Identifying Novel Copy Number Variants in Azoospermia Factor Regions and Evaluating Their Effects on Spermatogenic Impairment.

Ran Zhou,Jian Cheng,Jianxin Tan,Ping Hu,Yuguo Wang,Zhengfeng Xu,Dingyuan Ma

doi:10.3389/fgene.2019.00427

Abstract

Microdeletions in Y-chromosomal azoospermia factor (AZF) regions have been regarded as the risk factor of spermatogenic failure (SF). However, AZF-linked duplications or complex copy number variants (CNVs) (deletion + duplication) were rarely studied. In this study, we performed multiplex ligation-dependent probe amplification (MLPA) analysis on 402 fertile healthy male controls and 423 idiopathic infertile SF patients (197 azoospermia and 226 oligozoospermia) in Han Chinese population. In total, twenty-four types of AZF-linked CNVs were identified in our study, including eleven novel CNVs (one deletion, seven duplications, and three complex CNVs). Our study revealed that AZFc-linked duplications and the instability of Y chromosome might be associated with spermatogenesis. Besides, the complex CNVs (b2/b3 deletion + DAZ1/2 duplication) were confirmed to increase genetic risks for SF in Han Chinese population. This study illustrated a spectrum of AZF-linked CNVs and presented valuable information for understanding the clinical significance of AZF-linked CNVs in male infertility.

Highlights

Infertility affects an estimated 15% of couples globally at childbearing age, and male infertility is directly or indirectly responsible for about 50% of cases involving reproductive-age couples with fertility-related issues (Agarwal et al, 2015)
To validate those azoospermia factor (AZF)-linked copy number variants (CNVs) not confirmed by STSPCR, we performed real-time quantitative polymerase chain reaction (PCR)
According to the achieved results, we found that there was no significant difference between the control group and the spermatogenic failure (SF) group in selected characteristics including age, body mass index (BMI), and smoking (Table 1)

Summary

Introduction

Infertility affects an estimated 15% of couples globally at childbearing age, and male infertility is directly or indirectly responsible for about 50% of cases involving reproductive-age couples with fertility-related issues (Agarwal et al, 2015). The majority of infertile males were diagnosed with spermatogenic failure (SF) (Lo Giacco et al, 2014). Y-chromosome microdeletions (YCM) are the second most common genetic etiology for SF after the Klinefelter syndrome (Krausz et al, 2014). In YCM, azoospermia factor (AZF) [AZFa, AZFb, AZFc(b2/b4)] deletions have resulted in SF and testing these deletions had significant clinical values both in diagnosis and prognostication of testicular sperm retrieval in azoospermic men (Pryor et al, 1997; Rozen et al, 2012), while the clinical significance of partial AZFc deletions (gr/gr, b2/b3, and b1/b3) varies in different studies (Lu et al, 2009; Bansal et al, 2016; Krausz and Casamonti, 2017). All previous studies on AZF-linked copy number variants (CNVs) have mainly focused on deletions rather than duplications or complex CNVs (deletions + duplications).

Methods

Results

Conclusion