Chromosomal microarray analysis of infertile men with azoospermia factor microdeletions

Azoospermia factors, located in the long arm of the Y chromosome, are critical for spermatogenesis, the microdeletions of AZF are considered to be associated with male infertility. In addition to complete deletion, several AZFc partial deletions were also detected in infertile men with wide phenotypic heterogeneity. In this study, we investigated the relevance of Y chromosome deletions, Y-linked CNVs and variable phenotypes in infertile men. To clarify the relationship between phenotypic heterogeneity and Y chromosome deletion in male infertility, we performed chromosomal microarray analysis (CMA) capable of analyzing thousands of loci simultaneously to investigate Y-linked copy number variations (CNVs). Firstly, we reviewed the results of Y chromosome screening in 554 infertile patients and then compared the results of CMA to routine Y chromosome screening in 29 patients with Y chromosomal microdeletions. Then, the Y-linked CNVs associated with oligoasthenospermia were identified according to ACMG standards and guidelines. The results indicated that the prevalence of Yq microdeletions was 5.23% (29/554), with 93% (27/29) of the deletions in the AZFc region among 554 infertile men recruited in this study. The results of CMA and multiplex-PCR-based AZFc deletion analysis were generally concordant, but CMA provided more details about location, size and OMIM genes involved in deletion fragments of the AZF region. Of 29 clinically infertile phenotype-related CNVs detected by CMA, nine were pathogenic and the remaining 20 CNVs were OVUS. Except for a 15.69 Mb loss CNV in AZFa + b + c and an 8.25 Mb loss CNV in AZFb + c, others were located in the AZFc region. Based on a combination of the clinical symptoms and loss CNVs, we concluded that the CNV size and the involvement of spermatogenesis critical genes are two important factors that determine the relevance of a CNV in the AZFc region to the presence or absence of a clinically infertile phenotype.