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Whole exome sequencing identifies genes associated with non-obstructive azoospermia

By Hongguo Zhang, Hui Huang, Xinyue Zhang, Wei Li, Yuting Jiang, Jia Li, Leilei Li, Jing Zhao, Jing He, Mucheng Chen, Ruixue Wang, Jing Wu, Zhiyu Peng, Ruizhi Liu

Posted 29 May 2020
medRxiv DOI: 10.1101/2020.05.29.20116558

Background: Genetic etiology is the main cause of non-obstructive azoospermia, but little is known about the landscape of the disease causative genes. Objective: To identify the association of non-obstructive azoospermia and the putative causative genetic factors. Design, setting, and participants: A single-center perspective case-control study of 133 patients, with clinicopathologic non-obstructive azoospermia and 495 fertile men control was performed. Eleven trio families were available and enrolled from the 133 patients families. Outcome measurements and statistical analysis: Whole exome sequencing based rare variant association study between the cases and controls was performed by means of gene burden association testing. Linkage analysis on the trio family was also described to screen the causative genes. Results and limitations: Totally 80 genes (p < 0.05) were identified associated with non-obstructive azoospermia (2 of which were previously reported), meanwhile 5 novel genes out of which were also found potentially causative through the linkage analysis on the trio families. The pathway enrichment analysis was also provided to assess the potential interaction between genes identified in this study and previously reported together. The 5 novel identified overlap genes by both above mentioned test with the rare mutations account for an overall 20% (26 /133 patients) incidence, together with the 2 known genes together would account for an overall 20% incidence for non-obstructive azoospermia in this study. The study is limited by the lack of functional biological study. Conclusions: Five novel genes were identified associated with non-obstructive azoospermia by means of both rare variant association study and linkage analysis through trio families. They could account for about 20% clinical incidence among the patients in our study. Patient summary: 133 infertile patients (11 of them with parents enrolled) with idiopathic non-obstructive azoospermia and 300 fertile male controls were recruited from single clinic center. All patients underwent semen analyses at least on three different occasions.

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