Copy number variations (CNVs) have been found to be responsible for a wide range of human diseases; CNVs on sex chromosomes are more likely to play key roles in germ cell development [1, 2, 3, 4,]. In the past two decades, CNVs causing male infertility have been widely reported, such as the sex chromosome CNVs (Y chromosomal microdeletions and X-link CNVs) [5, 6, 7, 8, 9, 10]. Furthermore, the role of CNVs in female infertility is still poorly understood. A few studies have reported that CNVs may disrupt key genes and pathways of ovaries, leading to premature ovarian failure (POF). Some CNVs are also related to genetic factors causing female infertility, such as the associated microdeletions/duplications in XY gonadal dysgenesis syndrome (XY-GD), MRKH (Mayer-Rokitansky-Küster-Hauser) syndrome [11, 12, 13, 14]. However, the correlation between female infertility and CNVs still remains elusive, especially for the female infertility in China.
Array comparative genomic hybridization (aCGH) is the well-accepted standard for identifying CNVs, but aCGH has disadvantages including restrictive requirement of DNA quality and relatively high cost. In recent years, next generation sequencing (NGS) technologies have been widely applied in chromosome aneuploidy testing and CNVs detection [7,15,16]. Next generation sequencing has several advantages: low cost, short period, high resolution, high accuracy and, small amount of input DNA. The microdeletion and microrepetition of chromosomal fragments can be found by analyzing the CNVs. Dong
In this study, we investigated the correlation between the genome CNVs and female infertility by NGS. We further identified CNVs characteristics for Chinese female infertility samples and provide reference for female infertility etiology research.
The figure shows the distribution map of CNVs on different chromosomes. The x-axis represents the number of chromosome and the y-axis represents the count of different CNVs in the 324 samples. Different color depth means different CNVs on the same chromosome. Copy number variations of Xq22.31, 22qll.21 and 15qll.2 show high frequencies in this study.
Copy number variations detected and their descriptions. (The bolded CNVs indicate high frequencies.)
CNVs Type | Code | Chromosome Location | Start-End Position | Size (Mb) | Number of RefSeq Genes | Included in DGV, ISCA, DEC | Disease-Related Gene in OMIM | Phenotype |
---|---|---|---|---|---|---|---|---|
Deletion | R1701 | 7q31.31 | 120420001-1205-80000 | 0.16 | 1 | no | primary 4 years; infertility no symptoms | |
R1702 | 8p23.3-p23.2 | 160001-3880000 | 3.72 | 10 | yes | primary 4 years; infertility no symptoms | ||
R1703 | 16pl3.2-pl3.11 | 14720001-15300000 | 1.04 | 20 | yes | primary 5 years; infertility no symptoms | ||
R1704 | Xq21.33 | 93900001-95140000 | 1.24 | 0 | yes | primary infertility 5 years; no symptoms | ||
R1705 | Xp22.31 | 6420001-8160000 | 1.68 | 6 | yes | primary 6 years; infertility no symptoms | ||
Duplication | R1707 | 3q27.3-q28 | 187560001-188880000 | 1.32 | 2 | no | primary 5 years; infertility no symptoms | |
R1708 | 4q34.3 | 178120001-179840000 | 1.72 | 4 | no | secondary 1 year; no infertility symptoms | ||
R1709 | 5q21.3-q22.1 | 108900001-110020000 | 1.12 | 3 | no | primary infertility 4 years; no symptoms | ||
R1710 | 6ql6.3 | 102480001-103860000 | 1.36 | 1 | yes | (most of) | secondary infertility 5 years; no symptoms | |
R1711 | 7q21.13 | 88920001-90440000 | 1.20 | 7 | yes | primary 1 year; no infertility symptoms | ||
R1712 | 9q22.32-q22.33 | 98480001-99560000 | 1.08 | 8 | no | secondary 1 year; no infertility symptoms | ||
R1713 | 11q24.2 | 124580001-126980000 | 2.40 | 36 | no | primary infertility 3 years; no symptoms | ||
R1714 | 12pl3.33 | 640001-1720000 | 1.08 | 7 | no | primary 3 years; infertility no symptoms | ||
R1715 | 15qll.2 | 20840001-22780000 | 1.74 | 5 | yes | primary 1 year; no infertility symptoms | ||
R1716 | 15qll.2 | 20840001-22780000 | 1.74 | 5 | yes | primary infertility 5 years; no symptoms | ||
R1717 | 16pl3.11-pl2.3 | 15580001-18620000 | 2.12 | 15 | yes | secondary infertility 1 year; no symptoms | ||
R1718 | 17pl2 | 14610001-15440000 | 1.28 | 6 | yes | secondary 9 years; no infertility symptoms | ||
R1719 | 18pll.21 | 13880001-14040000 | 0.16 | 1 | yes | secondary 1 year; no infertility symptoms | ||
R1720 | 18pll.21 | 18620001-21820000 | 2.20 | 55 | yes | secondary infertility 5 years; no symptoms | ||
R1721 | 22qll.21 | 18960001-211000000 | 1.68 | 37 | yes | primary infertility 1 year; no symptoms | ||
R1722 | 22qll.21 | 18920001-21420000 | 2.04 | 47 | yes | primary infertility 1 year; no symptoms | ||
R1723 | Xql2-ql3.1 | 67060001-68060000 | 1.00 | 4 | no | primary infertility 5 years; no symptoms | ||
R1724 | Xql3.3 | 74180001-75380000 | 1.20 | 4 | no | secondary infertility 1 year; one spontaneous abortion | ||
R1725 | Xp21.1 | 33040001-34720000 | 1.68 | 3 | yes | primary infertility 1 year; no symptoms | ||
R1726 | Xq21.1-q21.2 | 83580001-84780000 | 1.20 | 5 | no | secondary infertility 1 one year; spontaneous two miscarriages; abortion | ||
6420001-8160000 | 1.68 | 6 | yes | secondary infertility 8 years; no symptoms | ||||
6420001-8160000 | 1.76 | 6 | yes | secondary infertility 4 years; no symptoms | ||||
6420001-8160000 | 1.72 | 5 | yes | secondary infertility 3 years; no symptoms | ||||
6420001-8160000 | 1.68 | 6 | yes | secondary infertility 1 one year; spontaneous one miscarriage; abortion |
RefSeq genes: Reference Sequence genes; DGV: Database of Genomic Variants; ISCA: International Standards of Cytogenomic Arrays; DEC: DECIPHER; OMIM: Online Mendelian Inheritance in Man.
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,
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
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 (22ql1.21) was also found in two types IMRKH (Mayer-Rokitansky-Küster-Hauser) syndrome [14, 23]. The association between 22ql 1.21 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),