Spermatogenesis and meiosis defects in patients with mosaicism and/or the Y chromosome structural abnormalities

Abstract

Unbalanced structural Y chromosome abnormalities and pathogenic Y chromosome microdeletions are common genetic cause of severe male infertility due to spermatogenesis damage. Sex chromosomes (gonosomes) abnormalities are often associated with mosaicism the presence and percentage of gonosomal mosaicism may modify the damage of the negative effect of sex chromosome abnormalities and X- and Y-linked mutations. The combined effect of structural abnormalities and mosaicism of the Y chromosome on male fertility and semen parameters has not been sufficiently studied. The aim of the study was the analysis of the spermatological and genetic examination in mosaic patients with/or without structural abnormalities of the Y chromosome to evaluate the spermatogenesis and meiosis defects. Material and methods. A group of 40 men aged 31±7 (from 16 to 49) years was examined, mosaicism and/or structural abnormalities/variants of the Y chromosome were found in the karyotype of patients. The karyotype detected on the results of a standard cytogenetic study (on cultured peripheral blood lymphocytes), a FISH study with DNA probes for X and Y chromosomes was additionally performed. The presence/absence of Y-specific sequences (SRY and AZFa,b,c loci) was determined by multiplex polymerase chain reaction. A standard spermiological examination was performed according to the WHO Laboratory Manual, quantitative karyological analysis (QKA) of immature germ cells (IGCs) was performed in 12 patients. Results. Y chromosome mosaicism was found in 29 (72.5%) patients. Pathogenic AZF microdeletions (AZFa+b+c, n=3; AZFb+c, n=19; AZFc, n=3) were detected in 25 (62.5%) men, 17 of them had the Y chromosome mosaicism. Non-obstructive azoospermia and severe oligozoospermia were found in 88% and 12% of men with AZF deletions, and without AZF deletions in 47% and 20% of patients, respectively. Normozoospermia and mild forms of pathozoospermia were revealed in patients without AZF deletions. Only severe forms of spermatogenesis defects were found in all men with Yq11.2 deletions, ring and pseudodicentric Y chromosomes. QKA of IGCs revealed cryptozoospermia in 7 out of 10 azoospermic patients (according to semen analyses data) and signs of a partial meiotic arrest of spermatogenesis at pachytene and/or at the pre-pachytene stages of prophase I of meiosis. Conclusion. In patients with mosaicism and/or structural abnormalities of the Y chromosome, the spermatogenesis disorders vary from their absence to their severe forms. The severity of the spermatogenesis depletion depends on structural anomalies and Yq11.2(AZF) deletions, their type, and the breakpoints location, the additional pathogenic factors. Gonosomal mosaicism is an additional pathogenic factor affected fertility that can increase genetic and phenotypic changes.