Hum. Reprod. Advance Access originally published online on February 5, 2007
Human Reproduction 2007 22(5):1292-1297; doi:10.1093/humrep/del507
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Complex chromosomal rearrangement and intracytoplasmic sperm injection: A Case Report
1 Laboratory of Cytogenetics 2 Reproductive Biology Laboratory, CECOS 3 Department of Gynecology and Obstetrics, Rouen University Hospital, Rouen Cedex, France 4 Department of Genetics, Hospital Necker Enfants-Malades, Paris, France 5 Laboratory of Cytogenetics, Nantes University Hospital, Nantes Cedex, France
6 To whom correspondence should be addressed at: Laboratory of Cytogenetics, Rouen University Hospital, 1 rue de Germont, 76031 Rouen Cedex, France. Tel: +33 2 32 88 82 20; Fax: +33 2 35 98 20 07; E-mail: geraldine.joly-helas{at}chu-rouen.fr
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Abstract |
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Complex chromosomal rearrangements (CCRs) are rare events in human pathology and are usually considered to induce severe reproductive impairment by disturbing the meiotic process and producing unbalanced gametes responsible for high reproductive risk. One-third of all CCRs are familial and tend to implicate fewer breakpoints and fewer chromosomes than de novo cases. CCRs are rarely transmitted through spermatogenesis and are primarily ascertained by male infertility. We report a familial balanced CCR, with seven breakpoints involving three chromosomes, which was detected prenatally in a female fetus conceived after intracytoplasmic sperm injection (ICSI) in a couple initially thought to be a carrier of a paternal reciprocal translocation involving two chromosomal breakpoints. Fluorescent in-situ hybridization (FISH) was used to elucidate the complexity of this CCR. The karyotype of the female CCR carrier was balanced and determined as 46,XX.ish t(1;4)(q42;q32)(WCP1+, D1Z5+, WCP4+, D1S3738–, D4S2930+; WCP4+, D4Z1+, WCP1+, D4S2930–, D1S3738+), ins(1;11)(q41;q23q24)(WCP1+,WCP11+, D11S2071–, MLL+; WCP11+, D11S2071+, WCP1–, MLL–), ins(4;11)(q23;q14q23)(WCP4+,WCP11+; WCP11+,WCP4–). The same balanced CCR was confirmed in her oligozoospermic father. We report, to our knowledge, the first case of ICSI performed in an infertile male with CCR, resulting in a balanced CCR carrier female with a normal clinical follow-up at 4 years of age. This particular case stresses the point of the relevance and feasibility of ICSI procedure in cases of balanced CCRs.
Key words: complex chromosomal rearrangement/FISH/genetic counselling/ICSI/male infertility
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Introduction |
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TopAbstractIntroductionCase reportMaterial and methodsResultsDiscussionAcknowledgementsReferences |
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Complex chromosomal rearrangements (CCRs) are defined as reciprocal exchange between three or more chromosomes. They are rare events in human pathology and only
100 CCRs have been defined as constitutional findings (Mercier et al., 1996
). Classifications have been proposed on the basis of the number of breaks and familial or de novo occurrence (Kleczkowska et al., 1982; Kousseff et al., 1993).
When the number of breakpoints (Kousseff et al., 1987) and the number of chromosomes implicated increase, the correct characterization of the rearrangement by the cytogeneticist becomes increasingly difficult (Tupler et al., 1992). The interpretation of CCRs by conventional banding techniques alone may be impossible, particularly when deletions, insertions or inversions are present in addition to the reciprocal translocations. Fluorescent in-situ hybridization (FISH) with chromosome-specific DNA probes allows to explore chromosome rearrangements in greater detail (Batista et al., 1993; Fuster et al., 1997; Wieczorek et al., 1998).
An empirical risk of 3.5% for malformation/mental retardation in offspring is estimated for each break occurring in euchromatic regions. The risk figure is lower for breaks involving heterochromatic blocks (Warburton 1991; Cotter et al., 1996).
Whereas consequences of simple reciprocal translocations for male fertility have been well investigated, CCRs are generally considered to lead to severe reproductive impairment via meiotic disturbance or production of unbalanced gametes. Spermatogenesis dysfunction in translocation carriers can now be bypassed by intracytoplasmic sperm injection (ICSI). The question still remains as to whether or not an ICSI procedure may be safely proposed to a CCR infertile carrier couple with a very high genetic risk.
We report a CCR involving three chromosomes, which was detected prenatally in a female fetus conceived after ICSI in a couple initially considered to carry a two breakpoint paternal balanced chromosomal reciprocal translocation.
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Case report |
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The couple presented in this case report was initially investigated at an infertility centre other than the Rouen University Hospital.
No familial history of infertility, recurrent spontaneous absortion (RSA), hereditary disease or malformation was present in this couple. The healthy 31-year-old woman had a normal gynaecological status and a 46,XX karyotype. The 35-year-old husband was unrelated to his wife. Three semen analyses over a 3-month period revealed azoospermia. Biochemical semen parameters and plasmatic levels of follicle-stimulating hormone, luteinizing hormone and testosterone were normal. The male was phenotypically normal, which was confirmed on urological and ultrasound examination of the testis, indicating a diagnosis of non-obstructive azoospermia. Cytogenetic evaluation was not performed at our Laboratory of Cytogenetics of Rouen University Hospital. The karyotype was considered as a balanced reciprocal translocation between the long arm of chromosome 4 and that of chromosome 11: 46,XY,t(4;11)(q34;q13.5). A first genetic counselling was performed in the initial infertility clinic. After this genetic counselling, taking account of the structural rearrangement, the couple accepted a bilateral testicular biopsy with testicular sperm extraction, which was not performed at our infertility centre. Unfortunately, no spermatozoa were found in the left and right testes. The couple decided to choose artificial insemination using donor sperm and was referred to our CECOS (Centre d'Etudes et de Conservation des 
ufs et du Sperme Humain) of Rouen University Hospital where another semen analysis was carried out. Surprisingly, it revealed cryptozoospermia. Rare motile spermatozoa were cryopreserved. An ICSI procedure was proposed to the couple. A second session of genetic counselling was given at our Rouen University Hospital Cytogenetic centre taking account of the structural rearrangement diagnosed out of our Laboratory of Cytogenetics and according to the theoretical data concerning the risk of fetal unbalanced karyotypes. The ‘pachytene diagram predictive method’ (Jalbert et al., 1980) was used and an estimation of 16.7% risk of malformation/mental retardation in offspring was concluded. According to this evaluation, the couple accepted an ICSI procedure instead of donor insemination. Prenatal diagnosis in the event of a successful pregnancy following ICSI was strongly advised (Baschat et al., 1996; Bonduelle et al., 1996; Testart et al., 1996).
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Material and methods |
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Ovarian stimulation and oocyte preparation
Oocyte retrieval was performed after pituitary desensitization with GnRH agonist (Décapetyl®, Ipsen, France) and ovulation induction with recombinant folliculo-stimulating hormone (GonalF®75, Sérono, France). According to sonographic and hormonal criteria, oocyte maturation was induced by administration of 5000 IU human chorionic gonadotrophin (Gonadotrophine Chorionique ‘Endo’®, Organon, France), and oocytes were collected under vaginal ultrasound-guided puncture 35 h later.
ICSI procedures
ICSI was carried out according to the procedure described by Rives et al. (1998). Briefly, oocytes were exposed to hyaluronidase (MediCult, Lyon, France). Oocytes with a first polar body were injected with rare spermatozoa isolated after migration on one layer (90%) of gradient density medium (Puresperm®, JCD, Lyon, France).
Culture of injected oocytes and embryos was performed in IVF medium (MediCult, France) under 5% CO2 at 37°C. Embryo cleavage and quality were evaluated 48 h after the injection, just prior to the transfer.
Cytogenetic and FISH investigations
Metaphase chromosomes were obtained from amniotic fluid cells from the mother and from the peripheral blood of the father. These samples were used for karyotype as well as for the FISH analysis. Constitutional karyotypes were established after R and G bandings according to conventional cytogenetics procedures. FISH was performed according to the manufacturer's instructions.
Dual colour FISH was undertaken using whole chromosome painting (WCP) libraries (Vysis, Downers Grove, IL, USA). WCPs for chromosomes 1, 4 and 11 were directly labelled with fluorescein isothiocyanate or cyanine 3.
Specific subtelomeric probes of chromosomes 1 and 4 (Vysis USA) were used to hybridize the q telomeres of these chromosomes.
The directly labelled MLL (11q23) dual colour probe (Vysis USA) was used to investigate the abnormal chromosome 11q.
Spectral analysis was performed according to the manufacturer's instructions (Applied Spectral Imaging). Briefly, 10 µl of the probes were hybridized to the fetus's metaphase chromosomes. Hybridization was performed for 2 days at 37°C. Images were acquired with an SD200 Spectracube (Applied Spectral Imaging) mounted on a Zeiss Axiophot II microscope.
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Results |
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During the first attempt, a total of 23 oocytes were recovered. Of these, 14 oocytes in metaphase II with a polar body were available for ICSI. A total of 10 two pronuclei oocytes were obtained and cleaved to produce 10 embryos. Two embryos were transferred 72 h after oocyte puncture and two embryos were frozen. No pregnancy was obtained after fresh embryos' transfer. Later, the transfer of two frozen–thawed embryos resulted in an ongoing pregnancy. An ultrasound examination at 7 weeks of gestation detected a unique gestational sac and cardiac activity. An amniocentesis was performed in the 17th week. Fetal cytogenetic evaluation was performed at our Laboratory of Cytogenetics of Rouen University Hospital. After a long-term culture of amniotic fluid cells, chromosomal analysis revealed, surprisingly, a female karyotype with a CCR involving three derivative chromosomes (Figure 1A). This CCR consisted of an apparent translocation between the long arm of chromosome 4 and that of chromosome 11, but also additional material in the distal long arm of chromosome 1. We could not gain access to the iconography of karyotype of the father. Therefore, we decided to examine his karyotype at our Laboratory of Cytogenetics of Rouen University Hospital. This analysis after RHG banding confirmed the presence of the same CCR, which was undiagnosed at the initial Laboratory of Cytogenetics. This aberration must have occurred de novo because karyotype analysis of his parents did not show any abnormality.
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High-resolution chromosomal R (RBG) and G (GTBG) bandings of the fetus and paternal chromosomes did not permit us to define this CCR (Figure 1B and C). FISH was, therefore, used on paternal and fetal metaphase spreads (Figure 2). Using WCP4 (Figure 2B and C), the derivative chromosome 4 showed hybridization signals along the entire euchromatic length, with the exception of a part in the middle region of the long arm and a small part in the distal region of the long arm. One additional signal of chromosome 4 origin was detected in the distal long arm region of the derivative chromosome 1. In addition to the normal chromosome 11, WCP11 (Figure 2A and B) showed hybridization signals along the entire euchromatic length of the derivative chromosome 11. One additional signal was detected on the derivative chromosome 1, inserted in the distal region of the long arm and another was inserted into the middle region of long arm of the derivative chromosome 4. After hybridization with WCP1 (Figure 2A and C), the derivative chromosome 1 lacked signal in the distal region of the long arm, whereas the rest of chromosome 1 was painted. One additional signal of chromosome 1 origin was detected in the distal long arm of derivative chromosome 4. Subtelomeric 1q and 4q probes were used to confirm the reciprocal translocation between the distal region of the long arm of chromosome 1 and that of chromosome 4 (Figure 2D and E). The specific probe of the locus MLL (11q23) was used to confirm the insertion of the distal segment of the long arm of chromosome 11 into the long arm of the derivative chromosome 1 (Figure 2F). These results (as summarized in Figure 3) were confirmed by spectral analysis (Figure 4).
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We concluded that this was a seven breakpoint CCR involving not only chromosomes 4 and 11, but also chromosome 1 (Figure 3). A reassessment of the mitotic karyotype revealed that the patient and the fetus were constitutional carriers of the same CCR. Comparison of the results of the FISH analysis and RHG, RBG and GTBG banding confirmed karyotypes to be: 46,XY or 46,XX.ish t(1;4)(q42;q32)(WCP1+, D1Z5+, WCP4+, D1S3738–, D4S2930+; WCP4+, D4Z1+, WCP1+, D4S2930–, D1S3738+), ins(1;11)(q41;q23q24)(WCP1+,WCP11+, D11S2071–, MLL+;WCP11+, D11S2071+, WCP1–, MLL–), ins(4;11)(q23;q14q23)(WCP4+, WCP11+;WCP11+,WCP4–)
(International System for Human Cytogenetic Nomenclature; Shaffer et al., 2005). Ultrasound investigation during the 12th and 21st gestational week showed normal fetal growth parameters. No morphological abnormalities were discovered. After a full-term pregnancy, a girl was born, 3.570 kg in weight and 51 cm in length. Apgar scores after 1, 5 and 10 mins were 10, 10 and 10, respectively. Different psychomotor evaluations were normal at birth, 1 and 4 years of age.
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Discussion |
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According to the theoretical meiotic study of the translocated chromosomes, in CCR carrier patients, a successful result of ICSI is unlikely and it seems unreasonable to consider this technique as a valuable procedure for treating their infertility (Johannisson et al., 1988
; Siffroi et al., 1997). In this present case, ICSI was initially offered when the man was believed to be a reciprocal translocation carrier. In fact, ICSI was successfully performed using spermatozoa from a male with a CCR involving three chromosomes and seven breakpoints. This ICSI led to the birth of a normal progeny with the same balanced CCR as her father. Different psychomotor evaluations were normal at birth and at 1 and 4 years of age. This result illustrates that ICSI can lead to a balanced offspring using spermatozoa from a male partner carrying a CCR. The balanced rearrangement transmitted through this carrier male could reflect chromosome pairing problems during spermatogenesis manifested as infertility. It could be hypothesized that the rare spermatozoa that are present were balanced. Batista et al. (1994) and Solari et al. (2001) demonstrated that X-inactivation was not affected and was not altered by the association of autosomal chromosomes. Further experiments have indicated that quadrivalent configurations have different degrees of asynapsis around the breakpoints in infertile men carrying chromosomal rearrangements. These regions may interact with the sex body (SB) and disturb SB formation and inactivation. The spreading of SB inactivation towards the translocated chromosome is a consequence of an asynapted region within the quadrivalent attaching to the SB. Pachytene cells with asynapsed regions, which have not achieved pairing in the SB, are responsible for pachytene checkpoints activation during prophase I, and these cells are subsequently arrested in the cell cycle and eliminated via apoptosis. In CCR cases, the number of breakpoints in the autosomes involved in the structural rearrangement is very numerous and increases the probability of asynapsis as well as of pachytene checkpoint activation. It results in a major decrease in post-meiotic cells including spermatozoa production. Spermatozoa produced may result from a normal and complete meiosis (Oliver-Bonet et al., 2005; Turner et al., 2005).
FISH from these interphase spermatozoa could offer an accurate and reliable method for analysing meiotic segregation in this male CCR carrier (Han et al., 1992; Holmes and Martin, 1993; Robbins et al., 1993; Guttenbach et al., 1994a, Miharu et al., 1994). Unfortunately, the number of breakpoints involved in our CCR was very high and not basically compatible with a study of FISH of interphase spermatozoa. In contrast, FISH was possible and necessary as an adjunct to conventional cytogenetic analysis in the characterization of CCRs. The increased resolution afforded by FISH in detecting additional complexity and cryptic insertions in the present and previously reported CCR cases is essential. Although painting FISH contributes in elucidating the complexity of CCR, FISH is limited in detecting submicroscopic deletions. Furthermore, performing ICSI leads to the propagation of paternal CCR into the next generation. Estimated reproductive risk is up to 53.7% for abnormal pregnancy outcome or 50% for RSA for CCR carriers. (Gorski et al., 1988; Batista et al., 1994; Cifuentes et al., 1998; Zahed et al., 1998; Fauth et al., 2006). In addition to abnormal segregation due to the parental CCR, there is the possibility of crossing over, which gives rise to live born children with recombinant chromosomal abnormalities, with gain or loss of material or even ‘breakage pathology’ (Zahed et al., 1998; Rothlisberger et al., 1999). Moreover, a painting FISH study would not be sensitive enough to demonstrate a subtle deletion produced during paternal meiosis or to identify changes in direct gene position. Indeed, in cases of new pregnancy, it is possible that prenatal diagnosis could fail to detect a subtle recombination. Furthermore, performing ICSI leads to the propagation of paternal CCR into the next generation. Consequently, the girl carrying balanced CCRs remains an increased reproductive risk. Therefore, the authors suggest that it would not be reasonable to accept a second ICSI for this couple or other patients carrying CCRs.
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Acknowledgements |
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The authors thank Marie-France Portnoï for her review of the manuscript and Richard Medeiros, Rouen University Hospital Medical Editor, for his valuable advice in editing the manuscript.
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Submitted on January 20, 2006; resubmitted on January 20, 2006; resubmitted on August 25, 2006; accepted on December 6, 2006.
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