New Clues Into Stuttering May Be Found in Genes

About the presenter:
Dennis Drayna, serves as Acting Section Chief at the National Institute on Deafness and Other Communication Disorders, at the National Institutes of Health. He received his Bachelor's degree from the University of Wisconsin and his PhD from Harvard University, and he served a postdoctoral fellowship at the Howard Hughes Medical Institute at the University of Utah. His research focuses on the genetics of human communication disorders, including stuttering.

New Clues into Stuttering May Be Found in Genes

by Dennis Drayna
from Maryland, USA

One of the most puzzling aspects of stuttering is its cause. While scientists have discovered many factors that can make stuttering worse, such as speaking to a large audience, or speaking on the telephone, the main causes of stuttering remain a mystery. Finding the causes of stuttering is particularly difficult because stuttering only occurs in people--it can't be observed in a test tube or in an animal such as a laboratory rat. In addition, at least part of the origins of stuttering reside in the brain, a complex and poorly understood organ whose inner workings are not easily studied.

One promising way to better understand the causes of stuttering is through genetics. Using laboratory methods, researchers are able to pinpoint the abnormal gene or genes that cause an inherited disorder. If a disorder is inherited and can be traced through a family's DNA, we can learn which gene or genes are responsible for the disorder, the gene product the gene encodes, the function of the gene product, and the location in the body that the gene product is most active, both in people who have the disorder as well as those who don't. Knowing the answers to these questions would provide a major step forward in our understanding of what causes stuttering.

For many years, the biggest roadblock to this approach was the fact that most stuttering isn't inherited in a noticeable pattern that we can trace in families. Over the past 25 years, however, evidence in favor of genetic factors in stuttering has been slowly building.

Genetic factors are not the only cause of stuttering, however. While about half of individuals who stutter have a close relative who also stutters, the other half do not, leading us to the generalization that perhaps 50 percent of stuttering cases are associated with genetic factors, while the other 50 percent are due to unknown causes.

It Takes Two: How Twin Studies Are Making New Inroads into Our Understanding of Stuttering

Three main types of evidence point to a genetic cause for stuttering, with the study of twins being one of the more powerful research tools. Twin studies are especially useful for untangling the traits that are caused by genes from the traits that are brought about by a child's environment, helping to settle the age-old question: is the trait caused by nature or nurture?

Twin studies rely on the fact that identical twins are genetic clones of each other, and share 100 percent of their genes. In contrast, fraternal twins are genetically no more similar than any other siblings, sharing only 50 percent of their genes. Thus, if a trait is strictly genetic, identical twins will always be alike for that trait, while fraternal twins will be alike roughly half the time. If, on the other hand, a trait is solely caused by the environment, not only will identical twins be alike, but fraternal twins also will be alike, assuming the twins being studied were raised together, which is usually the case.

A number of twin studies have already been conducted on stuttering, with studies differing by size, country, and evaluation method. While results have varied from study to study, they consistently find that identical twins are much more alike than fraternal twins when it comes to stuttering. Studies using sophisticated statistical analyses estimate the amount of stuttering due to genetic factors to be quite high -- as much as 70 percent.

More Compelling Evidence: Is There a Stuttering Gene?

A second type of evidence that supports a genetic cause for stuttering is called segregation analysis. In this type of study, the occurrence of a trait in a family is carefully documented and then compared with the predicted occurrence of that trait if it were purely genetic, purely environmental, or somewhere in between. Studies of this type have concluded that stuttering is found in repeated patterns, or "clusters," within some families, with the pattern of occurrence resembling the pattern that is typically associated with "dominant inheritance." If a trait has dominant inheritance, only one parent needs to pass the responsible gene to a child in order for the trait to be expressed. Traits that show dominant inheritance occur in every generation, and roughly half of all the people in the family are affected.

The third type of evidence involves the tracking of several large families in which a very high percentage of family members stutter. One such family lives in Utah and southern Idaho, and comprises more than 150 members, roughly one-third of whom stutter. In addition, we have been studying several large families in Cameroon, in equatorial West Africa, who also exhibit a high degree of stuttering. One of these large families has just over 100 members, 45 of whom stutter, while another family has 83 members, 36 of whom stutter. We have been assisted in this effort by the Speak Clear Association of Cameroon, an outstanding stuttering support organization that is one of the first such national organizations in Africa.

What Lies Ahead

Although no single study has proven that a specific genetic factor causes stuttering, the total body of evidence leaves no doubt that inherited factors play an important role in this disorder. However, several major hurdles remain before we can identify these genes.

First, the approaches and technologies of human genetics were originally developed for the study of inherited medical disorders, which are typically 100-percent genetic in origin. However, stuttering displays a number of characteristics that confound these traditional methods. For example, many more males are known to stutter than females. Also, if there is a stuttering gene, it would appear that many individuals must be carriers, though they do not stutter themselves. In addition, individuals often spontaneously recover from stuttering, typically in childhood. Thus, if a person in a stuttering family does not stutter, is it because they don't carry a stuttering gene, or because they carry a gene but recovered from long-forgotten childhood stuttering?

To help overcome these difficulties, my laboratory studies stuttering in several special populations. For example, we studied 44 highly inbred families in Pakistan, with a total of 175 affected individuals in these families . Inbred populations provide an advantage for researchers because there is less genetic diversity in the family, making it easier to locate a responsible gene or genes.

Our first effort in this population was to conduct a genetic linkage study. A linkage study determines the approximate location of a gene that causes a disorder. Normally a trait is inherited randomly with respect to any other gene or genetic marker, a known stretch of DNA along a chromosome. However in a few cases, co-inheritance occurs. This is called linkage, and it happens because the gene that causes the disorder resides very close to the genetic marker--so close that it is not easily separated from it by the normal mixing processes that occur each time genes are passed from parent to offspring. In our linkage study in the Pakistani families, we found strong linkage between stuttering and markers on chromosome 12. This means that in these families, there is a gene somewhere on chromosome 12 that causes stuttering. We are now engaged in a "door-to-door search"of all the genes in this region in an effort to pinpoint the specific gene that is responsible.

Our efforts in the Cameroon families are not far behind. In linkage studies, we have identified a region on chromosome 1 that appears to contain a gene that plays a strong role in stuttering in that family. Additional studies are underway to pinpoint the location of this gene, and perhaps find other genes at work in this population.

Overall, genetic approaches to understanding the causes of stuttering have moved beyond proving that genetic factors are involved--the evidence for such factors is indisputable. Despite the uncertainties and challenges to geneticists, progress is being made. While genetic factors cannot explain all of stuttering, they give us the possibility of understanding at least some causes of this disorder. At this point, absolute proof of even one of the underlying causes of stuttering would be an exciting advance indeed.