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A genomics approach to females with infertility and recurrent pregnancy loss.
Human Genetics ( IF 5.3 ) Pub Date : 2020-03-14 , DOI: 10.1007/s00439-020-02143-5
Sateesh Maddirevula 1 , Khalid Awartani 2 , Serdar Coskun 3 , Latifa F AlNaim 2 , Niema Ibrahim 1 , Firdous Abdulwahab 1 , Mais Hashem 1 , Saad Alhassan 2 , Fowzan S Alkuraya 1, 4
Affiliation  

Infertility affects 10% of reproductive-age women and is extremely heterogeneous in etiology. The genetic contribution to female infertility is incompletely understood, and involves chromosomal and single-gene defects. Our aim in this study is to decipher single-gene causes in infertile women in whom endocrinological, anatomical, and chromosomal causes have been excluded. Our cohort comprises women with recurrent pregnancy loss and no offspring from spontaneous pregnancies (RPL, n = 61) and those who never achieved clinical pregnancy and were referred for in vitro fertilization [primary infertility (PI), n = 14]. Whole-exome sequencing revealed candidate variants in 14, which represents 43% of those with PI and 13% of those with RPL. These include variants in previously established female infertility-related genes (TLE6, NLRP7, FSHR, and ZP1) as well as genes with only tentative links in the literature (NLRP5). Candidate variants in genes linked to primary ciliary dyskinesia (DNAH11 and CCNO) were identified in individuals with and without systemic features of the disease. We also identified variants in genes not previously linked to female infertility. These include one homozygous variant each in CCDC68, CBX3, CENPH, PABPC1L, PIF1, PLK1, and REXO4, which we propose as candidate genes for infertility based on their established biology or compatible animal models. Our study expands the contribution of single genes to the etiology of PI and RPL, improves the precision of disease classification at the molecular level, and offers the potential for future treatment and development of human genetics-inspired fertility regulators.

中文翻译:

基因组学方法用于不育和反复流产的女性。

不育症影响了10%的育龄妇女,病因学上极为不同。对女性不育症的遗传贡献尚不完全清楚,涉及染色体和单基因缺陷。我们在这项研究中的目的是破译不孕女性的单基因原因,这些女性的内分泌,解剖和染色体原因已被排除在外。我们的研究对象包括复发性流产且没有自然怀孕后代的女性(RPL,n = 61),以及从未达到临床妊娠并被推荐进行体外受精的女性[原发性不育(PI),n = 14]。全外显子组测序揭示了14种候选变体,占PI的43%和RPL的13%。其中包括先前建立的女性不育相关基因(TLE6,NLRP7,FSHR,和ZP1)以及文献中仅有暂定联系的基因(NLRP5)。在患有和不患有该疾病全身特征的个体中鉴定了与原发性睫状运动障碍有关的基因(DNAH11和CCNO)的候选变体。我们还鉴定了以前与女性不育症相关的基因变异。这些在CCDC68,CBX3,CENPH,PABPC1L,PIF1,PLK1和REXO4中各包含一个纯合变体,我们根据它们已建立的生物学或兼容动物模型提出将其作为不育的候选基因。我们的研究扩大了单个基因对PI和RPL病因的贡献,提高了分子水平上疾病分类的准确性,并为人类遗传学启发的生育调节剂的未来治疗和发展提供了潜力。
更新日期:2020-04-21
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