Imprinting disorders

Eggermann, Thomas; Monk, David; Nanclares, Guiomar Perez de; Kagami, Masayo; Giabicani, Éloïse; Riccio, Andrea; Tümer, Zeynep; Kalish, Jennifer M.; Tauber, Maïthé; Duis, Jessica; Weksberg, Rosanna; Maher, Eamonn R.; Begemann, Matthias; Elbracht, Miriam

doi:10.1038/s41572-023-00443-4

Cited by 19 publications

(14 citation statements)

References 205 publications

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“…Accurate estimates of diagnostic yield for individual imprinting disorders are not available as this is influenced by the stringency level of referral clinical indications resulting in lower diagnostic rates in patients routinely analyzed by genetic laboratories compared to those achieved in clinically well-characterized cohorts ( Mackay et al, 2022 ; Eggermann et al, 2023 ). The diagnostic workflow of a specific disorder depends on the frequencies of the different molecular mechanisms and on the expertise of laboratories, but generally, for most conditions, such as AS and Prader-Willi (PWS) or Beckwith-Wiedemann (BWS) and Silver Russell syndrome, mainly due to UPD, CNVs or imprinting defects, all leading to changes in the methylation pattern at specific genomic loci, it starts with tests targeting these epigenetic modifications.…”

Section: Methylation Changes At Imprinted Genomic Regionsmentioning

confidence: 99%

“…Methylation-Sensitive (MS)-MLPA, which simultaneously detects altered methylation and CNVs, has replaced MS bisulfite conversion-dependent methods and is now routinely applied as a first-tier test for clinically suspected imprinting disorders. This technique analyzes native DNA through methylation-sensitive restriction enzyme digestion, but cannot distinguish between UPD and imprinting defects with few exceptions, needing second-line assays to identify the exact underlying defect and thus enabling adequate genetic counseling with accurate estimation of recurrence risks ( Beygo et al, 2020 ; Eggermann et al, 2023 ). Reduced sensitivity for low-level mosaic alterations and allele dropout are major limitations, with the latter mitigated by using more probes for single loci.…”

Section: Methylation Changes At Imprinted Genomic Regionsmentioning

confidence: 99%

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Long read sequencing on its way to the routine diagnostics of genetic diseases

Olivucci,

Iovino,

Innella

et al. 2024

Front. Genet.

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The clinical application of technological progress in the identification of DNA alterations has always led to improvements of diagnostic yields in genetic medicine. At chromosome side, from cytogenetic techniques evaluating number and gross structural defects to genomic microarrays detecting cryptic copy number variants, and at molecular level, from Sanger method studying the nucleotide sequence of single genes to the high-throughput next-generation sequencing (NGS) technologies, resolution and sensitivity progressively increased expanding considerably the range of detectable DNA anomalies and alongside of Mendelian disorders with known genetic causes. However, particular genomic regions (i.e., repetitive and GC-rich sequences) are inefficiently analyzed by standard genetic tests, still relying on laborious, time-consuming and low-sensitive approaches (i.e., southern-blot for repeat expansion or long-PCR for genes with highly homologous pseudogenes), accounting for at least part of the patients with undiagnosed genetic disorders. Third generation sequencing, generating long reads with improved mappability, is more suitable for the detection of structural alterations and defects in hardly accessible genomic regions. Although recently implemented and not yet clinically available, long read sequencing (LRS) technologies have already shown their potential in genetic medicine research that might greatly impact on diagnostic yield and reporting times, through their translation to clinical settings. The main investigated LRS application concerns the identification of structural variants and repeat expansions, probably because techniques for their detection have not evolved as rapidly as those dedicated to single nucleotide variants (SNV) identification: gold standard analyses are karyotyping and microarrays for balanced and unbalanced chromosome rearrangements, respectively, and southern blot and repeat-primed PCR for the amplification and sizing of expanded alleles, impaired by limited resolution and sensitivity that have not been significantly improved by the advent of NGS. Nevertheless, more recently, with the increased accuracy provided by the latest product releases, LRS has been tested also for SNV detection, especially in genes with highly homologous pseudogenes and for haplotype reconstruction to assess the parental origin of alleles with de novo pathogenic variants. We provide a review of relevant recent scientific papers exploring LRS potential in the diagnosis of genetic diseases and its potential future applications in routine genetic testing.

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Section: Methylation Changes At Imprinted Genomic Regionsmentioning

confidence: 99%

Section: Methylation Changes At Imprinted Genomic Regionsmentioning

confidence: 99%

Long read sequencing on its way to the routine diagnostics of genetic diseases

Olivucci,

Iovino,

Innella

et al. 2024

Front. Genet.

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“…A notable exception to the general rule is the parental origin-specific methylation of approximately 20 CG-rich autosomal imprinting control regions (ICRs), ∼1-5 Kb in length. Methylation of these sequences is established during gametogenesis reflecting the parental sex by de novo methyltransferases and maintained post-fertilization by the DNA methyltransferase DNMT1 ( 1 ). As a result, in eutherian mammals, one parental ICR allele is methylated and the counterpart unmethylated.…”

Section: Introductionmentioning

confidence: 99%

Human promoter CpG islands contain primate-specific repeats, cluster and resist reprogramming

Mohan,

Anne,

Kumar

et al. 2024

Preprint

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Imperfect tandem repeats (TRs) of greater than or equal to 400nt are associated with 365 human 5-prime genic CpG islands (TR-CGIs). Most are clustered at chromosome ends, with a high density across chromosome 19. These genes are enriched in neurodevelopmental/behavioral disorders and show interindividual variation in methylation levels. A subset of TR-CGIs is highly methylated and remains so during reprogramming to primed iPSCs, but become unmethylated in naive PSCs, as do imprinting control regions. Transcript levels correlate with methylation for some TR-CGI genes. TR-CGIs occur as orthologs in primates, but the corresponding mouse promoter-CGIs are without TRs and unmethylated. Thus, non-imprinted TR-CGIs accompanied primate evolution, with unique ability to acquire methylation during embryonic development and resist reprogramming to a pluripotent stem cell state.

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“…Genomic imprinting is the gamete of origin-dependent epigenetic marking and expression of genes, and is required for normal development (Barlow and Bartolomei 2014). In humans, its deregulation affects growth, metabolism and neurological functions (Eggermann et al 2023). Imprinting disorders are associated with single or multi-locus DNA methylation abnormalities, which in turn can be traced back to genetic variants occurring in cis or in trans (Monk et al 2019).…”

Section: Introductionmentioning

confidence: 99%

A maternal-effectPadi6variant results in abnormal nuclear localization of DNMT1 and failure of epigenetic reprogramming and zygotic genome activation in mouse embryos

Giaccari,

Cecere,

Argenziano

et al. 2023

Preprint

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PADI6 belongs to the multi-protein sub-cortical maternal complex (SCMC) that is present specifically in mammalian oocytes and early embryos. Maternal inactivation of SCMC genes generally results in early embryo lethality. In humans, variants in a subset of SCMC genes have been found in the healthy mothers of children affected by genomic imprinting disorders and characterized by multi-locus imprinting disturbances (MLID). However, how the SCMC controls the DNA methylation required to regulate imprinting remains poorly defined. To address this issue, we generated a mouse line carrying a Padi6 missense variant that had been identified in the mother of two sisters affected by Beckwith-Wiedemann syndrome and MLID. We found that if homozygous in female mice this variant resulted in interruption of embryo development at the 2-cell stage. Single-cell DNA methylation and RNA analyses demonstrated genomic hypermethylation, down-regulation of zygotic genome activation (ZGA) genes and up-regulation of maternal decay genes in 2-cell embryos from homozygous females. In addition, immunofluorescence analysis showed abnormal localization of DNMT1 and UHRF1 in mutant oocytes and zygotes. Taken together, this study demonstrates that PADI6 controls the subcellular localization of DNMT1 that is necessary for pre-implantation epigenetic reprogramming and ZGA.

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Imprinting disorders

Cited by 19 publications

References 205 publications

Long read sequencing on its way to the routine diagnostics of genetic diseases

Long read sequencing on its way to the routine diagnostics of genetic diseases

Human promoter CpG islands contain primate-specific repeats, cluster and resist reprogramming

A maternal-effectPadi6variant results in abnormal nuclear localization of DNMT1 and failure of epigenetic reprogramming and zygotic genome activation in mouse embryos

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