Exonic enhancers: proceed with caution in exome and genome sequencing studies

Abstract

Exonic enhancers (eExons) are coding exons that also function as enhancers of the gene in which they reside or (a) nearby gene(s). Mutations that affect the enhancer activity of these eExons have been associated with human disease. Therefore, eExon mutations should be taken into account in exome and genome sequencing projects, not only because of the ability of these mutations to modify the encoded proteins but also because of their effects on enhancer activity.

Fig. 1

DYNC1I1 exonic enhancers (eExons) regulate DLX5 and DLX6. a The DYNC1I1-DLX5/6 locus has two known eExons, DYNC1I1 exons 15 and 17 (colored in blue), that are functional limb enhancers and were shown to interact with DLX5 and DLX6 [4]. A 106 kb deletion (red line) that contains these eExons was found in an individual with split hand and foot malformation (SHFM) [10]. b A fictional example of a mutation in an eExon that could be overlooked in exome or genome sequencing studies. The chromatogram shows a synonymous mutation in an eExon that could leave the protein sequence unchanged but could affect a transcription factor binding site (logo plot below) leading to changes in the enhancer function of this eExon. DLX5 Distal-less homeobox 5, DLX6 Distal-less homeobox 6, DYNC1I1 Dynein cytoplasmic 1 intermediate chain 1