European Journal of Medical Genetics 49 (2006) 346–348 http://france.elsevier.com/direct/ejmg
Letter to the editor Double aneuploidy (48,XXY,+21): molecular analysis demonstrates a maternal origin Keywords: Double aneuploidy; 48,XXY,+21
1. To the Editor The majority of cytogenetic abnormalities ascertained prenatally or from products of conception are single autosomal trisomies. In addition, 3–7% of cytogenetically abnormal fetuses possessed a double aneuploidy [1–4]. There is a maternal age effect for double aneuploidy, as exists for single chromosome aneuploidy [5]. We read with interest the report of Iliopoulos et al. [6] describing a patient with a double aneuploidy: 48,XXY,+21, a rarely reported phenomenon. Recently, we also identified a prenatal case of 48,XXY,+21 and investigated the parental origin of the double aneuploidy. Amniocentesis was performed at 16 weeks gestation due to advanced maternal age. Parents were non-consanguineous and there were no reported prenatal exposures. No ultrasound abnormalities were noted at mid trimester. Cytogenetic analysis from cultured amniocytes showed a non-mosaic 48,XXY,+21 karyotype. Following genetic counseling, the parents elected to terminate the pregnancy. To determine the parental origin of the additional chromosomes, molecular analysis of the fetus and the parents was performed using polymorphic STS markers. Genotyping for chromosome 21 [D21S1432 (21q21.1), GATA129D11 (21q32.1), GATA188F04 (21q22.2) and D21S1446 (21q22.3)] and the X chromosome [DXS6800 (Xq21.1) and GATA165B12 (Xq24)] were carried out as previously described in [7]. These results were consistent with a maternal meiosis-I origin for both the additional X chromosome and chromosome 21 (data not shown). Molecular analysis of other double autosomal trisomies showed a predominantly maternal origin, both meiosis-I and meiosis-II errors, similar to single autosomal trisomies [8]. Where the double aneuploidy consists of an autosome and a sex chromosome, differences in parental origin might be expected. Loss of the X chromosome in Turner syndrome is predominantly paternal [9] and in the XXY and XXX syndromes the additional sex chromosome can originate from either parent [10]. Molecular evaluation of double aneuploidy involving a sex chromosome and an autosome is uncommon. Lorda-Sanchez et al. [11] reported a liveborn case of 48,XXY,+21. Molecular analysis showed that the additional chromosome 21 was derived from a maternal meiosis-II non-disjunction and the additional X chromosome was the result of a paternal meiosis-I nondisjunction. In contrast, Park et al. [12] reported the prenatal identification of a 48,XXX,+21 case due to a double maternal meiosis-II non-disjunction. Chen et al. [13] reported a 48, XXX,+18 fetus with both additional chromosomes derived from a maternal meiosis-II non-dis-
Letter to the editor / European Journal of Medical Genetics 49 (2006) 346–348
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junction. Similarly in our case, we demonstrated a maternal meiosis-I origin for both the additional chromosome 21 and the extra X chromosome. Epidemiological analysis of sex chromosome and chromosome 21 double aneuploidy showed that a 48,XXY,+21 karyotype was associated with advanced maternal age in contrast to a 48,XYY,+21 karyotype which was not [14]. However, independent parental meiotic events may also underlie double aneuploidy as in the case of Lorda-Sanchez et al. [11]. Alternatively, there may be a genetic predisposition to both single (recurrent) and double non-disjunction in some families [14]. This comparison of molecular analysis of double aneuploidy shows that these are similar to single aneuploidy and predominantly of maternal origin. However, because the involvement of a sex chromosome non-disjunction, which is frequently of paternal origin, it is possible that other mechanisms such as independent non-disjunctions may play a role in the etiology of these types of double aneuploidy. Further studies will be required to fully characterize the mechanism(s) for double aneuploidy. References [1] M. Ohno, T. Maeda, A. Matsunobu, A cytogenetic study of spontaneous abortions with direct analysis of chorionic villi, Obstet. Gynecol. 77 (1991) 394–398. [2] S. Guerneri, D. Bettio, G. Simoni, B. Brambati, A. Lanzani, M. Fraccaro, Prevalence and distribution of chromosome abnormalities in a sample of first trimester internal abortions, Hum. Reprod. 2 (1987) 735–739. [3] T. Hassold, N. Chen, J. Funkhouser, T. Jooss, B. Manuel, J. Matsuura, et al., A cytogenetic study of 1000 spontaneous abortions, Ann. Hum. Genet. 44 (1980) 151–178. [4] A. Boue, J. Boue, A. Gropp, Cytogenetics of pregnancy wastage, Adv. Hum. Genet. 14 (1985) 1–57. [5] K.S. Reddy, Double trisomy in spontaneous abortions, Hum. Genet. 101 (1997) 339–345. [6] D. Iliopoulos, G. Poultsides, V. Peristeri, G. Kouri, A. Andreou, N. Voyiatzis, Double trisomy (48,XXY,+21) in monozygotic twins: case report and review of the literature, Ann. Genet. 47 (2004) 95–98. [7] P.D. Cotter, S. Kaffe, L.D. McCurdy, M. Jhaveri, J.P. Willner, K. Hirschhorn, Paternal uniparental disomy for chromosome 14: a case report and review, Am. J. Med. Genet. 70 (1997) 74–79. [8] Q.Y. Li, S. Tsukishiro, C. Nakagawa, M. Tanemura, M. Sugiura-Ogasawara, K. Suzumori, S. Sonta, Parental origin and cell stage of non-disjunction of double trisomy in spontaneous abortion, Congenit. Anom. (Kyoto) 45 (2005) 21–25. [9] T. Hassold, K. Arnovitz, P.A. Jacobs, K. May, D. Robinson, The parental origin of the missing or additional chromosome in 45,X and 47,XXX females, Birth Defects Orig. Artic. Ser. 26 (1990) 297–304. [10] M. MacDonald, T. Hassold, J. Harvey, L.H. Wang, N.E. Morton, P. Jacobs, The origin of 47,XXY and 47,XXX aneuploidy: heterogeneous mechanisms and role of aberrant recombination, Hum. Mol. Genet. 3 (1994) 1365– 1371. [11] I. Lorda-Sanchez, M.B. Petersen, F. Binkert, M. Maechler, W. Schmid, P.A. Adelsberger, et al., A 48,XXY,+21 Down syndrome patient with additional paternal X and maternal 21, Hum. Genet. 87 (1991) 54–56. [12] V.M. Park, R.R. Bravo, L.P. Shulman, Double non-disjunction in maternal meiosis II giving rise to a fetus with 48,XXX,+21, J. Med. Genet. 32 (1995) 650–653. [13] C.P. Chen, S.R. Chern, L.F. Yeh, W.L. Chen, L.F. Chen, W. Wang, Prenatal diagnosis and genetic analysis of double trisomy 48,XXX,+18, Prenat. Diagn. 20 (2000) 750–753. [14] N.V. Kovaleva, D.E. Mutton, Epidemiology of double aneuploidies involving chromosome 21 and the sex chromosomes, Am. J. Med. Genet. A 134 (2005) 24–32.
Ian A. Glass* Division of Genetics and Neurodevelopment, Department of Pediatrics, University of Washington, 4800 Sand Point Way NE, Seattle, WA 98105, USA E-mail address:
[email protected] (I.A. Glass).
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Letter to the editor / European Journal of Medical Genetics 49 (2006) 346–348
Lei Li Department of Pathology, University of California San Francisco, San Francisco, CA 94107, USA Philip D. Cotter Division of Medical Genetics, Children’s Hospital and Research Center at Oakland, 747 Fifty Second Street, Oakland, CA 94609, USA Available online 19 January 2006 *Corresponding
author. Tel.: +1 206 987 5142; fax: +1 206 987 2495.
1769-7212/$ - see front matter © 2006 Elsevier SAS. All rights reserved. doi:10.1016/j.ejmg.2005.12.005
