Excess of rare variants in genes that are key epigenetic regulators of spermatogenesis in the patients with non-obstructive azoospermia

Scientific Reports
Zesong LiYaoting Gui

Abstract

Non-obstructive azoospermia (NOA), a severe form of male infertility, is often suspected to be linked to currently undefined genetic abnormalities. To explore the genetic basis of this condition, we successfully sequenced ~650 infertility-related genes in 757 NOA patients and 709 fertile males. We evaluated the contributions of rare variants to the etiology of NOA by identifying individual genes showing nominal associations and testing the genetic burden of a given biological process as a whole. We found a significant excess of rare, non-silent variants in genes that are key epigenetic regulators of spermatogenesis, such as BRWD1, DNMT1, DNMT3B, RNF17, UBR2, USP1 and USP26, in NOA patients (P = 5.5 × 10(-7)), corresponding to a carrier frequency of 22.5% of patients and 13.7% of controls (P = 1.4 × 10(-5)). An accumulation of low-frequency variants was also identified in additional epigenetic genes (BRDT and MTHFR). Our study suggested the potential associations of genetic defects in genes that are epigenetic regulators with spermatogenic failure in human.

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Citations

Aug 5, 2015·Proceedings of the National Academy of Sciences of the United States of America·Priti Singh, John C Schimenti
Oct 9, 2015·Reproduction : the Official Journal of the Society for the Study of Fertility·Csilla KrauszChiara Chianese
Jul 25, 2015·PloS One·Lisha MouYaoting Gui
Nov 5, 2016·Biochemical and Biophysical Research Communications·Shirly Lahav-BaratzAaron Ciechanover
Nov 10, 2015·Scientific Reports·Motoko MaekawaTakeo Yoshikawa
Apr 7, 2018·Nature Reviews. Urology·Csilla Krausz, Antoni Riera-Escamilla
Dec 10, 2019·Science China. Life Sciences·Lu WenZi-Jiang Chen
Mar 20, 2019·Chromosoma·Natalia Felipe-MedinaAlberto M Pendás
Aug 9, 2016·Molecular Medicine Reports·Lisha Mou, Yaoting Gui
Dec 2, 2020·Journal of Hazardous Materials·Abik Nandi, Debapratim Kar Chowdhuri
Jun 28, 2021·Reproductive Biology and Endocrinology : RB&E·Zhiming LiShuiqiao Yuan

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Methods Mentioned

BETA
genotyping
PlinkSeq
biopsy
PCR

Software Mentioned

SAM
Illumina Genome Analyzer Pipeline
PlinkSeq

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