Phenotypic spectrum and extent of DNA methylation defects associated with multi-locus imprinting disturbances
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ABSTRACT:
PROVIDER: PRJNA314498 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-12-31 | GSE78956 | GEO
Project description:The aim of our study was to characterize the genotypic and phenotypic extent of multi-locus imprinting disturbances. Therefore, we analyzed the DNA methylation pattern of 37 individuals with different DNA methylation disturbances. Of these 37 individuals 17 were previously diagnosed with a multi-locus methylation disturbance (MLID) and the remaing 20 were diagnosed with a typical single locus imprinting disorder (SLID). We compared the DNA methylation of these 37 individuals to the DNA methylation of 38 evaluable individuals born small for gestational age. Our analysis revealed 21/37 individuals with a multi-locus methylation disturbances, characterzied by an aberrant DNA methylation in more than one imprintend gene region. Validation analyses were performed by bisulfite-pyrosequencing in the two imprinted gene regions ZDBF2 and FAM50B. Our analyses revealed each one patient previously diagnosed with Temple- and Angelman syndrome to have MLID. Furthermore, we showed that many of the aberrantly methylated imprinted gene regions in patients with MLID are not associated with the so far known typical imprinting disorders.
2016-12-31 | GSE78773 | GEO
Project description:Multi-locus imprinting Disturbances (MLID) are methylation defects affecting germline-derived Differentially Methylated Regions (gDMRs) and they have been associated with maternal-effect variants causing imprinting disorders in the offspring. In a family with multiple pregnancy losses, a child with Beckwith-Wiedemann syndrome (BWS) and a further child without any features of imprinting disorders, novel compound heterozygous variants in the NLRP5 gene of the mother were found. Locus-specific and whole-genome methylation analysis by using Infinium MethylationEPIC BeadChip (WG-317-1001, Illumina) revealed MLID with different methylation profiles in both the siblings. The proband and the normal sibling were found to cluster with other MLID cases as shown by principal component analysis and unsupervised hierarchical clustering and remain distinct from controls. However, we were unable to cluster MLID cases associated with specific clinical phenotypes. The identification of two novel maternal-effect variants of NLRP5 associated with poly-abortivity and MLID add further evidence to the role of NLRP5 in the maintenance of genomic imprinting in early embryos. Furthermore, our results demonstrate that within these pedigrees MLID can also be present in the progeny with healthy phenotype, indicating that some sort of compensation occurs between altered imprinted loci in these individuals.
2019-10-01 | GSE133774 | GEO
Project description:Reprogramming of somatic cells into Induced Pluripotent Stem Cells (iPSCs) provided a major leap towards more personalized cellular models for disease modelling and offers great prospects for regenerative medicine. Despite their considerable success, we still lack the ability to control the state of iPSCs fully, especially at the epigenetic level. This can be appreciated at chromosomal regions regulated by genomic imprinting which provides a good read-out for epigenetic fidelity in iPSCs. Indeed, imprinting defects have already been reported in both mouse and human iPSCs. However, the extent, nature, causes and consequences of these defects still remain to be analysed in a systematic manner. To fill this gap in knowledge, we used a controlled secondary reprogramming system whereby the donor mouse embryonic fibroblasts (MEFs) contain a doxycycline (DOX)-inducible Yamanaka cassette and also Single Nucleotide Polymorphisms (SNPs) to distinguish between the two parental alleles. Several female and male isogenic mouse iPSCs (miPSCs) were obtained using independent culture conditions (defined versus serum) and screened by allelic-specific IMPLICON, a targeted next-generation method to measure DNA methylation at imprinted regions with unprecedented genomic coverage of 1000-fold. Our results showed that imprinting defects are remarkably common in miPSCs. Interestingly, we found important differences in gender responses to culture conditions. In particular, female iPSCs exhibit widespread hypomethylation defects regardless of culture conditions, while male miPSCs show tendency for hypomethylation defects under defined conditions, and hypermethylation defects under serum conditions in particular loci. As expected, methylation defects at imprinted regions resulted in dysregulation of monoallelic expression of imprinted genes. Our results are of utmost importance to devise future reprogramming strategies to generate epigenetic error-free iPSCs
2022-07-15 | GSE148067 | GEO
Project description:Genome wide DNA methylation analysis using blood leukocyte DNA was performed on 15 patients with genomic imprinting disorders (13 Beckwith–Wiedemann syndrome [BWS], two Silver–Russell syndrome [SRS]), and four controls. The Illumina HumanMethylation850 BeadChip was used to obtain DNA methylation profiles at a more than 850,000 CpGs.
2023-08-23 | GSE237503 | GEO
Project description:Multi-locus imprinting disturbances in a family harboring a ZFP57 truncation
| PRJNA629286 | ENA
Project description:We previously reported a child with transient neonatal diabetes mellitus (TNDM), who upon molecular diagnosis was homozygous for a one base-pair deletion in ZFP57, inheriting the mutations from both heterozygous parents. Methylation profiling at diagnosis revealed severe hypomethylation at PLAGL1 and mosaic loss-of-methylation (LOM) at GRB10, NAP1L5 and GNAS-XL DMRs. Some years after the first child, a second sibling was born with a comparable clinical presentation. Upon molecular investigation this child was shown to have the same homozygous deletion. Using Illumina Infinium BeadChip arrays, we confirmed similar hypomethylated signatures at ubiquitous imprinted DMRs. To further characterize the stability of the imprinting defects and understand the role of this mutation in tissue-specific mosaicism, we hybridised buccal-derived DNA and a second leukocyte sample from first child to the HumanMethylationEPIC arrays. When comparing the two blood-derived samples, we observed that the hypomethylation signature is stable over time with the PLAGL1 DMR being the most severely affected, consistent with this being the disease-causing locus. Furthermore, when comparing the leukocyte and buccal samples, the same imprinted DMRs were affected to a similar extent.
2020-11-27 | GSE149568 | GEO
Project description:Our knowledge of genomic imprinting in primates is lagging behand that of mice largely due to the difficulties of allelic analyses in outbred animals. To understand imprinting dynamics in primates, we profiled transcriptomes, DNA methylomes and H3K27me3 in uniparental monkey embryos. We further developed single-nucleotide polymorphisms (SNP)-free methods, TARSII and CARSII, to identify germline differentially methylated regions (DMRs) in somatic tissues. Our comprehensive analyses showed that allelic DNA methylation, but not H3K27me3, is a major mark that correlates with paternal-biasedly expressed genes (PEGs) in uniparental monkey embryos. Interestingly, primate germline DMRs are different from PEG-associated DMRs in early embryos and are enriched in placenta. Strikingly, most placenta-specific germline DMRs are lost in placenta of cloned monkey. Collectively, our study establishes SNP-free germline DMR identification methods, defines developmental imprinting dynamics in primates and demonstrates imprinting defects in cloned monkey placenta, which provides important clues for improving primate cloning.
2021-09-07 | GSE159347 | 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:Systematic analysis of imprinting defects in female and male mouse iPSCs
| PRJNA622986 | ENA