Gene Spectrum and Clinical Traits of Nine Patients With Oocyte Maturation Arrest

Huo, Mingzhu; Zhang, Yile; Sheng, Shi; Shi, Hao; Liu, Yidong; Zhang, Lingyun; Wang, Yanchi; Niu, Wenbin

doi:10.3389/fgene.2022.772143

Cited by 6 publications

(4 citation statements)

References 27 publications

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“…The data on pathogenic PATL2 mutants reviewed by Sun et al and reported in a recent study were reanalysed ( Liu et al, 2021 ; Huang et al, 2022 ; Huo et al, 2022 ; Sun et al, 2022 ). A total of 34 patients with OOMD were included.…”

Section: Resultsmentioning

confidence: 99%

“…Evolutionary conservation of the variants among the species was analysed using ConSurf server ( http://consurftest.tau.ac.il ). The outcome data of the PATL2 pathogenic mutants reported in the literature ( Liu et al, 2021 ; Huang et al, 2022 ; Huo et al, 2022 ; Sun et al, 2022 ) were re-analysed.…”

Section: Methodsmentioning

confidence: 99%

“…Since the first case of homozygous mutation of PATL2 gene in a patient who suffered from assisted reproductive technology (ART) failure because of oocytes being arrested at the GV stage ( Chen et al, 2017 ) was reported, subsequent genetic testing was largely carried out and obtained important results in patients with phenotypes of recurrent failure in in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), empty follicle syndrome (EFS), high proportion of GV-arrested oocytes, extremely low fertilisation rate, abnormal oocyte morphology and abnormally large first polar body. However, OOMD is a rare disease, and scarce variations have been found in suspected patients ( Maddirevula et al, 2017 ; Christou-Kent et al, 2018 ; Huang et al, 2018 ; Wu et al, 2019 ; Liu et al, 2020 ; Wang et al, 2021 ; Huang et al, 2022 ; Huo et al, 2022 ; Lei et al, 2022 ; Sun et al, 2022 ); therefore, limited mutants are available for molecular epidemiological analysis. Furthermore, the phenotype caused by PATL2 gene mutation was found to be insidious among the population and even in infertile women who underwent ART.…”

Section: Introductionmentioning

confidence: 99%

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High carrier frequency of pathogenic PATL2 gene mutations predicted in population: a bioinformatics-based approach

et al. 2023

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Topoisomerase II homologue 2 (PATL2) has been confirmed to be a key gene that contributes to oocyte maturation. However, the allele distribution and carrier frequency of these mutations remain uncharacterized. So a bioinformatics subcategory analysis of PATL2 mutations from outcome data and Single Nucleotide Polymorphism (SNP) databases was conducted. Altogether, the causative PATL2 mutation number detected in patients with oocyte maturation defects in the clinical studies and pathogenic PATL2 mutation sites predicted by software based on the database was approximately 53. The estimated carrier frequency of pathogenic mutation sites was at least 1.14‰ based on the gnomAD and ExAC database, which was approximately 1/877. The highest frequency of mutations detected in the independent patients was c.223-14_223-2del13. The carrier frequency of this mutation in the population was 0.25‰, which may be a potential threat to fertility. Estimated allele and carrier frequency are relatively higher than those predicted previously based on clinical ascertainment. A review of PATL2 mutation lineage identified in 34 patients showed that 53.81%, 9.22% and 14.72% of the oocytes with PATL2 mutations were arrested at the germinal vesicle (GV) stage, metaphase I (MI) stage and first polar body stage, respectively. Oocytes that could develop to the first polar body stage were extremely rare to fertilise, and their ultimate fate was early embryonic arrest. Phenotypic variability is related to the function of the regions and degree of loss of function of PATL2 protein. A 3D protein structure changes predicted by online tools, AlphaFold, showed aberrations at the mutation sites, which may explain partially the function loss. When the mutated and wild-type proteins are not in the same amino acid category, the protein structure will be considerably unstable. The integration of additional mutation sites with phenotypes is helpful in drawing a complete picture of the disease. Bioinformatics analysis of PATL2 mutations will help reveal molecular epidemiological characteristics and provide an important reference for new mutation assessment, genetic counselling and drug research.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High carrier frequency of pathogenic PATL2 gene mutations predicted in population: a bioinformatics-based approach

et al. 2023

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“…In recent years, scientists have been exploring the specific mechanisms of oocyte maturation arrest (OMA) ( 6 ) and have identified several related genes, including TUBB8 ( 7 , 8 ), PATL2 ( 9 , 10 ), TRIP13 ( 11 ), and TBPL2 ( 12 , 13 ). Mutations of these genes could cause OMA at either GV or MI stage.…”

Section: Introductionmentioning

confidence: 99%

Oocyte phenotype, genetic diagnosis, and clinical outcome in case of patients with oocyte maturation arrest

Zhu

Yang²,

Jin³

et al. 2022

Front. Endocrinol.

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Backgroundoocyte maturation arrest (OMA) is currently one of the major causes of in vitro fertilization (IVF) failure, and several gene mutations were found to be associated with OMA. The purpose of this study was to identify the oocyte phenotype, genetic diagnosis, and clinical outcomes of patients with OMA and explore their possible interrelationships, thus providing a more individualized and efficient treatment strategy guidance accordingly.MethodsA retrospective study was conducted, involving 28 infertile women with OMA in the Reproductive Medicine Center of Tongji Hospital from 2018 to 2021. Whole-exome sequencing was performed for the detection of gene mutations. Patients were classified into three groups based on their oocyte phenotype, and for each group, the immature oocytes were cultured in vitro and mature oocytes were fertilized to evaluate both the maturation capacity and developmental potential. The clinical outcomes of OMA patients with different gene mutations or from different groups were further analyzed and compared.ResultsTwenty-eight women with OMA were evaluated in this study. According to the stage of OMA, 14 (50.0%) women were classified as OMA Type-1 (GV arrest), 5 (17.9%) were OMA Type-2 (MI arrest), and 9 (32.1%) were OMA Type-3 (with both GV and MI arrest). Immature oocytes from OMA patients exhibited significantly lower maturation rates even after IVM, compared to those in general patients. Seven patients (25.0%) were detected to have deleterious variations in two genes (PATL2 and TUBB8), known to be associated with the OMA phenotype. Patients with identified mutations were found to have little opportunity to obtain offspring with their own oocytes. Among the patients without mutations identified, those classified as OMA Type-1 or Type-3 still had a chance to obtain offspring through IVF or natural pregnancy, while all patients in the Type-2 group failed to obtain live birth.ConclusionsThree different phenotypes were observed in patients with OMA. The clinical outcomes of patients were associated with the presence of gene mutations and the classification of oocyte phenotype, thus a reasonable triage system was proposed to optimize the allocation of health care resources and maximize patient benefit.

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Identification novel mutations and phenotypic spectrum expanding in PATL2 in infertile women with IVF/ICSI failure

Ye,

Li,

Niu

et al. 2024

J Assist Reprod Genet

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Gene Spectrum and Clinical Traits of Nine Patients With Oocyte Maturation Arrest

Cited by 6 publications

References 27 publications

High carrier frequency of pathogenic PATL2 gene mutations predicted in population: a bioinformatics-based approach

High carrier frequency of pathogenic PATL2 gene mutations predicted in population: a bioinformatics-based approach

Oocyte phenotype, genetic diagnosis, and clinical outcome in case of patients with oocyte maturation arrest

Identification novel mutations and phenotypic spectrum expanding in PATL2 in infertile women with IVF/ICSI failure

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