Genetics meets DNA methylation in rare diseases

Abstract

Alterations in epigenetic landscapes are hallmarks of many complex human diseases, yet, it is often challenging to assess the underlying mechanisms and causal link with clinical manifestations. In this regard, monogenic diseases that affect actors of the epigenetic machinery are of considerable interest to learn more about the etiology of complex traits. Spectacular breakthroughs in medical genetics are largely the result of advances in genome‐wide approaches to identify genomic and epigenomic alterations in patients. These approaches have enabled the identification of an ever‐increasing number of hereditary disorders caused by defects in the establishment of epigenetic marks early during development or in the perpetuation of such marks at later stages. We focus our review on particular cases where DNA methylation landscapes are altered at the genome scale, whether it is a direct consequence of mutations in DNA methyltransferases (DNMT) or that it reflects initial alterations of chromatin states or guiding factors caused by mutations in chromatin modifiers or transcription factors. Collectively, increased knowledge of these rare diseases will add to our understanding of the genetic determinants of DNA methylation in humans. Moreover, investigating how perturbations to these determinants affect genome function has far‐reaching potential to understand various complex human diseases.

Patterns of Reliability: Assessing the Reproducibility and Integrity of DNA Methylation Measurement

“…This mechanism plays an important role in human development and disease, primarily by regulating gene expression. 1 Because of the modifiable nature of epigenetic influence, research into DNA methylation has heralded a new era in the elusive search for the route by which the external world might “get under the skin.” 2 By its very nature, this question spans multiple disciplines; geneticists, 3 biologists, 4 computational scientists, 5 neuroscientists, 6 social scientists, 7 and philosophers 8 have been drawn to massive new data about the epigenome with an eye toward how it might explain health, disease, and our very nature. The promise of the epigenetics revolution has been sweeping.…”

DNA Methylation in the Diagnosis of Monogenic Diseases

“…Correct DNA methylation is required for normal human development [9]. In principle, alterations of normal methylation patterns can arise in absence of DNA sequence changes (primary epimutation) or secondary to genetic variants that can either occur in cis or in trans (secondary epimutation).…”

“…More recently, methylated CpGs that correlate with chronological age and with risk of mortality or developing multi-factorial diseases have been demonstrated [12][13][14]. Specific DNA methylation patterns have been more rarely reported for monogenic diseases [7,9]. DNA methylation can be modified at a single locus generally as consequence of a variant occurring in cis, or at multiple loci possibly as consequence of a variant occurring in trans.…”

“…DNA methylation can be modified at a single locus generally as consequence of a variant occurring in cis, or at multiple loci possibly as consequence of a variant occurring in trans. In the latter case, genomic methylation landscapes may be directly altered by variants in DNMTs or indirectly by mutations in chromatin modifiers or transcription factors [9]. The recent availability of high-throughput screening platforms has led to the identifications of specific methylation signatures associated with an increasing number of disorders, indicating that DNA methylation analysis may represent a valid tool for a better classification of diseases with overlapping clinical features and for sorting cases with ambiguous genetic variants [15].…”

Preclinical and Clinical Epigenetic-Based Reconsideration of Beckwith-Wiedemann Syndrome

“…The progress in epigenetic drugs discovery ( Morera et al, 2016 ; Esteller, 2017 ; Velasco and Francastel, 2019 ), the involvement of epigenetic mutations in a wide range of diseases ( Dirks et al, 2016 ; Graca et al, 2016 ; Jones et al, 2016 ; Berdasco and Esteller, 2019 ) and the newly chromatin-based identified disease biomarkers ( Dirks et al, 2016 ) have suggested epi-based approaches as a promising tool for clinical applications. Evidently, potential new therapeutic options require better clinical knowledge.…”