Jennifer “Piper” Below, Ph.D., an associate professor of medicine at Vanderbilt University, talks about how a recent discovery has brought the medical community one step closer to finding a treatment for stuttering.
Interview conducted by Ivanhoe Broadcast News in December 2021.
What is it that you and your colleagues are looking at for the stuttering project?
Prof. Below: The stuttering project. For about the last ten years, I’ve been collaborating with Dr. Shelley Jo Kraft at Wayne State University in Detroit. And we have been working to understand the genetic basis of stuttering. Stuttering is a speech and language pathology that is a condition associated with prolongations of speech. The challenges for people who stutter are profound. But despite this, partly because people who stutter don’t usually come into the hospital and it’s not a life-threatening disorder, we frequently find that it’s difficult to ascertain samples for genetic studies. What we’ve done is taken a two-pronged approach to understanding and capturing the genetic architecture that underlies risk of stuttering.
How common is the stuttering condition?
Prof. Below: Between five and 10 percent of children stutter. However, most children who stutter recover. A small portion of children go on to recover persistently throughout adulthood. And that ranges between about one and three percent of adults have a persistent stutter. You might not actually notice it because a lot of adults will have coping strategies. They will do word avoidance or other strategies in order to not have their stutter be perceived. There’s probably a lot of people around you who do struggle with stuttering.
Are there some known risk factors that could predict if someone, will have a stutter or does have a stutter?
Prof. Below: There are a couple of different types of stuttering. There’s neurogenic stuttering and psychogenic stuttering. These have different causes that have been somewhat understood in the literature. Developmental stuttering has been a condition that while there’s been a lot of research and a lot of hypotheses into what might lead a person to develop or to have a developmental stutter, it’s not clear what the cause is. We have seen over the prior decades of research that it is enriched within families. Some people have hypothesized erroneously that that there might be a condition within the family or childhood abuse or trying to force a left-handed child to use their right hand or childhood trauma could induce a developmental stutter. This has all been proven to be false. The one thing we know about stuttering is that it is absolutely genetic. That has now been well-established for a long time. But what the genes are that actually contribute to risk have not been mapped until this set of studies.
What can you tell me about the gene discovery?
Prof. Below: We have two papers that came out simultaneously back-to-back. In one of the papers, we used DNA samples that were collected over the last 10 years by Shelley Jo Kraft in an international collaboration to address this issue of the genetic architecture of stuttering. Over the last 10 years, she’s been able to meet with clinicians and speech and language clinics around the world and collaborate with them to enroll children that are participating and their families into a study where we could directly look at the genetic basis of clinically ascertained stuttering. This was one of the papers. And this is a landmark paper in developmental stuttering because all of the prior papers that had looked at the specific genetic factors were done in small families. This is the first time we tried to look globally and at population level risk factors for stuttering. On the other hand, we had a study that we did here at Vanderbilt within our electronic health record system and our biobank. We had proposed originally that we would look in our biobank for stuttering and use that to replicate our clinical study. But as is so often the case in science, it didn’t work. And it didn’t work because we didn’t have enough cases. What we did was we turned to the electronic health record. We found a small number of people that we really believed did stutter, who had robust records of their developmental stuttering in their medical record. And we looked to see what constellation of traits co-occurred with that stuttering phenotype, with that stuttering trait. And we then used that constellation of co-occurring medical diagnostic codes to predict or impute back that stuttering trait. So that allowed us to go back into our DNA databank that we have here at Vanderbilt called Bio View. It’s got a little over 10,0000 genetic data samples in it. And we imputed this stuttering phenotype in that dataset and were able to identify almost 10,000 people who our algorithm predicted might stutter. We then did a genetic study on that classification. And in that case, we found multiple genome-wide significant hits that were suggestive that we were understanding something of the genetic contributions to not just stuttering but this suite of conditions that co-occur in people who stutter. But of course, that’s challenging because it’s not clear whether or not that is going to actually be the same genetics as a clinically ascertained set of kids that we’re seeing in speech and language clinics. One of the most important things that we did was validate across the two. And we found that indeed, we were picking up the same genetic factors across the two studies. That they were highly correlated, giving us a lot of confidence that the signatures that we picked up are real and are about the trait of developing a stutter as a child.
Did you ever meet up with those people from the database to see if they had a stutter or not?
Prof. Below: One of the challenges with working in electronic health record data is that in order to protect patient privacy, everything has been completely de-identified. We work with something that is technically termed the synthetic derivative. We have no ability to return to the patient. We have no ability to identify them. They’re completely protected but we are able to leverage the data, the mass amount of data. I think we used almost three million people’s health records in order to develop the algorithm that we used to predict people who stutter on the genetic data side. The power for discovery in that kind of data set is just unmatched with anything that you could do through boots on the ground, door to door kind of collections. It took us 10 years to collect under 1,500 samples of DNA from people who stutter. Within a few months, we were able to recapitulate 10,000 people who we had a strong suspicion might be at risk of stuttering based on their clinical health record.
With this information that you found, what can that mean in terms of a possible treatment?
Prof. Below: Absolutely. Some of the genes that have been found to impact stuttering risk in these small families that have been studied historically have implicated certain dopamine pathways suggesting that there might be something about how the brain is processing and signaling that could be disrupted in stuttering. Other pathways, other genes that have been previously implicated are involved in hormone regulation. Our main findings in both of these papers fits both of those narratives that there might be something going on with how dopamine is signaling in the brain, as well as how hormones are regulated and processed in the body. And this is a particularly interesting finding in stuttering because overwhelmingly the number of the proportion of people who recover are women. The children who stutter are roughly half and half girls and boys. However, the girls are much more likely to go on to recover. And that occurs in sort of the pre-adolescent years when there might be a lot of changes in hormones in the body that are happening. It’s possible that we might be actually uncovering some of the molecular pathways that underlie and explain why, more often than not, the growing and developing men are not recovering as often as the women.
For someone who stutters, what kind of challenges do they face daily?
Prof. Below: Stuttering is a really challenging condition for a lot of young people and adults. There can be perceptions that a child is not performing as well in school, or that an adult is not performing as well in work when that’s not actually the case. It’s an outward perception of the person who stutters because of their speech impediment. There’s also elevated risks of anxiety, depression, suicidality among people who stutter. That is again likely not due to a common biological cause but rather how society perceives people who stutter and the hardships that that incurs. Because of a lot of these perceptions, it’s also true that on average, there’s lower socioeconomic status among people who stutter than the general population or matched population. These challenges aggregate and can really affect quality of life for people who stutter.
What’s the next step that’s coming out of this now?
Prof. Below: These studies have really opened the door to where we can go and what the kinds of things that we can learn about risk factors for developmental stuttering and the pathways that are involved and hopefully highlight opportunities for improved and precision therapeutics for people who stutter. That said, we’re only scratching the surface. We’ve gone from 1,500 cases of clinically ascertained cases to 10000 that we were able to impute in our medical record. And our next step is to even expand that further with a partnership with 23 and Me where we are going to look at over a hundred thousand people who self-report that they have a challenge with a stutter or a stammer and a million people who say that they do not. And the hope is that with increased power, we’re going to be able to detect a genetic signature that can then be correlated across other genetic signatures to understand really the common underpinnings of this condition and how we can potentially open doors to improve therapeutics and treatment for people who want to seek that.
Do other types of therapies help them as an adult to recover? Or is this something that you go through life, women are more likely to recover than men for some reason or less likely to?
Prof. Below: I’ll just say up front, I am not a speech language pathologist. I’m a lowly geneticist. I partner with people who are experts in the speech and language pathology and the treatment aspect of this. What my studies are hoping to do is to understand that underlying risk and what pathways or even what parts of the brain or what kind of traits are disrupted so that we could improve therapies. Now it is absolutely the case that for some children, therapy works wonders and that the treatments that they’re able to receive in schools and clinics can really change outcomes for them. But that’s not true for all children. And we see that with the proportion that carry on to persist. Now understanding some of the genetic risk factors that could differentiate between kids who are likely to recover versus that are likely to persist into adulthood is another key future direction for our research. In addition, we would really like to understand some of the differences in the genetic risk factors between women and men. Since we see such a different pathology where women recover so much more frequently than men do, it’ll be really exciting to then carry this research into the future and look at the whether or not we can find signatures underlying that risk that are discriminating between women and men.
If somebody has a family member who stutters what is the likelihood that you would have a stutter?
Prof. Below: One of the most important things that we’ve found and that we reiterate and echo in this study from what we have known for a long time is that stuttering is genetic. A lot of families feel guilt. A lot of people who persist into adulthood feel that stuttering is a personal failure. And that’s not the case. It’s not because your parents got divorced or because you had a childhood trauma or you changed schools. That’s not the cause. I think that being able to let families know and really show them that we’ve been able to study the specific factors that are contributing to the risk of their stuttering, my hope is that will help alleviate some of these feelings of guilt or failure that we know that some people experience and that contributes to the associations we see with anxiety and depression and other outcomes for stuttering. I think that might be one of the most important things that this study is able to highlight that. Stuttering is genetic.
END OF INTERVIEW
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