Genetics meets DNA methylation in rare diseases

Clin Genet. 2019 Feb;95(2):210-220. doi: 10.1111/cge.13480. Epub 2018 Dec 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Chromatin / genetics
  • DNA (Cytosine-5-)-Methyltransferase 1 / genetics
  • DNA Methylation*
  • Epigenesis, Genetic*
  • Gene Expression Regulation
  • Genetic Association Studies
  • Genetic Markers
  • Genetic Predisposition to Disease*
  • Humans
  • Mutation
  • Rare Diseases / diagnosis
  • Rare Diseases / genetics*
  • Transcription Factors / metabolism


  • Chromatin
  • Genetic Markers
  • Transcription Factors
  • DNA (Cytosine-5-)-Methyltransferase 1