{"title":"与人类早期胚胎骤停相关的PATL2、WEE2和TUBB8新变异的鉴定和表型谱的扩展","authors":"Haijing Zhao, Nengyong Ouyang, Songbang Ou, Haiyan Lin, Zaowen Liao, Wenyi Liu, Hui Chen, Ping Yuan","doi":"10.1007/s10815-025-03501-w","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to identify the genetic variants associated with early embryonic developmental arrest (EDA) in infertile patients and to expand the genotypic and phenotypic spectrum of maternal-effect genes, including PATL2, WEE2, and TUBB8, which are critical for oocyte maturation arrest (OMA) and fertilization failure (FF) as previously reported.</p><p><strong>Methods: </strong>Whole-exome sequencing was performed on 84 unrelated patients who experienced multiple in vitro fertilization and embryo transfer failures due to EDA. The effects of the variants in arrested embryos were assessed by morphological observations. Variants in PATL2, WEE2, and TUBB8 were confirmed by Sanger sequencing, followed by bioinformatic analysis, structural modeling of proteins, and functional assays.</p><p><strong>Results: </strong>We identified seven variants in five patients, including five novel variants (PATL2: c.802G>C; WEE2: c.487T>A, c.1165_1168delAAAC; TUBB8: c.604A>T, c.848C>A) and two previously reported variants (PATL2: c.805C>A; TUBB8: c.322G>A). The variants were predicted to be deleterious, affecting amino acid residues that are highly conserved across species. In vitro experiments confirmed that the PATL2 missense mutation (p.Gln269Lys) resulted in elevated mRNA levels compared to the wild type in HEK293T cells, while the WEE2 variant (p.Tyr163Asn) showed a 20.97% reduction in enzymatic activity. The patients displayed a wide range of infertility phenotypes, including OMA, FF, cleavage failure, and EDA. A literature-based analysis further highlighted the broad and variable phenotype spectrum associated with variants in these genes, enhancing our understanding of genotype-phenotype correlations.</p><p><strong>Conclusions: </strong>This study highlights the diverse phenotypic outcomes associated with variants in PATL2, WEE2, and TUBB8. The findings provide a clearer picture of the genetic and phenotypic spectrums in patients, contributing to the advancement of molecular diagnostics in infertility.</p>","PeriodicalId":15246,"journal":{"name":"Journal of Assisted Reproduction and Genetics","volume":" ","pages":"1961-1973"},"PeriodicalIF":3.2000,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Identification of novel variants and expansion of the phenotypic spectrum in PATL2, WEE2, and TUBB8 associated with human early embryonic arrest.\",\"authors\":\"Haijing Zhao, Nengyong Ouyang, Songbang Ou, Haiyan Lin, Zaowen Liao, Wenyi Liu, Hui Chen, Ping Yuan\",\"doi\":\"10.1007/s10815-025-03501-w\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>This study aimed to identify the genetic variants associated with early embryonic developmental arrest (EDA) in infertile patients and to expand the genotypic and phenotypic spectrum of maternal-effect genes, including PATL2, WEE2, and TUBB8, which are critical for oocyte maturation arrest (OMA) and fertilization failure (FF) as previously reported.</p><p><strong>Methods: </strong>Whole-exome sequencing was performed on 84 unrelated patients who experienced multiple in vitro fertilization and embryo transfer failures due to EDA. The effects of the variants in arrested embryos were assessed by morphological observations. Variants in PATL2, WEE2, and TUBB8 were confirmed by Sanger sequencing, followed by bioinformatic analysis, structural modeling of proteins, and functional assays.</p><p><strong>Results: </strong>We identified seven variants in five patients, including five novel variants (PATL2: c.802G>C; WEE2: c.487T>A, c.1165_1168delAAAC; TUBB8: c.604A>T, c.848C>A) and two previously reported variants (PATL2: c.805C>A; TUBB8: c.322G>A). The variants were predicted to be deleterious, affecting amino acid residues that are highly conserved across species. In vitro experiments confirmed that the PATL2 missense mutation (p.Gln269Lys) resulted in elevated mRNA levels compared to the wild type in HEK293T cells, while the WEE2 variant (p.Tyr163Asn) showed a 20.97% reduction in enzymatic activity. The patients displayed a wide range of infertility phenotypes, including OMA, FF, cleavage failure, and EDA. A literature-based analysis further highlighted the broad and variable phenotype spectrum associated with variants in these genes, enhancing our understanding of genotype-phenotype correlations.</p><p><strong>Conclusions: </strong>This study highlights the diverse phenotypic outcomes associated with variants in PATL2, WEE2, and TUBB8. The findings provide a clearer picture of the genetic and phenotypic spectrums in patients, contributing to the advancement of molecular diagnostics in infertility.</p>\",\"PeriodicalId\":15246,\"journal\":{\"name\":\"Journal of Assisted Reproduction and Genetics\",\"volume\":\" \",\"pages\":\"1961-1973\"},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2025-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Assisted Reproduction and Genetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s10815-025-03501-w\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/5/21 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Assisted Reproduction and Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10815-025-03501-w","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/5/21 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Identification of novel variants and expansion of the phenotypic spectrum in PATL2, WEE2, and TUBB8 associated with human early embryonic arrest.
Purpose: This study aimed to identify the genetic variants associated with early embryonic developmental arrest (EDA) in infertile patients and to expand the genotypic and phenotypic spectrum of maternal-effect genes, including PATL2, WEE2, and TUBB8, which are critical for oocyte maturation arrest (OMA) and fertilization failure (FF) as previously reported.
Methods: Whole-exome sequencing was performed on 84 unrelated patients who experienced multiple in vitro fertilization and embryo transfer failures due to EDA. The effects of the variants in arrested embryos were assessed by morphological observations. Variants in PATL2, WEE2, and TUBB8 were confirmed by Sanger sequencing, followed by bioinformatic analysis, structural modeling of proteins, and functional assays.
Results: We identified seven variants in five patients, including five novel variants (PATL2: c.802G>C; WEE2: c.487T>A, c.1165_1168delAAAC; TUBB8: c.604A>T, c.848C>A) and two previously reported variants (PATL2: c.805C>A; TUBB8: c.322G>A). The variants were predicted to be deleterious, affecting amino acid residues that are highly conserved across species. In vitro experiments confirmed that the PATL2 missense mutation (p.Gln269Lys) resulted in elevated mRNA levels compared to the wild type in HEK293T cells, while the WEE2 variant (p.Tyr163Asn) showed a 20.97% reduction in enzymatic activity. The patients displayed a wide range of infertility phenotypes, including OMA, FF, cleavage failure, and EDA. A literature-based analysis further highlighted the broad and variable phenotype spectrum associated with variants in these genes, enhancing our understanding of genotype-phenotype correlations.
Conclusions: This study highlights the diverse phenotypic outcomes associated with variants in PATL2, WEE2, and TUBB8. The findings provide a clearer picture of the genetic and phenotypic spectrums in patients, contributing to the advancement of molecular diagnostics in infertility.
期刊介绍：
The Journal of Assisted Reproduction and Genetics publishes cellular, molecular, genetic, and epigenetic discoveries advancing our understanding of the biology and underlying mechanisms from gametogenesis to offspring health. Special emphasis is placed on the practice and evolution of assisted reproduction technologies (ARTs) with reference to the diagnosis and management of diseases affecting fertility. Our goal is to educate our readership in the translation of basic and clinical discoveries made from human or relevant animal models to the safe and efficacious practice of human ARTs. The scientific rigor and ethical standards embraced by the JARG editorial team ensures a broad international base of expertise guiding the marriage of contemporary clinical research paradigms with basic science discovery. JARG publishes original papers, minireviews, case reports, and opinion pieces often combined into special topic issues that will educate clinicians and scientists with interests in the mechanisms of human development that bear on the treatment of infertility and emerging innovations in human ARTs. The guiding principles of male and female reproductive health impacting pre- and post-conceptional viability and developmental potential are emphasized within the purview of human reproductive health in current and future generations of our species.
The journal is published in cooperation with the American Society for Reproductive Medicine, an organization of more than 8,000 physicians, researchers, nurses, technicians and other professionals dedicated to advancing knowledge and expertise in reproductive biology.
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