Whole Exome Sequencing Identifies Genes Associated With Non-Obstructive Azoospermia

Overview

Journal Front Genet

Date 2022 May 2

PMID 35495142

Authors

Hongguo Zhang

Wei Li

Yuting Jiang

Jia Li

Mucheng Chen

Ruixue Wang

Jing Zhao

Zhiyu Peng

Hui Huang

Ruizhi Liu

Affiliations

Soon will be listed here.

Abstract

Non-obstructive azoospermia (NOA) affects nearly 1% of men; however, the landscape of the causative genes is largely unknown. To explore the genetic etiology which is the fundamental cause of NOA, a prospective case-control study and parental-proband trio linkage analysis were performed. A total of 133 patients with clinicopathological NOA and 343 fertile controls were recruited from a single large academic fertility center located in Northeast China; in addition, eleven trio families were available and enrolled. Whole exome sequencing-based rare variant association study between the cases and controls was performed using the gene burden association testing. Linkage analysis on the trio families was also interrogated. In total, 648 genes were identified to be associated with NOA (three of which were previously reported), out of which six novel genes were found further associated based on the linkage analysis in the trio families, and involved in the meiosis-related network. : The six currently identified genes potentially account for a fraction (3.76%, 5 out of 133 patients) of the heritability of unidentified NOA, and combining the six novel genes and the three previously reported genes together would potentially account for an overall 6.77% (9 out of 133 patients) heritability of unidentified NOA in this study.

Citing Articles

Whole exome sequencing analysis of 167 men with primary infertility.

Zhou H, Yin Z, Ni B, Lin J, Luo S, Xie W BMC Med Genomics. 2024; 17(1):230.

PMID: 39267058 PMC: 11391607. DOI: 10.1186/s12920-024-02005-3.

Identification of a novel intronic mutation of MAGED2 gene in a Chinese family with antenatal Bartter syndrome.

Yan X, Hu Y, Zhang X, Gao X, Zhao Y, Peng H BMC Med Genomics. 2024; 17(1):23.

PMID: 38238844 PMC: 10795325. DOI: 10.1186/s12920-024-01797-8.

QTLs and Candidate Genes Associated with Semen Traits in Merino Sheep.

Hodge M, de Las Heras-Saldana S, Rindfleish S, Stephen C, Pant S Animals (Basel). 2023; 13(14).

PMID: 37508063 PMC: 10376747. DOI: 10.3390/ani13142286.

Fertility problems in men carrying a translocation involved in breakpoints on chromosome 17p13: A retrospective, observational study.

Li R Medicine (Baltimore). 2023; 101(49):e32216.

PMID: 36626513 PMC: 9750576. DOI: 10.1097/MD.0000000000032216.

Diverse monogenic subforms of human spermatogenic failure.

Nagirnaja L, Lopes A, Charng W, Miller B, Stakaitis R, Golubickaite I Nat Commun. 2022; 13(1):7953.

PMID: 36572685 PMC: 9792524. DOI: 10.1038/s41467-022-35661-z.

References

Loiodice I, Alves A, Rabut G, van Overbeek M, Ellenberg J, Sibarita J . The entire Nup107-160 complex, including three new members, is targeted as one entity to kinetochores in mitosis. Mol Biol Cell. 2004; 15(7):3333-44. PMC: 452587. DOI: 10.1091/mbc.e03-12-0878. View

Gou L, Kang J, Dai P, Wang X, Li F, Zhao S . Ubiquitination-Deficient Mutations in Human Piwi Cause Male Infertility by Impairing Histone-to-Protamine Exchange during Spermiogenesis. Cell. 2017; 169(6):1090-1104.e13. PMC: 5985145. DOI: 10.1016/j.cell.2017.04.034. View

Nakamura S, Kobori Y, Ueda Y, Tanaka Y, Ishikawa H, Yoshida A . STX2 is a causative gene for nonobstructive azoospermia. Hum Mutat. 2018; 39(6):830-833. DOI: 10.1002/humu.23423. View

Tan Y, Tu C, Meng L, Yuan S, Sjaarda C, Luo A . Loss-of-function mutations in TDRD7 lead to a rare novel syndrome combining congenital cataract and nonobstructive azoospermia in humans. Genet Med. 2019; 21(5):1209-1217. DOI: 10.1038/gim.2017.130. View

He W, Tu C, Liu Q, Meng L, Yuan S, Luo A . mutation that causes human non-obstructive azoospermia and premature ovarian insufficiency identified by whole-exome sequencing. J Med Genet. 2018; 55(3):198-204. DOI: 10.1136/jmedgenet-2017-104992. View

Ionita-Laza I, Lee S, Makarov V, Buxbaum J, Lin X . Sequence kernel association tests for the combined effect of rare and common variants. Am J Hum Genet. 2013; 92(6):841-53. PMC: 3675243. DOI: 10.1016/j.ajhg.2013.04.015. View

Krausz C, Riera-Escamilla A . Genetics of male infertility. Nat Rev Urol. 2018; 15(6):369-384. DOI: 10.1038/s41585-018-0003-3. View

Mou L, Gui Y . A novel variant of androgen receptor is associated with idiopathic azoospermia. Mol Med Rep. 2016; 14(4):2915-20. PMC: 5042743. DOI: 10.3892/mmr.2016.5587. View

Arafat M, Har-Vardi I, Harlev A, Levitas E, Zeadna A, Abofoul-Azab M . Mutation in TDRD9 causes non-obstructive azoospermia in infertile men. J Med Genet. 2017; 54(9):633-639. DOI: 10.1136/jmedgenet-2017-104514. View

10.

Ayhan O, Balkan M, Guven A, Hazan R, Atar M, Tok A . Truncating mutations in TAF4B and ZMYND15 causing recessive azoospermia. J Med Genet. 2014; 51(4):239-44. DOI: 10.1136/jmedgenet-2013-102102. View

11.

Yatsenko A, Georgiadis A, Ropke A, Berman A, Jaffe T, Olszewska M . X-linked TEX11 mutations, meiotic arrest, and azoospermia in infertile men. N Engl J Med. 2015; 372(22):2097-107. PMC: 4470617. DOI: 10.1056/NEJMoa1406192. View

12.

Kasak L, Punab M, Nagirnaja L, Grigorova M, Minajeva A, Lopes A . Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia. Am J Hum Genet. 2018; 103(2):200-212. PMC: 6080835. DOI: 10.1016/j.ajhg.2018.07.005. View

13.

Ramasamy R, Bakircioglu M, Cengiz C, Karaca E, Scovell J, Jhangiani S . Whole-exome sequencing identifies novel homozygous mutation in NPAS2 in family with nonobstructive azoospermia. Fertil Steril. 2015; 104(2):286-91. PMC: 4522373. DOI: 10.1016/j.fertnstert.2015.04.001. View

14.

Zhoucun A, Zhang S, Yang Y, Ma Y, Zhang W, Lin L . The common variant N372H in BRCA2 gene may be associated with idiopathic male infertility with azoospermia or severe oligozoospermia. Eur J Obstet Gynecol Reprod Biol. 2005; 124(1):61-4. DOI: 10.1016/j.ejogrb.2005.09.001. View

15.

Riera-Escamilla A, Enguita-Marruedo A, Moreno-Mendoza D, Chianese C, Sleddens-Linkels E, Contini E . Sequencing of a 'mouse azoospermia' gene panel in azoospermic men: identification of RNF212 and STAG3 mutations as novel genetic causes of meiotic arrest. Hum Reprod. 2019; 34(6):978-988. DOI: 10.1093/humrep/dez042. View

16.

Xu J, Jiang L, Yu W, Guo H, Zhang H, Wei D . A novel functional variant in Wilms' Tumor 1 (WT1) is associated with idiopathic non-obstructive azoospermia. Mol Reprod Dev. 2016; 84(3):222-228. DOI: 10.1002/mrd.22768. View

17.

Rodrigues V, Polisseni F, Pannain G, Carvalho M . Genetics in human reproduction. JBRA Assist Reprod. 2020; 24(4):480-491. PMC: 7558894. DOI: 10.5935/1518-0557.20200007. View

18.

Okutman O, Muller J, Baert Y, Serdarogullari M, Gultomruk M, Piton A . Exome sequencing reveals a nonsense mutation in TEX15 causing spermatogenic failure in a Turkish family. Hum Mol Genet. 2015; 24(19):5581-8. DOI: 10.1093/hmg/ddv290. View

19.

Schultz N, Hamra F, Garbers D . A multitude of genes expressed solely in meiotic or postmeiotic spermatogenic cells offers a myriad of contraceptive targets. Proc Natl Acad Sci U S A. 2003; 100(21):12201-6. PMC: 218736. DOI: 10.1073/pnas.1635054100. View

20.

Gershoni M, Hauser R, Yogev L, Lehavi O, Azem F, Yavetz H . A familial study of azoospermic men identifies three novel causative mutations in three new human azoospermia genes. Genet Med. 2017; 19(9):998-1006. DOI: 10.1038/gim.2016.225. View