Identification of novel variants and expansion of the phenotypic spectrum in PATL2, WEE2, and TUBB8 associated with human early embryonic arrest.

IF 3.2 3区医学 Q2 GENETICS & HEREDITY

Journal of Assisted Reproduction and Genetics Pub Date : 2025-06-01 Epub Date: 2025-05-21 DOI:10.1007/s10815-025-03501-w

Haijing Zhao, Nengyong Ouyang, Songbang Ou, Haiyan Lin, Zaowen Liao, Wenyi Liu, Hui Chen, Ping Yuan

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引用次数: 0

Abstract

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.

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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

目的：本研究旨在鉴定与不孕患者早期胚胎发育停滞（EDA）相关的遗传变异，并扩大母体效应基因的基因型和表型谱，包括PATL2、WEE2和TUBB8，这些基因在之前报道的卵母细胞成熟停滞（OMA）和受精失败（FF）中起关键作用。方法：对84例因EDA导致多次体外受精和胚胎移植失败的患者进行全外显子组测序。通过形态学观察来评估这些变异对冻结胚胎的影响。通过Sanger测序确认PATL2、WEE2和TUBB8的变异，随后进行生物信息学分析、蛋白质结构建模和功能分析。结果：我们在5例患者中发现了7个变体，包括5个新变体(PATL2: C . 802g >C；WEE2: c.487T>A, c.1165_1168delAAAC；TUBB8: c.604A>T, c.848C>A)和两个先前报道的变体(PATL2: c.805C>A；TUBB8: c.322G >)。据预测，这些变异是有害的，会影响跨物种高度保守的氨基酸残基。体外实验证实，与野生型相比，HEK293T细胞中PATL2错义突变（p.Gln269Lys）导致mRNA水平升高，而WEE2变体（p.Tyr163Asn）的酶活性降低了20.97%。患者表现出广泛的不育表型，包括OMA、FF、卵裂失败和EDA。一项基于文献的分析进一步强调了与这些基因变异相关的广泛和可变的表型谱，增强了我们对基因型-表型相关性的理解。结论：本研究强调了与PATL2、WEE2和TUBB8变异相关的不同表型结果。研究结果提供了患者遗传和表型谱的更清晰的图像，有助于不孕症分子诊断的进步。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Assisted Reproduction and Genetics 医学-妇产科学

CiteScore

5.70

自引率

9.70%

发文量

286

审稿时长

1 months

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.