Identification of genetic polymorphisms in unexplained recurrent spontaneous abortion based on whole exome sequencing br

作者全名："Mou, Jiang-Tao; Huang, Shi-Xing; Yu, Li-Li; Xu, Jing; Deng, Qiao-Ling; Xie, Yi-Shan; Deng, Kun"

作者地址："[Mou, Jiang-Tao; Xie, Yi-Shan; Deng, Kun] Chongqing Med Univ, Affiliated Hosp 3, Dept Lab Med, 1st Shuanghu Branch Rd, Chongqing 401120, Peoples R China; [Huang, Shi-Xing] Chongqing Univ, Three Gorges Hosp, Dept Obstet & Gynecol, Chongqing, Peoples R China; [Yu, Li-Li; Xu, Jing] Chongqing Med Univ, Affiliated Hosp 3, Dept Obstet & Gynecol, Chongqing, Peoples R China; [Deng, Qiao-Ling] Second Peoples Hosp Jiulongpo Dist, Dept Obstet & Gynecol, Chongqing, Peoples R China"

通信作者："Deng, K (通讯作者)，Chongqing Med Univ, Affiliated Hosp 3, Dept Lab Med, 1st Shuanghu Branch Rd, Chongqing 401120, Peoples R China."

来源：ANNALS OF TRANSLATIONAL MEDICINE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000808591800069

JCR分区：Q3

影响因子：3.616

年份：2022

卷号：10

期号：10

开始页：　

结束页：　

文献类型：Article

关键词：Whole exome sequencing; unexplained recurrent spontaneous abortion (URSA); genetic polymorphisms; signaling pathway

摘要："Background: The precise etiology of approximately 50% of patients with recurrent spontaneous abortion (RSA) is unclear, known as unexplained recurrent spontaneous abortion (URSA). This study identified the genetic polymorphisms in patients with URSA. Methods: Genomic DNA was extracted from 30 couples with URSA and 9 couples with normal reproductive history for whole exome sequencing. Variations in annotation, filtering, and prediction of harmfulness and pathogenicity were examined. Furthermore, predictions of the effects of changes in protein structure, Sanger validation, and functional enrichment analyses were performed. The missense mutated genes with significant changes in protein function, and genes with mutations of premature stop, splice site, frameshift, and in-frame indel were selected as candidate mutated genes related to URSA. Results: In 30 unrelated couples with URSA, 50%, 20%, and 30% had 2, 3, and more than 4 miscarriages, respectively. Totally, 971 maternal and 954 paternal mutations were found to be pathogenic or possibly pathogenic after preliminary filtering. Total variations were not associated with age nor the number of miscarriages. In 28 patients (involving 23 couples), 22 pathogenic or possibly pathogenic variants of 19 genes were found to be strongly associated with URSA, with an abnormality rate of 76.67%. Among these, 12 missense variants showed obvious changes in protein functions, including ANXA5 (c.949G>C; p.G317R), APP (c.1530G>C; p.K510N), DNMT1 (c.2626G>A; p.G876R), FN1 (c.5621T>C; p.M1874T), MSH2 (c.1168G>A; p.L390F), THBS1 (c.2099A>G; p.N700S), KDR (c.2440G>A; p.D814N), POLR2B(c.406G>T; p.G136C), ITGB1 (c.655T>C; p.Y219H), PLK1 (c.1210G>T; p.A404S), COL4A2 (c.4808 A>C; p.H1603P), and LAMA4 (c.3158A>G; p.D1053G). Six other genes with mutations of premature stop, splice site, frameshift, and in-frame indel were also identified, including BUB1B (c.1648C>T; p.R550*) and MMP2(c.1462_1464delTTC; p.F488del) from the father, and mutations from mother and/or father including BPTF (c.396_398delGGA; p.E138 del and c.429_431GGA; p.E148del), MECP2 (c.21_23delCGC; p.A7del), LAMA2 (HGVS: NA; Exon: NA; SPLICE_SITE, DONOR), and SOX21 (c.640 _641insT; p. A214fs, c.644dupC; p. A215fs and c.644_645ins ACGCGTCTTCTTCCCGCAGTC; p. A215dup). Conclusions: These pathogenic or potentially pathogenic mutated genes may be potential biomarkers for URSA and may play an auxiliary role in the treatment of URSA."

基金机构：Science and Technology Research Project of Chongqing Education Commission [KJQN202100427]; Young and Middle-Aged Medical Talents Project of Chongqing Municipal Health Commission/Chongqing Science and Technology Bureau [2022GDRC001]

基金资助正文：This study was funded by the Science and Technology Research Project of Chongqing Education Commission (No. KJQN202100427) and the Young and Middle-Aged Medical Talents Project of Chongqing Municipal Health Commission/Chongqing Science and Technology Bureau (No. 2022GDRC001).