Impaired DNA methylation in oocytes with a mutation in KHDC3L causing recurrent hydatidiform mole
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ABSTRACT:
PROVIDER: PRJNA506728 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8239850_1.fastq.gz | Fastqsanger.gz | |||
| SRR8239850_2.fastq.gz | Fastqsanger.gz | |||
| SRR8239851_1.fastq.gz | Fastqsanger.gz | |||
| SRR8239851_2.fastq.gz | Fastqsanger.gz | |||
| SRR8239852_1.fastq.gz | Fastqsanger.gz |
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Project description:Mutations in components of the subcortical maternal complex (SMC) of the human oocyte are enigmatically associated with DNA methylation abnormalities specifically at imprinted genes in conceptuses, but the developmental timing, genomic extent and mechanistic details of these defects are unknown. Here, we show, by single-cell bisulphite sequencing, that mutation in human KHDC3L that causes recurrent hydatidiform mole results in a genome-wide deficit of de novo methylation in oocytes.
2019-11-21 | GSE122872 | GEO
Project description:Maternal-effect mutations in components of the subcortical maternal complex (SCMC) of the human oocyte can cause early embryonic failure, gestational abnormalities and recurrent pregnancy loss. Enigmatically, they are also associated with DNA methylation abnormalities at imprinted genes in conceptuses, in the devastating gestational abnormality biparental complete hydatidiform mole (BiCHM) or in multi-locus imprinting disease (MLID). However, the developmental timing, genomic extent and mechanistic basis of these imprinting defects are unknown. Here, we studied methylation level of a women reported with familial recurrent hydatidiform mole and multiple pregnancy loss. Genotype analysis revealed homozygous mutation in KHDC3L. We obtained biparental mole from patient (Patient D) and compared it’s whole-genome methylation profile with respect to control placentas and sporadic mole (AnCHM) using Infinium MethylationEPIC BeadChip (WG-317-1001, Illumina). We also used endometrium samples from their respective mother for the comparison purposes. Molar conceptuses were observed with methylation defects at genome-wide level and profound loss of methylation at multiple genome-derived differentially methylated regions (gDMRs) confirming MLID.
2019-11-21 | GSE138864 | GEO
Project description:A KHDC3L mutation resulting in recurrent hydatidiform mole causes genome-wide DNA methylation loss in oocytes and persistent imprinting defects post-fertilisation.
| PRJNA577637 | ENA
Project description:Complete Hydatidiform Mole (HM) is a gestational trophoblastic disease resulting in hyper proliferation of trophoblast cells and absence of embryo development. Mutations in NLRP7 gene is a major cause of familial recurrent complete HM, where no embryonic tissue is present during the pregnancy. NLRP7 is a novel protein and its function is poorly understood. Lack of NLRP7 in the mouse genome and challenges in studying human embryogenesis as well as human trophoblast differentiation has prevented elucidation of the pathophysiology of this disease and the function of NLRP7 in HM. Here, we established an in vitro model of HM using NLRP7 deficient patient-derived human induced pluripotent stem cells (iPSCs). Whole transcriptome profiling during trophoblast differentiation revealed that NLRP7 deficiency results in precocious downregulation of pluripotency factors, activation of trophoblast genes and promotes maturation of differentiated extraembryonic cell types such as syncytiotrophoblasts. We further showed that these phenotypes are dependent on BMP4 signaling and BMP pathway inhibition prevented excessive trophoblast differentiation of HM-iPSCs. Taken together, this novel human iPSC model of a genetic placental disease recapitulates aspect of trophoblast biology and sheds light on early human embryogenesis by identifying NLRP7 as an important regulator of this process.
2021-09-09 | GSE125592 | GEO
Project description:BACKGROUND:Maternal effect mutations in the components of the subcortical maternal complex (SCMC) of the human oocyte can cause early embryonic failure, gestational abnormalities and recurrent pregnancy loss. Enigmatically, they are also associated with DNA methylation abnormalities at imprinted genes in conceptuses: in the devastating gestational abnormality biparental complete hydatidiform mole (BiCHM) or in multi-locus imprinting disease (MLID). However, the developmental timing, genomic extent and mechanistic basis of these imprinting defects are unknown. The rarity of these disorders and the possibility that methylation defects originate in oocytes have made these questions very challenging to address. METHODS:Single-cell bisulphite sequencing (scBS-seq) was used to assess methylation in oocytes from a patient with BiCHM identified to be homozygous for an inactivating mutation in the human SCMC component KHDC3L. Genome-wide methylation analysis of a preimplantation embryo and molar tissue from the same patient was also performed. RESULTS:High-coverage scBS-seq libraries were obtained from five KHDC3Lc.1A>G oocytes, which revealed a genome-wide deficit of DNA methylation compared with normal human oocytes. Importantly, germline differentially methylated regions (gDMRs) of imprinted genes were affected similarly to other sequence features that normally become methylated in oocytes, indicating no selectivity towards imprinted genes. A range of methylation losses was observed across genomic features, including gDMRs, indicating variable sensitivity to defects in the SCMC. Genome-wide analysis of a pre-implantation embryo and molar tissue from the same patient showed that following fertilisation methylation defects at imprinted genes persist, while most non-imprinted regions of the genome recover near-normal methylation post-implantation. CONCLUSIONS:We show for the first time that the integrity of the SCMC is essential for de novo methylation in the female germline. These findings have important implications for understanding the role of the SCMC in DNA methylation and for the origin of imprinting defects, for counselling affected families, and will help inform future therapeutic approaches.
| S-EPMC6918611 | biostudies-literature
Project description:Background:Hydatidiform mole (HM) is an abnormal human pregnancy with excessive trophoblastic proliferation and abnormal embryonic development, dividing into two complete HM (CHM) and partial HM (PHM) groups. One subcategory of the CHMs is recurrent and familial, which is known as biparental HM (BiHMs) or recurrent HM (RHM). NLRP7, KHDC3L and PADI6 are maternal-effect genes involved in RHMs. NLRP7 is a major gene responsible for RHMs. This study was performed on patients with molar pregnancies and miscarriage. The aim of this study was to genetic screen for mutations in NLRP7 and KHDC3L genes in an affected woman with previous history of 5RHM and the sibling with history of miscarriage. Materials and Methods:In this experimental study, DNA was extracted from blood samples. KHDC3L and NLRP7 were polymerase chain reaction (PCR) amplified. The PCR products were purified and Sanger sequenced. Results:In this study, there is no mutation in KHDC3L gene but a novel mutation was identified in the NACHT domain of NLRP7 gene. Patient with five recurrent moles had this mutation in the homozygous state while her sister with one miscarriage and one normal child showed this mutation in the heterozygous state. Conclusion:In this study, we identified a new mutation in NLRP7 gene of a patient with recurrent HM. Following egg donation, this patient has a normal boy. The sister of this patient with heterozygous mutation has a spontaneous abortion and one normal child that confirm the impact of a defective allele of NLRP7 on reproductive wastage in a recent finding.
| S-EPMC6500085 | biostudies-literature
Project description:PurposeTo study the application of next-generation sequencing on preimplantation genetic testing for recurrent hydatidiform mole patients.MethodsA total of ten recurrent hydatidiform mole patients aged 27-34 years with a history of at least twice hydatidiform moles and no normal pregnancy were collected from 2019 to 2020. The diagnosis of hydatidiform mole type was clarified using short tandem repeat genotyping on products of conception, and whole-exome sequencing was applied for all patients and their partners. Seven recurrent hydatidiform mole patients with complete hydatidiform mole/partial hydatidiform mole type among previous hydatidiform mole tissues and no Pathogenetic/Likely pathogenetic/Uncertain significance variants in NLRP7/KHDC3L/MEI1/C11orf80 underwent a procedure of preimplantation genetic testing. Next-generation sequencing for analyzing the copy number variants and the numbers of heterozygous single nucleotide polymorphism was adopted to clarify the ploidy and parental origin of the embryo chromosomes in vitro. Embryos with biparental diploidy were selected for transfer.ResultsSeven patients have undergone the procedure of preimplantation genetic testing, and twenty-three embryos were obtained, among which 82.6% (n = 19) were identified transferrable and 17.4% (n = 4) were identified aneuploid. Two patients have delivered healthy babies and another is currently in the second trimester after transfer.ConclusionAnalyzing the copy number variants and the numbers of heterozygous single nucleotide polymorphism on the basis of next-generation sequencing can be utilized in the procedure of preimplantation genetic testing among part of recurrent hydatidiform mole patients. The current study is effective to reduce the occurrence of hydatidiform mole with improved clinical strategy, the advanced testing technology and analysis methods, as three of seven patients have conceived or delivered successfully.
| S-EPMC8608948 | biostudies-literature
Project description:Recurrent hydatidiform mole (RHM) is defined by the occurrence of repeated molar pregnancies in affected women. Two genes, NLRP7 and KHDC3L, play a causal role in RHM and are responsible for 48-80% and 5% of cases, respectively. Here, we report the results of screening these two genes for mutations in one Iranian and one Indian patient with RHM. No mutations in NLRP7 were identified in the two patients. KHDC3L sequencing identified two novel protein-truncating mutations in a homozygous state, a 4-bp deletion, c.17_20delGGTT (p.Arg6Leufs*7), in the Iranian patient and a splice mutation, c.349+1G>A, that affects the invariant donor site at the junction of exon 2 and intron 2 in the Indian patient. To date, only four mutations in KHDC3L have been reported. The identification of two additional mutations provides further evidence for the important role of KHDC3L in the pathophysiology of RHM and increases the diversity of mutations described in Asian populations.
| S-EPMC5007383 | biostudies-literature
Project description:A Patient specific iPSC-based model of Hydatidiform mole reveals abnormal BMP4 signaling caused by NLRP7 deficiency
| PRJNA516890 | ENA
Project description:Methylation profiling of hydatidiform moles
| PRJNA279849 | ENA