COPY NUMBER VARIATIONS IN FEMALE INFERTILITY IN CHINA
Huang W*, Wang J, Pang M, Zhao Q, Kong L, Mao Y, Li W, Liang B
*Corresponding Author: Professor Weidong Huang, Reproductive Medicine Center, XinJiang JiaYin Hospital, 48 Nanhu North Road, Shuimogou District, Urumchi, Xinjiang Province, 830000, People’s Republic of China. Tel: +86-2363631402. Fax: +86-9914887187. E-mail: hwd@jynk.com
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DISCUSSION

This research showed the CNV preference for chromosome X in the 324 female infertility patients. The X chromosome is the key chromosome for female sexual organ development, and the long arm of the X chromosome was a key area of gonad development. The variation in chromosome X was prone to cause abnormal developments of gonad and infertility [17]. The presence of CNVs in the female genome may result in abnormalities in gamete formation and meiosis of oocyte, thereby influence fertility. One sample exhibited CNV on Xq21.1-q21.2, which involved a gene, POF1B. Loss of function in POF1B could lead to exaggerated germ cell apoptosis and POF [this gene included by the Online Mendelian Inheritance in Man (OMIM)], but this CNV was duplication instead of deletion [18,19]. Combined with clinical phenotype and female sex hormone levels detection, we believed that this CNV duplication may influence fertility. For CNV (9q22.32-q22.33) duplication, it contained HSD17B3 gene. The HSD17B3 gene mutations could impair testosterone bio-synthesis and causing male under masculinization [20], but its function has not been reported in females. For the rest of these CNVs, some contain protein coding genes related to diseases in the OMIM database, but they are mostly associated with other genetic disorders such as neuropathy, brain, skin and retina. Thus, the association between female infertility and CNVs are still unclear. Our data showed that CNVs may be not the main cause of unexplained infertility. In these 29 CNVs, there were five deletions and 24 duplications (Table 1). Our method cannot detect the inversions and translocations, which may lead to the low detection rate of the actual CNVs. We also found five recurring CNVs on Xp22.31, and three times on 22q11.21. The average size of Xp22.31 CNVs was about 1.6 M, including one deletion and four duplications. For clinical phenotypes, four patients with normal phenotype (sex hormone level and normal uterus), and one patient had one miscarriages and one spontaneous abortion. Xp22.31 contained the encoding genes of STS, VCX2, VCX, VCX3A, PNPLA4, HDHD1, etc. It was reported that the deletion, reduplication, and rearrangement of Xp22.31 can lead to X-linked ichthyosis. These five patients all showed no X-linked ichthyosis clinical phenotype. In 2010, Krausz et al. [21] found the CNVs on Xp22.31 for two male infertility patients. So far, there has been no report about Xp22.31 on female infertility. The Xp22.31 exhibits a frequency of 0.15% in a healthy population [22]. Thus, the correlation between Xp22.31 and female infertility needs to be further investigated. Three of the female infertility patients had CNVs on 22q11.21 duplications. The average size of Xp22.31 CNVs was about 2 M. The clinical phenotypes of these three patients were unexplained primary infertility, and their husbands exhibited normal sperm. The deletion CNV (22q11.21) was also found in two types I MRKH (Mayer- Rokitansky-Küster-Hauser) syndrome [14,23]. The association between 22q11.21 deletions and Müllerian aplasia has been reported [24,25]. Moreover, our patients have normal uterus and menstruation. There are many factors that influence female infertility including POF, leiomyomas, endometriosis and polycystic ovarian syndrome (PCOS), etc. For the first time, our study explored the correlation between CNVs and female infertility using NGS technology, and also provided genetic evidence and references for future study and infertility etiology research. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Funding. This study was supported by Natural Science funds of Xinjiang Uygur Autonomous Region [2017D01B10].



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