The latest instalment in a series of big studies to understand the genetics of Huntington disease (HD) just hit the shelves. These studies have focused on how small changes in the genetic letters of a person with HD can impact when they develop symptoms of the disease. The previous instalments in this series have been particularly important for opening up new ways to understand HD and to develop new treatments. So let’s have a look at how this study was done, and what this newest volume tells us that is different from the previous ones.

The genome is a book, but we all have spelling changes

The genome of every person is made up of 4 letters – C, A, G, and T. They’re combined in different ways to make every gene in our body, like how the 26 letters of alphabet can spell out all sorts of different words on each page of a book. 

But we each have spelling changes on individual pages of our personal book (our genome) that differ from other people. You can think of these spelling changes as differences of a few letters that spell a similar word, like gray and grey. Sometimes a T is replaced by a G, or C is replaced by a A, just to give two examples. These changes can be shared with many other people – what we call common variants – or they might only be found in few other people around the world – which we call rare variants.

For many years, a group of talented scientists called the Genetic Modifiers of HD Consortium, or GeM-HD for short, have been looking at the impact of common variants – common genetic spelling changes – on how people develop HD. What this means is that they found common genetic spelling changes in people with HD and then looked to see if their symptoms of HD differed based on the spelling changes. 

To date, the GeM-HD consortium has studied thousands of people with HD and hundreds of thousands of spelling changes in every single person. That’s a lot of data to analyze! So new volumes in the series are only published about once every 5 years. 

The latest volume

This new study from the GeM-HD Consortium is the third. It comes after two big studies that the Consortium published in 2015 and 2019. 

The first study, published in 2015, was a true bestseller. It revealed that spelling changes in people who develop HD earlier or later happen on very specific pages (genes) of the human genome. Many of these pages (genes) with spelling changes that make HD appear earlier or later seem to be connected with how the CAG repeat that causes HD becomes longer or shorter. 

The discoveries by the Consortium in the first volume set off a major change in how scientists think HD develops – focused on how the CAG repeat gets longer or shorter in the body, a process called somatic instability. It also changed how drug companies think about developing new medications to treat HD.

The GeM-HD sequel, which hit the shelves in 2019, told us even more: that there are multiple spelling changes on specific pages (genes) that can impact HD in opposite ways. For example, one spelling change might make HD develop faster, but a different spelling change further down the page might make HD develop slower. 

But this second volume ended with a cliffhanger mystery: do the spelling changes in people who develop HD earlier or later also change the length of the CAG repeat in people? Up to that point, it was mostly guessing, based on the pages where the spelling changes were found. That’s what this third instalment is about.

The plot twist

To explore whether the spelling changes that impact symptoms of HD also alter the length of the CAG repeat, the Consortium scientists took a clever approach: they compared the previously studied spelling changes on those pages (genes) with the number of letters for the CAG repeat on the HD page (gene), each on different pages of the book. 

Surprisingly, and perhaps confusingly, the answer is not always yes, and sometimes no. The Consortium scientists found that sometimes a spelling change can make symptoms of HD worse but have no impact on the length of the CAG repeat at all. The opposite can also occur – sometimes there are spelling changes that change the CAG repeat but don’t change the symptoms of HD. 

Does this mean that new drugs being designed to stop changes in the CAG repeat will not work? It’s not clear, since the Consortium scientists were only looking at changes in CAG repeats in the blood, which may have little to do with what’s happening the brain. That’s a story for another volume. But the third volume ends with one clear glimmer of hope.

A hero for the next story?

One of the pages (genes) where the spelling changes do what scientists hoped they would is MSH3. You might have already heard of MSH3 as a new drug target for HD, a strategy based on work from other skilled HD scientists, including teams in the UK and US. 

On the page (gene) for MSH3, the GeM-HD Consortium scientists found that spelling changes impact the CAG repeat in blood in a way that matches what drug hunters are now trying to imitate. This means that there is good evidence from the genetics of people with HD that the therapeutic approach of targeting MSH3 may work. However, we still don’t know exactly how all the spelling changes in MSH3 and other genes are impacting HD in the brain.

Perhaps we will find out more in the next volume from these scientists! But fans of the series may not want to wait another five years. 

Science made possible thanks to HD families

These pioneering studies of genetic spelling changes and how they impact HD could not have happened without the participation of thousands of people with HD and their families who donated their blood and DNA for research. Every person with HD who donated their blood and DNA to research helped to make these discoveries possible.

TL;DR

• GeM-HD scientists have released their third major study exploring how small genetic variations (spelling changes in DNA) influence when symptoms of HD begin.
• Earlier studies revealed some changes are linked to how the CAG repeat in the HTT gene changes, a key factor in HD. This new study asked whether those same genetic changes also directly affect the CAG repeat’s length.
• The answer? It’s complicated. Some variants influence symptoms without changing the CAG repeat, and others change the repeat without affecting symptoms. So, while CAG repeat instability matters, it’s not the whole story.
• One key finding supports the current drug-development strategy: changes in the gene MSH3 both affect the CAG repeat and align with symptom changes, reinforcing MSH3 as a promising drug target.
• This work, made possible by thousands of HD families donating DNA, continues to shape how we understand and treat HD, and hints at more discoveries to come in future “volumes.”

Learn more

Original research article, Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease highlight shared and tissue-specific effects (open access).