1 Institute for Human Genetics, University of Göttingen and 2 Department of Obstetrics and Gynaecology, University of Göttingen, Germany
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Abstract |
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Key words: genetic counselling/germ line mosaicism/gonadal mosaicism/parental origin/translocation
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Introduction |
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A case is reported in which a seemingly de-novo translocation pseudodicentric chromosome recurred in a second pregnancy. The results of molecular and cytogenetic studies strongly suggest that maternal gonadal mosaicism was the cause for the increased risk of recurrence.
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Materials and methods |
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Molecular investigations
DNA was extracted from peripheral blood of both parents and from a long-term culture of chorionic villi (abortus) according to standard procedures. DNA from the first child was not available.
Eleven microsatellites from chromosome 5, 7, 9 and 21 (D5S455, D5S418, D5S260, D5S253, D5S208, D7S1870, D9S886, D9S887, D9S888, D9S889, D21S11) have been investigated. The primer sequences were deposited under the following accession identification numbers of the GDB database (www.gdb.org): 189314, 188337, 181109, 196355, 180557, 377150, 304578, 304744, 304753, 304735, 188664). The polymerase chain reaction (PCR) was carried out in a volume of 25 µl and 100 ng DNA with the HSTaq MasterMix (Qiagen, Hilden, Germany) according to the manufacturers instructions under the following conditions: denaturation/polymerase activation at 97°C for 15 min followed by 30 cycles with a denaturation at 96°C for 20 s, annealing at 55°C for 30 s and extension at 72°C for 30 s in a Primus cycler (MWG, Ebersberg, Germany). The polymorphic CAG repeats of the SCA1 gene on chromosome 6 and the CAG repeat of the MJD gene on chromosome 14 were analysed as described (Orr et al., 1993; Kawaguchi et al., 1994
). All PCR was carried out with fluorescence-labelled primers. The size of the product was determined by gel electrophoresis on a ABI 373 automated sequencer by the Genscan computer programm (ABI, Weiterstadt, Germany).
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Results |
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Discussion |
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Byers et al. reported data on recurrence risk of autosomal dominant osteogenesis imperfecta (Byers et al., 1988). The authors postulated that the 6% empirical recurrence risk of the disorder is best explained by gonadal mosaicism in one of the parents. In Duchenne muscular dystrophy the proportion of germline mosaicism was estimated at 15% (Passos-Bueno et al., 1992
). Germline mosaicism has been demonstrated also for interstitial deletions in chromosome 22q11 (Hatchwell et al. 1998
), Smith-Magenis syndrome 17p11.2 (Zori et al. 1993
), Ehlers-Danlos syndrome type IV (Milewicz et al., 1993
), and Williams-Beuren-syndrome (Kara-Mostefa et al. 1999
).
Only a few reports exist in the literature about gonadal mosaicism for chromosome rearrangements. In 1990 Sachs et al. detected mosaicism in two couples with three and four pregnancies in which trisomy 21 was found (Sachs et al., 1990). In one couple ovarian biopsy showed 44 and 47% trisomic cells in the right and left ovary respectively. Gross et al. reported on a female patient with mosaicism for two different Robertsonian translocations, both involving chromosome 21 (Gross et al., 1996
). The patient had cells with an unbalanced karyotype with an i(21q) and balanced cell with der(21;22)(q11;q11). In skin fibroblasts only balanced karyotypes were observed. In lymphocytes and in one-third of the cells in the ovarian biopsy the unbalanced karyotype with the i(21q) was observed. The patient was phenotypically normal but two of her children inherited the i(21q) and had Down's syndrome. Yu et al. reported on maternal gonadal mosaicism for a Robertsonian translocation (21;21) (Yu et al., 1998
). Molecular cytogenetic detection of confined gonadal mosaicism in a conceptus with trisomy 16 placental mosaicism has also been reported (Stavropoulos et al., 1998
).
One problem in genetic counselling of couples with suspected gonadal mosaicism for chromosomal aberration is the question of recurrence risk. While analysis of spermatozoa by means of multicolour FISH allows the assessment of risk for the offspring in cases with paternal gonadal mosaicism (Mercier and Bresson, 1997), maternal gonadal mosaicism is not readily amenable to diagnostic procedures.
Due to the high risk of Down's syndrome pregnancies in the couples reported by Yu et al. and Conn et al., the couples elected to pursue preimplantation genetic diagnosis (PGD) (Yu et al., 1998; Conn et al., 1999
). Because of the elevated recurrence risk in further pregnancies for the same chromosomal aberration, our patients might well ask for new diagnostic techniques such as PGD or polar body analysis.
Due to the present legal situation, PGD in Germany is not possible. However, we could offer polar body analysis, chorionic villous sampling or amniocentesis for prenatal diagnosis in further pregnancies. Ovarian biopsy and subsequent chromosomal analysis does not provide the necessary information for risk estimation. When doing a chromosomal analysis on ovarian tissue only the cells from the stromal tissue are analysed. These cells are not more closely related to the germ cells than, for example, lymphocytes. The usefulness of ovarian biopsy in estimating the recurrence risk for such abnormalities is very questionable.
Because germline mosaicism can never be effectively excluded, the possibility of germ line mosaicism should always be borne in mind.
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Acknowledgments |
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Notes |
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References |
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Submitted on June 28, 2000; accepted on October 5, 2000.