De novo enhancer creation by a noncoding mutation

Decoding the noncoding genome has been a recurring theme in my past posts. Today, I have another fascinating story under this theme. It's about a noncoding variant underlying a newly discovered rare, Mendelian heart condition characterized by a distinct ECG pattern and sudden cardiac death.

One of the biggest mysteries of human genome that we will see scientists incrementally solve over the next decades is the biological mechanism through which noncoding variants influence disease-risks and trait variations. Solving this mystery not only will bring genetic diagnoses for hundreds of rare diseases (as we've seen in the recent RNU4-2 story) but I believe it will also bring breakthroughs in drug development.

As a scientist working in drug development, I try to understand how genetic variants increase or decrease gene function, and how this information could be used identify potential drug targets. So far, the field has been mainly relying on coding variants to do this. We specifically look for rare coding variants to understand the beneficial and harmful phenotypic consequences of increasing or decreasing the function of a gene.

There are limitations to relying solely on coding variants. For example, most of the variants often decrease the gene function rather than increase it. Of course, there are examples of coding variants that increase the gene function. But they are not as common as loss of function variants, and also, they are neither easily identified nor confidently interpreted. The ones we confidently interpret today are mostly loss of function variants such as frameshift, stop gain variants that truncates the protein and abolish its function.

Another limitation of studying coding variants is that their effects are often omnipresent in the human body across space and time. A person born with one copy of a protein truncating variant in, let's say, gene X will be deficient of that gene since their conception in utero until their death. They will be deficient of the gene in every cell of their body that expresses it and at every phase of their life when the gene is expressed. Of course there are