SRY+ Derivative X Chromosome in a Female With Apparently Typical Sexual Development

Abstract

Background: When the SRY gene is present in a 46,XX fetus, some degree of testicular development is expected. Our laboratory performed prenatal genetic testing for a fetus that had screened positive for Y chromosome material by noninvasive prenatal screening (NIPS) but that had apparently typical female development by ultrasound imaging. The aim of this study was to determine the clinical relevance of the NIPS results.

Methods: We analyzed fetal material obtained via amniocentesis procedure by G-banding, microarray, and fluorescence in situ hybridization (FISH). Optical genome mapping (OGM) was also performed.

Results: G-band analysis revealed a normal 46,XX karyotype. Microarray and FISH analyses together detected an SRY+ gain of 5.7 Mb from terminal Yp that was translocated to terminal Xq, with a loss of 1.6 Mb from terminal Xq. The final karyotype was 46,X,der(X)t(X;Y)(q28;p11.2). Prenatal ultrasound and postnatal physical examination revealed apparently typical female genitalia. The Xq deletion encompassed a gene, IKBKG, that is sensitive to loss of function, suggesting that preferential inactivation of the derivative X chromosome allowed for typical female development. OGM software did not directly identify this translocation.

Conclusion: This case demonstrates how the SRY gene may be present in a 46,XX biological female without differences of sexual development.

Keywords: X inactivation; differences of sexual development; ovotesticular; sex reversal.

FIGURE 1

(a) Partial G‐banding karyotype of X chromosomes from amniotic fluid cells. The homologous X chromosomes were indistinguishable by G‐banding. (b) Schematic representation of X chromosomes with a cryptic, unbalanced translocation between X and Y. The gained Y material containing PAR1 and SRY localized to Xqter of the derivative X, replacing PAR2. (c) Prenatal microarray results for the Y chromosome. (d) Prenatal microarray results for the X chromosome. (e) Metaphase FISH for SRY (red probe) and the X centromere (green probe). (f) Metaphase FISH for the pseudoautosomal gene SHOX (red probe) and the X centromere (blue probe). Der(X), derivative X chromosome; PAR1, pseudoautosomal region 1; PAR2, pseudoautosomal region 2; pter, terminus of the p arm; qter, terminus of the q arm.