CHARGE syndrome and related disorders: a mechanistic link

Hum Mol Genet. 2021 Nov 16;30(23):2215-2224. doi: 10.1093/hmg/ddab183.


CHARGE syndrome is an autosomal dominant malformation disorder caused by pathogenic variants in the chromatin remodeler CHD7. Affected are craniofacial structures, cranial nerves and multiple organ systems. Depending on the combination of malformations present, its distinction from other congenital disorders can be challenging. To gain a better insight into the regulatory disturbances in CHARGE syndrome, we performed RNA-Seq analysis on blood samples of 19 children with CHARGE syndrome and a confirmed disease-causing CHD7 variant in comparison with healthy control children. Our analysis revealed a distinct CHARGE syndrome pattern with downregulation of genes that are linked to disorders described to mimic the CHARGE phenotype, i.e. KMT2D and KDM6A (Kabuki syndrome), EP300 and CREBBP (Rubinstein-Taybi syndrome) and ARID1A and ARID1B (Coffin-Siris syndrome). Furthermore, by performing protein-protein interaction studies using co-immunoprecipitation, direct yeast-two hybrid and in situ proximity ligation assays, we could demonstrate an interplay between CHD7, KMT2D, KDM6A and EP300. In summary, our data demonstrate a mechanistic and regulatory link between the developmental disorders CHARGE-, Kabuki- and Rubinstein Taybi-syndrome providing an explanation for the overlapping phenotypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • CHARGE Syndrome / diagnosis*
  • CHARGE Syndrome / genetics*
  • CHARGE Syndrome / metabolism
  • Carrier Proteins
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Profiling
  • Genetic Association Studies* / methods
  • Genetic Diseases, Inborn / diagnosis*
  • Genetic Diseases, Inborn / genetics*
  • Genetic Diseases, Inborn / metabolism
  • Genetic Markers
  • Genetic Predisposition to Disease*
  • Genetic Variation
  • Humans
  • Immunoprecipitation
  • Mutation
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Phenotype
  • Protein Binding
  • RNA-Seq


  • Carrier Proteins
  • DNA-Binding Proteins
  • Genetic Markers
  • KMT2D protein, human
  • Neoplasm Proteins
  • DNA Helicases
  • CHD7 protein, human