CHROMOSOME Y ISODICENTRICS IN TWO CASES WITH AMBIGUOUS GENITALIA AND FEATURES OF TURNER SYNDROME
Lungeanu A1,*, Arghir A1, Arps S2, Cardos G1, Dumitriu N3, Budisteanu M4, Chirieac S1, Rodewald A5
*Corresponding Author: Agripina Lungeanu, Ph.D., Senior Scientist, Head of Medical Genetics Laboratory, “Victor Babes” National Institute of Pathology, 99-101 Splaiul Independentei, Bucharest 050096, Romania; Tel.: +40-021-319-27-32/218; Fax: +40-021-319-45-28; e-mail: genetica@vbabes.ro
page: 51

RESULTS

     More than 100 metaphase spreads were analyzed from each subject. In Case 1, GTG-banded karyotyping revealed the presence of two cell lines: a hypodiploid line with monosomy X in 90% of the cells, and a pseudodiploid line with idic(Y) in 10% of cells. The karyotype formula was established as a mosaic with 45,X[90]/46,X,idic(Y)(p11.3) [10] (Figure 1a). The karyotypes of both parents were normal.

      The staining pattern of the constitutive heterochro­matin (HC) revealed by CBG-banding, exhibited a mirror image distribution on the derivative Y chromosome (Figure 1b), suggesting that the error occurred during gameto­genesis, before the spermatid stage, or more probably, during the first division after fertilization. We propose that initially, both centromeres were functional, each being attached to the dividing spindle, and in migration to the opposite poles, the idic(Y) lagged behind and did not appear in the metaphase plate. In this way, a great majority of the daughter cells lack the idic(Y) chromosome.

      The FISH analysis was performed in several successive steps to extend the range of molecular characterization of the chromosome Y derivative. Fluorescence in situ hybridization with a Y-specific painting probe showed the identity of the entire derivative isochromosome to be Y (Figure 1c). Double color FISH with an SRY DNA probe (Yp11.3) and a centromeric probe for X, DXZ1 (XCEN) showed two signals for the SRY gene located on derivative Y and one for the centromeric region of a normal X chromosome (Figure 1d). Dual color FISH with centromeric probes DYZ3 (YCEN) and DYZ1 (Yq12) exhibited two signals with a mirror image appearance (Figure 1e). The FISH results obtained with subtelomeric probes for the Xp and Yp locus DXYS130 plus Xq and Yq, locus DXYS224, are shown in Figure 1f. Two signals for the Yp subtelo­meric probe were detected in the median region of an abnormal Y chromosome. The signal for subtelomeric locus Xq and Yq was detected on the normal location on Xq, but on both ends of the idic(Y) chromosome.

      The breakpoint on both chromatids was located sub­telomerically on the p arm, distal from the SRY gene locus in the Y euchromatic region. The presence of duplicated active SRY genes may explain the male features development. The karyotype in this case is 45,X[90]/46,X,idic(Y) (p11.3).ish idic(Y)(p11.3)(wcpY+,DXYS130++,SRY++, DYZ3++,DYZ1++,DYS224++)[10].

      Two PCR products were obtained (106 bp from the X chromosome and 112 bp from the Y chromosome) with the Amelogenin gene probes (Figure 2a). The marker, DYS392 microsatellite was present in Case 1 (Figure 2b). All methods that we used for characterization of the derivative Y chromosome clearly demonstrated that it is an isodicentric that resulted from an almost entire Y chromosome, and the breakpoint was located distal from subtelomeric locus DXYS130 in Yp.

      The chromosome analysis of Case 2 showed a mosaic karyotype with a hypodiploid cell line 45,X and a diploid cell line bearing an abnormal Y chromosome. The mosaic karyotype is: 45,X[65]/46,X idic?(Yp)[35]. Figure 3a shows a karyotype with 46,X,idic(Y)(q11). By C-banding, only centromeric HC was revealed, but not constitutive HC characteristics for the Yq chromosome (Figure 3b).

      Fluorescence in situ hybridization with the SRY probe showed two copies of the SRY locus distributed symmetrically on the distal ends of isodicentric (Y)(p) (Figure 3c). No signals for the RP11-140H23 probe (q11.2) were observed, showing that the breakpoint was located proximally to this locus. Isodicentric Y chromosome with fusion in Yq11, may be pseudoisodicentric.

      The karyotype in this case is: 46,X,idic(Y)(q11).ish idic(Y)(SRY++,RP11-140H23-). Two PCR products were obtained (106 bp from the X chromosome and 112 bp from the Y chromosome) for the Amelogenin gene (Figure 3c), showing the presence of the short arm of the Y chromosome sequence p11.2 which is located proximally to the SRY gene locus.            

      The second PCR marker, DYS392 microsatellite, produced negative results (Figure 3b). We infer that the very small isodicentric, identified in 35% of metaphases, lost a large part of the long arm of Y chromosome, but retained the SRY gene on p11. In this case, the derivative Y is different in size and shape from that of Case 1, but had similar consequences in phenotype features. These results demonstrated that the derivative chromosome was an iso­dicentric one that resulted from the short arm of the Y chromosome, with the breakpoint in the long arm and the fusion point proximal to the DYS392 locus in the euchro­matic region q11.




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