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

Recurrent pregnancy loss (RPL) is a common reproductive problem affecting around 5% of couples worldwide. At present, about half of RPL cases remained unexplained. Previous studies have suggested an important role for genetic determinants in the etiology of RPL. Here, we performed whole-exome sequen...

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Autores principales:	Huifen Xiang, Chunyan Wang, Hong Pan, Qian Hu, Ruyi Wang, Zuying Xu, Tengyan Li, Yezhou Su, Xu Ma, Yunxia Cao, Binbin Wang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	recurrent pregnancy loss whole-exome sequencing coagulation FOXA2 KHDC3L Genetics QH426-470
Acceso en línea:	https://doaj.org/article/13d61ea43dbe42aeacff9b588cfb2dd7
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spelling	oai:doaj.org-article:13d61ea43dbe42aeacff9b588cfb2dd72021-12-02T09:16:33ZExome-Sequencing Identifies Novel Genes Associated with Recurrent Pregnancy Loss in a Chinese Cohort1664-802110.3389/fgene.2021.746082https://doaj.org/article/13d61ea43dbe42aeacff9b588cfb2dd72021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fgene.2021.746082/fullhttps://doaj.org/toc/1664-8021Recurrent pregnancy loss (RPL) is a common reproductive problem affecting around 5% of couples worldwide. At present, about half of RPL cases remained unexplained. Previous studies have suggested an important role for genetic determinants in the etiology of RPL. Here, we performed whole-exome sequencing (WES) analysis on 100 unrelated Han Chinese women with a history of two or more spontaneous abortions. We identified 6736 rare deleterious nonsynonymous variants across all patients. To focus on possible candidate genes, we generated a list of 95 highly relevant genes that were functionally associated with miscarriage according to human and mouse model studies, and found 35 heterozygous variants of 28 RPL-associated genes in 32 patients. Four genes (FOXA2, FGA, F13A1, and KHDC3L) were identified as being strong candidates. The FOXA2 nonsense variant was for the first time reported here in women with RPL. FOXA2 knockdown in HEK-293T cells significantly diminished the mRNA and protein expression levels of LIF, a pivotal factor for maternal receptivity and blastocyst implantation. The other genes, with 29 variants, were involved in angiogenesis, the immune response and inflammation, cell growth and proliferation, which are functionally important processes for implantation and pregnancy. Our study identified several potential causal genetic variants in women with RPL by WES, highlighting the important role of genes controlling coagulation, confirming the pathogenic role of KHDC3L and identifying FOXA2 as a newly identified causal gene in women with RPL.Huifen XiangHuifen XiangChunyan WangChunyan WangHong PanHong PanQian HuQian HuRuyi WangRuyi WangZuying XuZuying XuTengyan LiYezhou SuYezhou SuXu MaXu MaYunxia CaoYunxia CaoBinbin WangBinbin WangFrontiers Media S.A.articlerecurrent pregnancy losswhole-exome sequencingcoagulationFOXA2KHDC3LGeneticsQH426-470ENFrontiers in Genetics, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	recurrent pregnancy loss whole-exome sequencing coagulation FOXA2 KHDC3L Genetics QH426-470
spellingShingle	recurrent pregnancy loss whole-exome sequencing coagulation FOXA2 KHDC3L Genetics QH426-470 Huifen Xiang Huifen Xiang Chunyan Wang Chunyan Wang Hong Pan Hong Pan Qian Hu Qian Hu Ruyi Wang Ruyi Wang Zuying Xu Zuying Xu Tengyan Li Yezhou Su Yezhou Su Xu Ma Xu Ma Yunxia Cao Yunxia Cao Binbin Wang Binbin Wang Exome-Sequencing Identifies Novel Genes Associated with Recurrent Pregnancy Loss in a Chinese Cohort
description	Recurrent pregnancy loss (RPL) is a common reproductive problem affecting around 5% of couples worldwide. At present, about half of RPL cases remained unexplained. Previous studies have suggested an important role for genetic determinants in the etiology of RPL. Here, we performed whole-exome sequencing (WES) analysis on 100 unrelated Han Chinese women with a history of two or more spontaneous abortions. We identified 6736 rare deleterious nonsynonymous variants across all patients. To focus on possible candidate genes, we generated a list of 95 highly relevant genes that were functionally associated with miscarriage according to human and mouse model studies, and found 35 heterozygous variants of 28 RPL-associated genes in 32 patients. Four genes (FOXA2, FGA, F13A1, and KHDC3L) were identified as being strong candidates. The FOXA2 nonsense variant was for the first time reported here in women with RPL. FOXA2 knockdown in HEK-293T cells significantly diminished the mRNA and protein expression levels of LIF, a pivotal factor for maternal receptivity and blastocyst implantation. The other genes, with 29 variants, were involved in angiogenesis, the immune response and inflammation, cell growth and proliferation, which are functionally important processes for implantation and pregnancy. Our study identified several potential causal genetic variants in women with RPL by WES, highlighting the important role of genes controlling coagulation, confirming the pathogenic role of KHDC3L and identifying FOXA2 as a newly identified causal gene in women with RPL.
format	article
author	Huifen Xiang Huifen Xiang Chunyan Wang Chunyan Wang Hong Pan Hong Pan Qian Hu Qian Hu Ruyi Wang Ruyi Wang Zuying Xu Zuying Xu Tengyan Li Yezhou Su Yezhou Su Xu Ma Xu Ma Yunxia Cao Yunxia Cao Binbin Wang Binbin Wang
author_facet	Huifen Xiang Huifen Xiang Chunyan Wang Chunyan Wang Hong Pan Hong Pan Qian Hu Qian Hu Ruyi Wang Ruyi Wang Zuying Xu Zuying Xu Tengyan Li Yezhou Su Yezhou Su Xu Ma Xu Ma Yunxia Cao Yunxia Cao Binbin Wang Binbin Wang
author_sort	Huifen Xiang
title	Exome-Sequencing Identifies Novel Genes Associated with Recurrent Pregnancy Loss in a Chinese Cohort
title_short	Exome-Sequencing Identifies Novel Genes Associated with Recurrent Pregnancy Loss in a Chinese Cohort
title_full	Exome-Sequencing Identifies Novel Genes Associated with Recurrent Pregnancy Loss in a Chinese Cohort
title_fullStr	Exome-Sequencing Identifies Novel Genes Associated with Recurrent Pregnancy Loss in a Chinese Cohort
title_full_unstemmed	Exome-Sequencing Identifies Novel Genes Associated with Recurrent Pregnancy Loss in a Chinese Cohort
title_sort	exome-sequencing identifies novel genes associated with recurrent pregnancy loss in a chinese cohort
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/13d61ea43dbe42aeacff9b588cfb2dd7
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Exome-Sequencing Identifies Novel Genes Associated with Recurrent Pregnancy Loss in a Chinese Cohort

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