Exome-Sequencing Identifies Novel Genes Associated with Recurrent Pregnancy Loss in a Chinese Cohort

Xiang, Hui-Xian; Wang, Chunyan; Pan, Hong; Hu, Qian; Wang, Ruyi; Xu, Zhouwei; Li, Tengyan; Su, Yezhou; Ma, Xu; Cao, Yunxia; Wang, Binbin

doi:10.3389/fgene.2021.746082

Cited by 13 publications

(14 citation statements)

References 56 publications

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“…They emphasized the role of hemostatic balance in normal pregnancy and screening of coagulation factor gene variants even in asymptomatic women (bleeding complications) with recurrent pregnancy loss. 43 Another finding of this study, consistent with previous reports, is the emphasis on the strong role of fibrinogen and FXIII among coagulation factors in pregnancy loss. [44][45][46] In a study on 160 women with recurrent miscarriages screened for coagulopathies, one was found to have FXIII deficiency, but FXIII levels were not mentioned.…”

Section: Pregnancy Losssupporting

confidence: 92%

“…This difference between the two groups was small and within the normal range. 43 Therefore, the occurrence of PPH with an incidence of 34% in women with heterozygous FXIII deficiency for PPH in one study is not an unusual finding. 39 Therefore, early substitution of FXIII could reduce postpartum blood loss in heterozygous FXIII deficiency and needs to be investigated.…”

Section: Heterozygous Fxiii Deficiency Dorgalalehmentioning

confidence: 77%

“…12,17,18,82 Therefore, FXIII deficiency may be considered as a possible cause of PPH. [41][42][43] FXIII activity decreases markedly in the second and third trimesters, causing FXIII levels to decrease before delivery. 41 On the other hand, FXIII level is…”

Section: Postpartum Hemorrhagementioning

confidence: 99%

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Novel Insights into Heterozygous Factor XIII Deficiency

Dorgalaleh¹

2023

Semin Thromb Hemost

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The prevalence and clinical significance of heterozygous factor XIII (FXIII) deficiency has long been debated, with controversial reports emerging since 1988. In the absence of large epidemiologic studies, but based on a few studies, a prevalence of 1 per 1,000 to 5,000 is estimated. In southeastern Iran, a hotspot area for the disorder, a study of more than 3,500 individuals found an incidence of 3.5%. Between 1988 and 2023, a total of 308 individuals were found with heterozygous FXIII deficiency, of which molecular, laboratory, and clinical presentations were available for 207 individuals. A total of 49 variants were found in the F13A gene, most of which were missense (61.2%), followed by nonsense (12.2%) and small deletions (12.2%), most occurring in the catalytic domain (52.1%) of the FXIII-A protein and most frequently in exon 4 (17%) of the F13A gene. This pattern is relatively similar to homozygous (severe) FXIII deficiency. In general, heterozygous FXIII deficiency is an asymptomatic condition without spontaneous bleeding tendency, but it can lead to hemorrhagic complications in hemostatic challenges such as trauma, surgery, childbirth, and pregnancy. Postoperative bleeding, postpartum hemorrhage, and miscarriage are the most common clinical manifestations, while impaired wound healing has been rarely reported. Although some of these clinical manifestations can also be observed in the general population, they are more common in heterozygous FXIII deficiency. While studies of heterozygous FXIII deficiency conducted over the past 35 years have shed light on some of the ambiguities of this condition, further studies on a large number of heterozygotes are needed to answer the major questions related to heterozygous FXIII deficiency.

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Section: Pregnancy Losssupporting

confidence: 92%

Section: Heterozygous Fxiii Deficiency Dorgalalehmentioning

confidence: 77%

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Novel Insights into Heterozygous Factor XIII Deficiency

Dorgalaleh¹

2023

Semin Thromb Hemost

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“…Recently, whole-exome sequencing has been widely used in adverse pregnancy outcomes including RSA. Based on whole-exome sequencing, some mutant genes were detected in RSA, such as IFT122, DYNC2H1, ALOX15, FOXA2, FGA, FGA and KHDC3L (12,15,17). In this study, a total of 971 maternal and 954 paternal mutations were found to be pathogenic or possibly pathogenic in 30 couples with URSA through whole-exome sequencing analysis.…”

Section: Discussionmentioning

confidence: 70%

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

Mou

Huang

et al. 2022

Ann Transl Med

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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),

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“…The causes of spontaneous abortions and repeated implantation failure are numerical and structural chromosomal abnormalities [41]. From the fact that PGT-A could not signi cantly decrease the MR, unlike implantation rate, the main causes for miscarriages might be the structural chromosomal abnormalities and gene mutations [42].Or it's probably because of the small study groups failing to identify a statistically signi cant difference.…”

Section: The Chance To Baby For Rif Patientsmentioning

confidence: 99%

Preimplantation genetic testing for aneuploidy helps to achieve a live birth with fewer transfer cycles for the blastocyst FET patients with unexplained recurrent implantation failure

Wang

Liu²,

Ma³

et al. 2022

Preprint

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Purpose: This retrospective cohort study aimed to investigate the value of preimplantation genetic testing for aneuploidy (PGT-A) as a screening test for patients suffered from unexplained recurrent implantation failure (RIF). Methods: After screening patients in one reproductive medicine center, twenty-nine, eighty-seven and thirty-eight women (<40-year-old) who had suffered unexplained RIF with PGT-A, or RIF without PGT-A, or no RIF with PGT-A were included. The clinical pregnancy rate and live birth rate per transfer, the conservative and optimal cumulative clinical pregnancy rates (CCPR) and live birth rates (CLBR) after three blastocyst FETs were analyzed. Results: The live birth rate per transfer was significantly higher in the RIF+PGT-A group than that in the RIF+NO PGT-A group (47.4% vs 31.6%) after adjusting the confounder (the maternal age). After 3 cycles of FET, RIF+PGT-A group had a significantly higher conservative cumulative live birth rate (CLBR) compared to the RIF+PGT-A group (69.0% vs 42.5%, odds ratio [OR] 3.777, p=0.005), but had similar CLBR compared to the NO RIF+PGT-A group (69.0% vs 81.6%). The optimal CLBR in the RIF+PGT-A patients was similar to those in the other 2 groups. The miscarriage rate per clinical pregnancy was not different between the RIF+PGT-A and RIF+NO PGT-A, RIF+PGT-A and NO RIF+PGT-A groups. Conclusion: Although PGT-A could land on the non-beneficial side after three blastocyst FETs, it did be superior in reducing the number of transfer cycles required to achieve a similar live birth rate. Further studies to identify the RIF patients who would benefit most from PGT-A are necessary.

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Exome-Sequencing Identifies Novel Genes Associated with Recurrent Pregnancy Loss in a Chinese Cohort

Cited by 13 publications

References 56 publications

Novel Insights into Heterozygous Factor XIII Deficiency

Novel Insights into Heterozygous Factor XIII Deficiency

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

Preimplantation genetic testing for aneuploidy helps to achieve a live birth with fewer transfer cycles for the blastocyst FET patients with unexplained recurrent implantation failure

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