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Genome-Wide DNA Methylation Analysis in Hereditary Disorders
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Genome-Wide DNA Methylation Analysis in Hereditary Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 11954

Special Issue Editor

Assoc. Prof. Bekim Sadikovic

E-Mail Website
Guest Editor
Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 5C1, Canada

Special Issue Information

Dear Colleagues,

The adoption of genomic sequencing technologies has drastically improved the diagnosis of patients with Mendelian conditions. In spite of these advances, more than half of the patients with hereditary neurodevelopmental disorders lack a genetic diagnosis. Novel insights into molecular mechanisms beyond the DNA sequence are beginning to highlight the underlying biological complexity and are enabling the discovery of novel biomarkers. Epigenomics mechanisms, including genomic DNA methylation patterns, are now recognized to be disrupted in an increasing number and wider spectrum of these disorders. These DNA methylation episignatures are, often, highly sensitive and specific markers of the underlying genetic defects. In addition to resolving the underlying genetic variation and ambiguous clinical presentation, episignature analysis is providing insights into functional aspects of the associated genetic defects. This has enabled adoption of DNA methylation analysis for clinical testing in diagnostic laboratories, and forms the basis of large-scale clinical trials designed to assess the impact of healthcare systems’ adoption of epigenomics profiling on clinical testing of patients with Mendelian disorders. This Special Issue in the International Journal of Molecular Sciences entitled “Genome-Wide DNA Methylation Analysis in Hereditary Disorders” invites studies, reviews, and commentaries related to this emerging area of genomic medicine.

Assoc. Prof. Bekim Sadikovic
Guest Editor

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Keywords

  • epigenomics
  • epigenetics
  • DNA methylation
  • rare disorders
  • Mendelian syndromes
  • genetic testing
  • episignature

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Published Papers (3 papers)

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Research

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22 pages, 3205 KiB  
Article
Interplay between Histone and DNA Methylation Seen through Comparative Methylomes in Rare Mendelian Disorders
by Guillaume Velasco, Damien Ulveling, Sophie Rondeau, Pauline Marzin, Motoko Unoki, Valérie Cormier-Daire and Claire Francastel
Int. J. Mol. Sci. 2021, 22(7), 3735; https://doi.org/10.3390/ijms22073735 - 3 Apr 2021
Cited by 6 | Viewed by 4317
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Genome-Wide DNA Methylation Analysis in Hereditary Disorders)
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13 pages, 2495 KiB  
Article
Detection of a DNA Methylation Signature for the Intellectual Developmental Disorder, X-Linked, Syndromic, Armfield Type
by Sadegheh Haghshenas, Michael A. Levy, Jennifer Kerkhof, Erfan Aref-Eshghi, Haley McConkey, Tugce Balci, Victoria Mok Siu, Cindy D. Skinner, Roger E. Stevenson, Bekim Sadikovic and Charles Schwartz
Int. J. Mol. Sci. 2021, 22(3), 1111; https://doi.org/10.3390/ijms22031111 - 23 Jan 2021
Cited by 9 | Viewed by 3392
Abstract
A growing number of genetic neurodevelopmental disorders are known to be associated with unique genomic DNA methylation patterns, called episignatures, which are detectable in peripheral blood. The intellectual developmental disorder, X-linked, syndromic, Armfield type (MRXSA) is caused by missense variants in FAM50A. [...] Read more.
A growing number of genetic neurodevelopmental disorders are known to be associated with unique genomic DNA methylation patterns, called episignatures, which are detectable in peripheral blood. The intellectual developmental disorder, X-linked, syndromic, Armfield type (MRXSA) is caused by missense variants in FAM50A. Functional studies revealed the pathogenesis to be a spliceosomopathy that is characterized by atypical mRNA processing during development. In this study, we assessed the peripheral blood specimens in a cohort of individuals with MRXSA and detected a unique and highly specific DNA methylation episignature associated with this disorder. We used this episignature to construct a support vector machine model capable of sensitive and specific identification of individuals with pathogenic variants in FAM50A. This study contributes to the expanding number of genetic neurodevelopmental disorders with defined DNA methylation episignatures, provides an additional understanding of the associated molecular mechanisms, and further enhances our ability to diagnose patients with rare disorders. Full article
(This article belongs to the Special Issue Genome-Wide DNA Methylation Analysis in Hereditary Disorders)
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Review

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14 pages, 842 KiB  
Review
Diagnostic Utility of Genome-Wide DNA Methylation Analysis in Mendelian Neurodevelopmental Disorders
by Sadegheh Haghshenas, Pratibha Bhai, Erfan Aref-Eshghi and Bekim Sadikovic
Int. J. Mol. Sci. 2020, 21(23), 9303; https://doi.org/10.3390/ijms21239303 - 6 Dec 2020
Cited by 22 | Viewed by 3605
Abstract
Mendelian neurodevelopmental disorders customarily present with complex and overlapping symptoms, complicating the clinical diagnosis. Individuals with a growing number of the so-called rare disorders exhibit unique, disorder-specific DNA methylation patterns, consequent to the underlying gene defects. Besides providing insights to the pathophysiology and [...] Read more.
Mendelian neurodevelopmental disorders customarily present with complex and overlapping symptoms, complicating the clinical diagnosis. Individuals with a growing number of the so-called rare disorders exhibit unique, disorder-specific DNA methylation patterns, consequent to the underlying gene defects. Besides providing insights to the pathophysiology and molecular biology of these disorders, we can use these epigenetic patterns as functional biomarkers for the screening and diagnosis of these conditions. This review summarizes our current understanding of DNA methylation episignatures in rare disorders and describes the underlying technology and analytical approaches. We discuss the computational parameters, including statistical and machine learning methods, used for the screening and classification of genetic variants of uncertain clinical significance. Describing the rationale and principles applied to the specific computational models that are used to develop and adapt the DNA methylation episignatures for the diagnosis of rare disorders, we highlight the opportunities and challenges in this emerging branch of diagnostic medicine. Full article
(This article belongs to the Special Issue Genome-Wide DNA Methylation Analysis in Hereditary Disorders)
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