Inter-Tissue Gonosomal Mosaicism in Patients with Disorders of Sex Development, Associated with Abnormalities of Gonadal Differentiation

We present results of the study to identify gonosomal mosaicism and examine its inter-tissue variability in peripheral blood lymphocytes, buccal epithelium, and gonadal tissue in patients with disorders of sex development (DSD) associated with sex chromosome abnormalities (gonosomal DSD, n = 8) and gonad differentiation anomalies (46,XY DSD, n = 10). The study used a set of methods for analyzing individual cells: karyotyping and interphase FISH. According to the study results, gonosomal mosaicism was detected in 12 (67%) of the 18 examined patients. Cryptic, isolated by gonadal tissue, somatic mosaicism with 45,X cell line was detected in 4/10 46,XY DSD group patients. True inter-tissue mosaicism with two cell lines, one of which 45,X, was detected in 8/8 gonosomal DSD group patients. We propose using a new approach for mosaicism examination and quantifying mosaic cell lines variability. For this purpose, the coefficient of variation ( CV ) was used, the range of detected values was from 2.3 to 49%. In accordance with the obtained CV values, the inter-tissue variability was estimated as low, moderate or high. The correlation analysis revealed a statistically significant ( p < 0.1) inverse correlation between Prader's stage and 45,X cell line percentage in lymphocytes, buccal epithelium, and gonadal tissue, as well as a direct correlation between the 45,X cell line presence in one of the tissues and its presence in other tissues. The search for mosaicism in tissues of different histogenesis origin using a set of methods for analyzing individual cells allows us to get a more complete picture of the gonosomal constitution and reveal a hidden imbalance, which is very important in examining patients with DSD. We proposed and used in this study the coefficient of variation ( CV ), which is a convenient statistical metric for quantifying the variability of cell lines in different tissues of a single patient and a step towards standardizing the results of genetic studies.