DNA Methylation Possible Adjunct to Screening for Neurodevelopmental Syndromes: DNA methylation signatures were identified for several neurodevelopmental Mendelian disorders, and hold promise as a supplement to standard procedures for screening and detect

DNA methylation (DNAme) profiling is used to establish specific biomarkers to improve the diagnosis of patients with inherited neurodevelopmental disorders and to guide mutation screening. In the specific case of mendelian disorders of the epigenetic machinery, it also provides the basis to infer mechanistic aspects with regard to DNAme determinants and interplay between histone and DNAme that apply to humans. Here, we present comparative methylomes from patients with mutations in the de novo DNA methyltransferases DNMT3A and DNMT3B, in their catalytic domain or their N-terminal parts involved in reading histone methylation, or in histone H3 lysine (K) methylases NSD1 or SETD2 (H3 K36) or KMT2D/MLL2 (H3 K4). We provide disease-specific DNAme signatures and document the distinct consequences of mutations in enzymes with very similar or intertwined functions, including at repeated sequences and imprinted loci. We found that KMT2D and SETD2 germline mutations have little impact on DNAme profiles. In contrast, the overlapping DNAme alterations downstream of NSD1 or DNMT3 mutations underlines functional links, more specifically between NSD1 and DNMT3B at heterochromatin regions or DNMT3A at regulatory elements. Together, these data indicate certain discrepancy with the mechanisms described in animal models or the existence of redundant or complementary functions unforeseen in humans.

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Functional annotation of genomic variation: DNA methylation episignatures in neurodevelopmental Mendelian disorders

Human Molecular Genetics ◽

10.1093/hmg/ddaa144 ◽

2020 ◽

Vol 29 (R1) ◽

pp. R27-R32 ◽

Cited By ~ 2

Author(s):

Bekim Sadikovic ◽

Michael A Levy ◽

Erfan Aref-Eshghi

Keyword(s):

Dna Methylation ◽

Diagnostic Yield ◽

Genetic Diagnosis ◽

Genomic Variation ◽

Mendelian Disorders ◽

The Past ◽

Clinical Utilization ◽

Sequencing Technologies ◽

Genomic Technologies ◽

Diagnostic Technology

Abstract The breadth and complexity of genetic testing in patients with suspected Mendelian neurodevelopmental disorders has rapidly expanded in the past two decades. However, in spite of advances in genomic technologies, genetic diagnosis remains elusive in more than half of these patients. Epigenomics, and in particular genomic DNA methylation profiles, are now known to be associated with the underpinning genetic defects in a growing number of Mendelian disorders. These often highly specific and sensitive molecular biomarkers have been used to screen these patient populations, resolve ambiguous clinical cases and interpret genetic variants of unknown clinical significance. Increasing the diagnostic yield beyond genomic sequencing technologies has rapidly propelled epigenomics to clinical utilization, with recent introduction of DNA methylation ‘EpiSign’ analysis in clinical diagnostic laboratories. This review provides an overview of the principles, applications and limitations of DNA methylation episignature analysis in patients with neurodevelopmental Mendelian disorders, and discusses clinical implications of this emerging diagnostic technology.

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Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

Human Genetics and Genomics Advances ◽

10.1016/j.xhgg.2021.100075 ◽

2021 ◽

pp. 100075

Author(s):

Michael A. Levy ◽

Haley McConkey ◽

Jennifer Kerkhof ◽

Mouna Barat-Houari ◽

Sara Bargiacchi ◽

...

Keyword(s):

Dna Methylation ◽

Mendelian Disorders

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Correction: Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders

Genetics in Medicine ◽

10.1038/s41436-021-01130-z ◽

2021 ◽

Author(s):

Bekim Sadikovic ◽

Michael A. Levy ◽

Jennifer Kerkhof ◽

Erfan Aref-Eshghi ◽

Laila Schenkel ◽

...

Keyword(s):

Dna Methylation ◽

Methylation Analysis ◽

Mendelian Disorders ◽

Genome Wide ◽

Dna Methylation Analysis

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Effect of Niacin on Mitochondria of Allium Cepa Root Cells

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100060404 ◽

1967 ◽

Vol 25 ◽

pp. 78-79

Author(s):

M. Arif Hayat

Keyword(s):

Nicotinamide Adenine Dinucleotide ◽

Hydrogen Transfer ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Nicotinamide Adenine ◽

Root Tips ◽

Root Cells ◽

Transfer Processes ◽

Standard Procedures ◽

A Cell ◽

Critical Interest

Although it is recognized that niacin (pyridine-3-carboxylic acid), incorporated as the amide in nicotinamide adenine dinucleotide (NAD) or in nicotinamide adenine dinucleotide phosphate (NADP), is a cofactor in hydrogen transfer in numerous enzyme reactions in all organisms studied, virtually no information is available on the effect of this vitamin on a cell at the submicroscopic level. Since mitochondria act as sites for many hydrogen transfer processes, the possible response of mitochondria to niacin treatment is, therefore, of critical interest.Onion bulbs were placed on vials filled with double distilled water in the dark at 25°C. After two days the bulbs and newly developed root system were transferred to vials containing 0.1% niacin. Root tips were collected at ¼, ½, 1, 2, 4, and 8 hr. intervals after treatment. The tissues were fixed in glutaraldehyde-OsO4 as well as in 2% KMnO4 according to standard procedures. In both cases, the tissues were dehydrated in an acetone series and embedded in Reynolds' lead citrate for 3-10 minutes.

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Microstructure of Electro-Eroded Cemented Carbide Surfaces

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100101165 ◽

1968 ◽

Vol 26 ◽

pp. 284-285

Author(s):

V. N. Filimonenko ◽

M. H. Richman ◽

J. Gurland

Keyword(s):

Surface Layer ◽

Cobalt Content ◽

Cemented Carbides ◽

Face Centered Cubic ◽

X Ray Diffraction ◽

Metallographic Examination ◽

Standard Procedures ◽

Face Centered ◽

Diamond Paste ◽

Plastic Carbon

The high temperatures and pressures that are found in a spark gap during electrical discharging lead to a sharp phase transition and structural transformation in the surface layer of cemented carbides containing WC and cobalt. By means of X-ray diffraction both W2C and a high-temperature monocarbide of tungsten (face-centered cubic) were detected after electro-erosion. The W2C forms as a result of the peritectic reaction, WC → W2C+C. The existence and amount of the phases depend on both the energy of the electro-spark discharge and the cobalt content. In the case of a low-energy discharge (i.e. C=0.01μF, V = 300v), WC(f.c.c.) is generally formed in the surface layer. However, at high energies, (e.g. C=30μF, V = 300v), W2C is formed at the surface in preference to the monocarbide. The phase transformations in the surface layer are retarded by the presence of larger percentages of cobalt.Metallographic examination of the electro-eroded surfaces of cemented carbides was carried out on samples with 5-30% cobalt content. The specimens were first metallographically polished using diamond paste and standard procedures and then subjected to various electrical discharges on a Servomet spark machining device. The samples were then repolished and etched in a 3% NH4OH electrolyte at -0.5 amp/cm2. Two stage plastic-carbon replicas were then made and shadowed with chromium at 27°.

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The early development of antenna and antennal sensilla in the noctuid moth, Agrotis segetum (Insecta: Lepidoptera)

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100160066 ◽

1990 ◽

Vol 48 (3) ◽

pp. 502-503

Author(s):

Eric Hallberg ◽

Lina Hansén

Keyword(s):

Cell Death ◽

Stem Cell ◽

Early Development ◽

Larval Stage ◽

Pupal Stage ◽

Agrotis Segetum ◽

Antennal Sensilla ◽

Noctuid Moth ◽

Standard Procedures

The antennal rudiments in lepidopterous insects are present as disks during the larval stage. The tubular double-walled antennal disk is present beneath the larval antenna, and its inner layer gives rise to the adult antenna during the pupal stage. The sensilla develop from a cluster of cells that are derived from one stem cell, which gives rise to both sensory and enveloping cells. During the morphogenesis of the sensillum these cells undergo major transformations, including cell death. In the moth Agrotis segetum the pupal stage lasts about 14 days (temperature, 25°C). The antennae, clearly seen from the exterior, were dissected and fixed according to standard procedures (3 % glutaraldehyde in 0.15 M cacaodylate buffer, followed by 1 % osmiumtetroxide in the same buffer). Pupae from day 1 to day 8, of both sexes were studied.

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DNA methylation in satellite repeats disorders

Essays in Biochemistry ◽

10.1042/ebc20190028 ◽

2019 ◽

Vol 63 (6) ◽

pp. 757-771 ◽

Cited By ~ 4

Author(s):

Claire Francastel ◽

Frédérique Magdinier

Keyword(s):

Dna Methylation ◽

Human Genome ◽

Repetitive Dna ◽

Dna Sequences ◽

Satellite Repeats ◽

Tremendous Progress ◽

Genes Encoding ◽

Dna Elements ◽

Near Future

Abstract Despite the tremendous progress made in recent years in assembling the human genome, tandemly repeated DNA elements remain poorly characterized. These sequences account for the vast majority of methylated sites in the human genome and their methylated state is necessary for this repetitive DNA to function properly and to maintain genome integrity. Furthermore, recent advances highlight the emerging role of these sequences in regulating the functions of the human genome and its variability during evolution, among individuals, or in disease susceptibility. In addition, a number of inherited rare diseases are directly linked to the alteration of some of these repetitive DNA sequences, either through changes in the organization or size of the tandem repeat arrays or through mutations in genes encoding chromatin modifiers involved in the epigenetic regulation of these elements. Although largely overlooked so far in the functional annotation of the human genome, satellite elements play key roles in its architectural and topological organization. This includes functions as boundary elements delimitating functional domains or assembly of repressive nuclear compartments, with local or distal impact on gene expression. Thus, the consideration of satellite repeats organization and their associated epigenetic landmarks, including DNA methylation (DNAme), will become unavoidable in the near future to fully decipher human phenotypes and associated diseases.

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