (red; Q-BIOgene) were used in the second round; finally, CEP X/Y probe (Spectrum Green/Orange; Abbott) specific for chromosomes X and Y was used in the third round. Hybridizations were performed according to the manufacturer's protocols. The criteria for signal scoring described previously by Munne et al (1998) were used.
Statistic Analysis— The data were analyzed by means of the coincidence test for relative frequencies. Statistic analysis was performed by the Statistical Package for Social Sciences (version 15.0 for Windows; SPSS Inc, Chicago, Illinois) software package. The differences were assumed to be significant when the P value was lower than .05.
|
-satellite and satellite III probes for chromosome
15 (Figure 2) helped us specify
the origin of the marker. Thus, the sSMC was identified as a heterochromatic
dicentric marker, and the proband's karyotype was therefore defined as 47,XY,
+mar.ish inv dup(15) (D15Z1++,D15Z4+).
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Preimplantation Embryos— In the first cycle, 13 oocytes were retrieved, and 8 oocytes were successfully fertilized. In the second cycle, 26 oocytes were obtained, and 22 oocytes were successfully fertilized. Five embryos from the first cycle and 19 embryos from the second cycle were biopsied; the remaining embryos were unsuitable for PGD analysis (low number of cells and/or fragmentation). A total of 24 embryos (38 blastomeres) were evaluated, of which 10 (41.7%) carried sSMC(15). The results of screening for sSMC and aneuploidy in the tested chromosomes are summarized in Table 2. In the first cycle, no embryos could be transferred because all evaluated embryos carried chromosomal aneuploidy and had poor morphology (no embryo developed to blastocyst). A total of 8 blastocysts (42.1%) were obtained in the second cycle. In this cycle, all chromosomally normal embryos without sSMCs and with good morphology (2 hatching blastocysts and 1 expanded blastocyst) were transferred to the uterus, but no pregnancy was achieved.
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Discussion
Isodicentric chromosomes 15 (idic(15) or inv dup(15) chromosomes) are the
most common sSMCs in humans (Webb,
1994). Several studies reported an increased incidence of sSMC(15)
in infertile males with oligozoospermia or azoospermia
(Martin-Lucas et al, 1986;
Manenti, 1992;
Gentile et al, 1993;
Morel et al, 2004). Females
with sSMC(15) usually show a normal fertility, which could be the reason for
the prevalence of maternal inheritance of the familial sSMC(15) reported by
some authors (Steinbach et al,
1983; Buckton et al,
1985; Webb, 1994;
Leana-Cox et al, 1994;
Blennow et al, 1995;
Liehr et al, 2004). However,
some later studies showed an almost equal inheritance of the marker from both
parents (Eggermann et al,
2002; Crolla et al,
2005). Our patient described here is a carrier of a familial
heterochromatic dicentric sSMC, which was characterized by FISH analysis as an
inv dup(15)(D15Z1++, D15Z4+). He inherited this sSMC from his father. The
father of the proband was obviously fertile, and the proband's sperm
apparently fertilized normally with ICSI. The normal phenotype of the proband
and his father is consistent with the observation that sSMC(15) contains only
heterochromatin.
As yet, sSMC segregation in meiosis has been studied in only 6 males. Based on the human IVF with the hamster egg bioassay, Martin et al (1986) reported that the frequency of sperm nuclei containing the marker chromosome in 2 cases of unrelated fertile males (who were carriers of a bisatellited marker chromosome of unknown origin, but not chromosome 15) was not significantly different from the expected 50%. However, this method allows analysis of only a small number of sperm. Wiland et al (2005) identified sSMC(20) in 4% of lymphocytes and 8.25% of sperm in a phenotypically normal male by FISH. This finding indicated mosaicism among the gametogenic cells, in which the proportion of cells containing the sSMC(20) may reach a minimum of 16%. Concerning sSMC(15), only Mennicke et al (1997), using FISH analysis, confirmed the expected 1:1 segregation in the sperm of a healthy male with a history of infertility. On the other hand, Cotter et al (2000) and Paetzold et al (2006) detected only 6.23% and 17%, respectively, of sperm with the sSMC in the cases they investigated.
In our case, the sSMC(15) was observed in 26.55% of sperm nuclei analyzed. These data indicate some form of selection process against the marker during spermatogenesis or the possibility of a tissue-specific mosaicism. Unfortunately, no additional tissue samples from the patient were available for the assessment of potential tissue-specific mosaicism. A similar selection during meiosis was observed in fertile XYY males, who predominantly produced normal sperm containing a single-sex chromosome. It was proposed that any germ cell(s) eliminating the extra Y chromosome would have a selective advantage, with only 46,XY cells completing meiosis (Faed et al, 1976; Gabriel-Robez et al, 1996). Thus, in those males in whom the extra Y was eliminated, spermatogenesis would proceed normally. A comparable mechanism may exist in some sSMC carriers (Cotter et al, 2000). The association of other chromosomal material with the XY bivalent was found to be correlated with the impairment of spermatogenesis. When the marker chromosome associates with the XY bivalent, spermatogenetic failure occurs during prophase of meiosis I, leading to an early disruption of spermatogenesis (Jaafar et al, 1994). Similar associations of the trivalent or quadrivalent with the XY bivalent were observed in infertile translocation carriers with spermatogenetic impairment. In fertile translocation carriers, such associations are less likely to occur (Solari, 1999). In 2 subfertile male carriers of the sSMC, the marker was observed predominantly as univalent (Chandley, 1970). We also tested the hypothesis of whether the marker preferentially segregates into gametes with either X or Y chromosome. There was no difference between the frequency of X- and Y-bearing sperm with sSMC(15).
Sperm analysis of our patient showed that 1% of sperm was disomic for chromosome 15. This result is significantly higher than the published frequency of chromosome 15 disomy in healthy males (Spriggs et al, 1995; Mercier et al, 1998; Templado et al, 2005) and also higher than the 0.3% frequency of disomy 15 ascertained by Paetzold et al (2006) in the sperm of a carrier of similar sSMC(15). Accordingly, it seems that each sSMC(15) individually affects the segregation of normal chromosome 15 during meiosis.
Several early reports suggested that the sSMCs interfere with the segregation of other chromosomes during meiosis (interchromosomal effect), resulting in an increase of nondisjunction (aneuploidy) associated with the sSMC (Ramos et al, 1979; Bartsch et al, 1980; Anneren et al, 1984). Martin et al (1986) reported an increase in aneuploidy of chromosomes 18, 21, 22, X, and Y in sperm of the sSMC carrier. However, the authors analyzed only 31 sperm cells. Cotter et al (2000) detected that there was no ICE leading to nondisjunction of chromosome 18 due to the presence of a del(15) marker chromosome in their carrier. We examined the frequency of disomy for chromosomes 13, 16, 18, 21, 22, X, and Y in sperm of the sSMC(15) carrier. The frequency of sperm nuclei with disomy 21 in our patient was significantly increased compared with the published data (Rubes et al, 2005); this could indicate an ICE. However, it should be taken into consideration that the frequency of sperm disomy increases by only a few tenths of one percent and obviously does not markedly affect reproductive functions in its carrier. The risk to the progeny is also very low. Steinbach and Djalali (1983) concluded from a review of the literature that there was no increase in trisomic conceptions or miscarriages in sSMC carriers. We observed a significantly lower occurrence of sperm nuclei with disomy of chromosome 22 in our patient, compared with the mean published by Templado et al (2005). However, they presented the mean frequency of disomy for this chromosome only from 2 cases, and an extremely high frequency—that is, 1.21%—was described in one of them (Martin and Rademaker, 1999).
In our case, sSMC(15) was observed in 41% of preimplantation embryos. A total of 33.3% embryos were euploid for chromosomes 13, 15, 16, 18, 21, 22, X, and Y in 2 IVF cycles. This is in accordance with the previously published frequencies, which ranged between 29.7% and 36% of chromosomally normal embryos. These were found by preimplantation genetic diagnosis—aneuploidy screening—in extensive studies performed by Bahce et al (2000), Gianaroli et al (2001), Munne et al (2003) and Baart et al (2006). Our frequency of chromosomally normal embryos in PGD analysis was 40% (3787 tested embryos from 2003–2008; unpublished data). It seems that the presence of sSMC(15) does not adversely affect the early development of the embryos' appearance. The percentage of blastocysts (42.1%) in the second cycle was higher than our clinic's average at that time. (The average percentage of blastocysts at that time, ie, 2004, was 31.7%; unpublished data). When the sperm of an anonymous donor was used in the third IVF cycle of the couple without PGD analysis, 2 excellent blastocysts were transferred, and pregnancy was established. However, the pregnancy ended with an early miscarriage. Therefore, this couple may have a female factor for infertility, and the presence of an sSMC may be a coincidental rather than a causative factor.
Paetzold et al (2006) suggested that genetic risk is low to the offspring of a male carrier of familial heterochromatic sSMC(15). They concluded that a potential increase in nondisjunction of chromosome 15 with trisomy rescue mechanism after fertilization (uniparental disomy 15 or mosaic trisomy 15) and unequal crossing over of a normal chromosome 15 with the sSMC(15) during male meiosis (duplication or deletion of 15q11.2 in the normal chromosome 15 or an insertion of euchromatic material into the marker) can also become risk factors. Generally, satellite sSMC carriers are considered to be at low risk for abnormal phenotype, as are individuals with inherited markers (Douet-Guilbert et al, 2007).
This report provides further information about inheritance of sSMC(15) from a paternal carrier and about variability in segregation of the sSMC. Selection against the sSMC(15) during spermatogenesis is suggested in some patients, but the influence of the sSMC on the fertility of the proband could not be ascertained from the data available. Further studies are necessary to evaluate why and under what circumstances spermatogenesis is prone to failure, selection against, or transmission of the marker chromosome. The significance of sSMC such as reported in this case remains unclear for the purpose of genetic counseling.
Footnotes
Supported by the Grant Agency of the Ministry of Health (NS 9842-4/2008).
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