The Mendelian disorders of the epigenetic machinery

Abstract

The Mendelian disorders of the epigenetic machinery are genetic disorders that involve disruption of the various components of the epigenetic machinery (writers, erasers, readers, and remodelers) and are thus expected to have widespread downstream epigenetic consequences. Studying this group may offer a unique opportunity to learn about the role of epigenetics in health and disease. Among these patients, neurological dysfunction and, in particular, intellectual disability appears to be a common phenotype; however, this is often seen in association with other more specific features in respective disorders. The specificity of some of the clinical features raises the question whether specific cell types are particularly sensitive to the loss of these factors. Most of these disorders demonstrate dosage sensitivity as loss of a single allele appears to be sufficient to cause the observed phenotypes. Although the pathogenic sequence is unknown for most of these disorders, there are several examples where disrupted expression of downstream target genes accounts for a substantial portion of the phenotype; hence, it may be useful to systematically map such disease-relevant target genes. Finally, two of these disorders (Rubinstein-Taybi and Kabuki syndromes) have shown post-natal rescue of markers of the neurological dysfunction with drugs that lead to histone deacetylase inhibition, indicating that some of these disorders may be treatable causes of intellectual disability.

Figure 1.

Characteristic features of the Mendelian disorders of the epigenetic machinery. The most common phenotypic feature is intellectual disability (yellow). Other features include growth retardation (red), overgrowth (green), immune dysfunction (purple), and various limb abnormalities (orange). The components of the epigenetic machinery (horizontal labels) and genetic syndromes (vertical labels) are divided into four categories (writer, eraser, reader, or remodeler). The majority of these genes demonstrate dosage sensitivity (filled circle).

Figure 2.

The Mendelian disorders of the epigenetic machinery exhibit phenotypic breadth. (A) When all phenotypic features are tallied in available OMIM clinical synopsis, the Mendelian disorders of the epigenetic machinery have a shift in the distribution toward higher bins, indicating phenotypic breadth compared with all other diseases with available clinical synopsis. (B) Similarly, there is shift in distribution toward higher number of organ systems affected in the Mendelian disorders of the epigenetic machinery compared with other diseases.

Figure 3.

Acetylation machinery has diverse functions. A subset of target genes may require the presence of both copies of either of the histone acetyltransferases “writers” (CREBBP and EP300). The full complement of histone acetyltransferases may ensure open chromatin and expression from some loci (top, middle). Alternatively, other genes may be dominated by HDACs that favor repressed chromatin (top, sides). However, HDAC8 also plays a role in removing the acetylation mark from cohesins and may also have other roles in cytoplasm. Similarly, CREBBP and EP300 regulate other proteins such as TP53 through acetylation in nucleus and ubiquitination in the cytoplasm. There are also other components that interact with the components of the epigenetic or cohesion machinery, such as RPS6KA3 and ESCO1, that also lead to intellectual disability.