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DOI: 10.1369/jhc.4B6437.2005
Volume 53 (3): 355-357, 2005
Copyright ©The Histochemical Society, Inc.
BRIEF REPORT |
A Highly Complex Chromosomal Rearrangement between Five Chromosomes in a Healthy Female Diagnosed in Preparation for Intracytoplasmatic Sperm Injection
Institute of Human Genetics and Anthropology (AK,MZ,UC,TL), Department of Radiotherapy (AK), Friedrich-Schiller-University, Jena, Germany; Center of Human Genetics, University of Bremen, Bremen, Germany (CB,BR,JB); and Practice of Gynecology, Westoverledingen, Germany (JA)
Correspondence to: Dr. Alma Kuechler, Institute of Human Genetics and Anthropology, Kollegiengasse 10, D-07743 Jena, Germany. E-mail: almu{at}mti.uni-jena.de
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Summary |
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 Top Summary Literature Cited |
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We report a case of a de novo complex chromosomal rearrangement among five chromosomes found in a clinically healthy woman. The only indication for chromosome analysis was a planned intracytoplasmatic sperm injection. Physical examination, including internal and external genitals, and ovaries and hormone status were normal. Banding cytogenetics showed a rearrangement among chromosomes #3, #4, #7, #9, and #17. Twenty-four-color fluorescence in situ hybridization and multicolor banding were applied to characterize the translocations and breakpoints more precisely. This confirmed the involved chromosomes and revealed two breakpoints in chromosome #4. This six-breakpoint rearrangement [der(3)t(3;4), der(4)t(17;4;7), der(7)t(3;7), der(9)t(4;9), and der(17)t(9;17)] seemed to be balanced on a molecular cytogenetic level, although submicroscopic deletions or duplications close to the breakpoints cannot be excluded. (J Histochem Cytochem 53:355–357, 2005)
Key Words: complex chromosomal • rearrangements • 24-color fluorescence in situ • hybridization • multicolor banding • intracytoplasmatic sperm • injection
COMPLEX CHROMOSOMAL REARRANGEMENTS (CCR) involve by definition at least three chromosomes with three or more breakpoints. Most diagnosed CCRs are three-way rearrangements, and only a minority consists of highly complex aberrations (for review see Batanian and Eswara 1998
; Houge et al. 2003). CCR were subdivided by Kousseff et al. (1993) into two groups based on the number of breaks (four or fewer—group I, more than four breaks—group II). Following this suggestion, highly complex chromosomal rearrangements (hCCR) are herewith defined as CCR with five or more involved breakpoints. hCCRs are often associated with physical signs, mental retardation, or malformations. They are rarely found in phenotypically normal individuals and are usually detected in connection with reduced fertility, i.e., in- or subfertility in male carriers or recurrent miscarriages in female carriers (for review see Madan et al. 1997). If fertility is maintained, the birth of a child with malformations can indicate familial occurrence of a CCR (Röthlisberger et al. 1999; Berend et al. 2002).
We report here on a clinically healthy, 34-year-old woman. She was referred for genetic diagnosis because of unwanted childlessness. Moreover, she had a history of two early abortions. Gynecological examination, including external and internal genitals and ovaries, and hormone status, were normal. Her partner was diagnosed with oligoasthenoteratozoospermia I. Therefore, use of an artificial reproductive technology was planned. In preparation for intracytoplasmatic sperm injection (ICSI), chromosome analysis was performed on both partners. The male had a normal karyotype [46,XY], but the GTG-banding results of the female showed a hCCR involving five chromosomes (chromosomes #3, #4, #7, #9, and #17, see Figure 1). These aberration occurred de novo as karyotype analyses of her parents showed no cytogenetic abnormalities.
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Further characterization of this rearrangement was performed using molecular cytogenetic techniques. Twenty-four-color fluorescence in situ hybridization (FISH) according to Senger et al. (1998)
indicated the following aberrations: del(3), der(4)t(17;4;7), der(7)t(3;7), der(9)t(4;9), and der(17)t(9;17) (see Figure 2). To substantiate from which chromosomal arm the translocated material was derived, arm-specific probes were also used. This revealed that the derivative chromosome 3 had no simple deletion but contained a subtle translocation of material of chromosome 4q. In the next step, multicolor banding (MCB) (Liehr et al. 2002) was applied to characterize the breakpoints more precisely and to define the orientation of the involved chromosomal material.
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By this comprehensive analysis, the karyotype could be established as follows:
- ish 46,XX,der(3)t(3;4)(3pter
3q22::4q34
354qter),
- der(4)t(17;4;7)(17pter17p1312::4p144q3435:: 7p13127pter),
- der(7)t(3;7)(3qter3q22::7p13127qter),
- der(9)t(4;9)(4pter4p14::9q139pter),
- der(17)t(9;17)(9qter9q13::17p131217qter).
The rearrangement contained in summary six breakpoints derived from five chromosomes and seemed to be balanced on a molecular cytogenetic level. The hybridization results of 24-color FISH and MCB for all five aberrant chromosomes are depicted in Figure 3.
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Despite the knowledge of this hCCR result, one course of ICSI was performed but without success.
As mentioned above, there are few cases of reported hCCR involving five or more chromosomes. The number of descriptions increased with the introduction of new techniques (Astbury et al. 2004), which also improved detection of intrachromosomal rearrangements (Weise et al. 2003), but they remain rare findings. In our case, we detected in summary six breakpoints, all not located in known heterochromatic regions (such as 1q12 or centromeric regions). Thus, we speculate that all six breaks did not affect important genes or, more precisely, gene functions; however, this suspicion cannot be proven with the applied molecular cytogenetics approaches. Additionally, submicroscopic deletions or duplications close to the breakpoints could be excluded only by sequencing of the breakpoints.
The infertility of the couple, especially the history of two abortions, can easily be explained by the complexity of the hCCR itself and the extremely low probability of a cytogenetically balanced or normal pregnancy (Madan et al. 1997; Siffroi et al. 1997). In such cases, the ICSI method also reaches its limits (Siffroi et al. 1997), and careful genetic counseling of affected couples is required.
The lesson learned from this case is that, in preparation for ICSI, chromosome analysis should always be performed on both partners.
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Footnotes |
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Presented in part at the 14th Workshop on Fetal Cells and Fetal DNA: Recent Progress in Molecular Genetic and Cytogenetic Investigations for Early Prenatal and Postnatal Diagnosis, Friedrich-Schiller-University, Jena, Germany, April 17–18, 2004.
Received for publication June 10, 2004; accepted November 19, 2004
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Literature Cited |
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TopSummaryLiterature Cited |
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Astbury C, Christ LA, Aughton DJ, Cassidy SB, Fujimoto A, Pletcher BA, Schafer IA, et al. (2004) Delineation of complex chromosomal rearrangements: evidence for increased complexity. Hum Genet 114:448–457[Medline]
Batanian JR, Eswara MS (1998) De novo apparently balanced complex chromosome rearrangement (CCR) involving chromosomes 4, 18, and 21 in a girl with mental retardation: report and review. Am J Med Genet 78:44–51[CrossRef][Medline]
Berend SA, Bodamer OA, Shapira SK, Shaffer LG, Bacino CA (2002) Familial complex chromosomal rearrangement resulting in a recombinant chromosome. Am J Med Genet 109:311–317[Medline]
Houge G, Liehr T, Schoumans J, Ness GO, Solland K, Starke H, Claussen U, et al. (2003) Ten years follow up of a boy with a complex chromosomal rearrangement: going from a > 5 to 15-breakpoint CCR. Am J Med Genet 118A:235–240[CrossRef]
Kousseff BG, Papenhausen P, Essig YP, Torres MP (1993) Complex chromosome rearrangement with ankyloblepharon filiforme adnatum. J Med Genet 30:167–170
Liehr T, Heller A, Starke H, Rubtsov N, Trifonov V, Mrasek K, Weise A, et al. (2002) Microdissection based high resolution multicolor banding for all 24 human chromosomes. Int J Mol Med 9:335–339[Medline]
Madan K, Nieuwint AW, van Bever Y (1997) Recombination in a balanced complex translocation of a mother leading to a balanced reciprocal translocation in the child. Review of 60 cases of balanced complex translocations. Hum Genet 99:806–815[CrossRef][Medline]
Röthlisberger B, Kotzot D, Brecevic L, Koehler M, Balmer D, Binkert F, Schinzel A (1999) Recombinant balanced and unbalanced translocations as a consequence of a balanced complex chromosomal rearrangement involving eight breakpoints in four chromosomes. Eur J Hum Genet 7:873–883[CrossRef][Medline]
Senger G, Chudoba I, Plesch A (1998) Multicolor-FISH—the identification of chromosome aberrations by 24 colors. Bioforum 9:499–503
Siffroi JP, Benzacken B, Straub B, Le Bourhis C, North MO, Curotti G, Bellec V, et al. (1997) Assisted reproductive technology and complex chromosomal rearrangements: the limits of ICSI. Mol Hum Reprod 3:847–851
Weise A, Rittinger O, Starke H, Ziegler M, Claussen U, Liehr T (2003) De novo 9-break-event in one chromosome 21 combined with a microdeletion in 21q22.11 in a mentally retarded boy with short stature. Cytogenet Genome Res 103:14–16[Medline]
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