By Dr. Dennis Drayna
Two recent studies have once again focused attention on the role of genetic factors in stuttering. These studies used approaches not previously applied to stuttering, and identified new genetic variants correlated with this disorder. The first study was led by Jennifer Below at Vanderbilt University Medical Center, who studied their health database, which contains over 92,000 individuals. The second, led by Shelly Jo Kraft at Wayne State University, studied an additional 16,000 individuals. The researchers on both papers collaborated extensively with each other and with researchers at the University of North Carolina, the Irish Stammering Association, and Curtin University in Perth, Australia.
A problem they faced at the outset was that very few of the individuals in the Vanderbilt database (less than 2 tenths of one percent) had a clear diagnosis of stuttering based on standard criteria. Because stuttering is much more common than this, thought to exist in roughly 5 percent of all individuals, the investigators sought to identify others in their database who likely stuttered. This estimate identified over 9,000 individuals, or about 10 percent of everyone in their database, who were classified as likely affected with stuttering. The researchers then used an approach known as a genome-wide association study (GWAS) to study genetic variants, taking advantage of pre-existing genetic typing that had been done at hundreds of thousands of specific locations in the DNA of each of these individuals. Then, they compared the genetic variants present in those with predicted stuttering with the variants in those who were not predicted to stutter. This comparison identified one variant near the CYR1A gene on chromosome 2 as significantly associated in European ancestry populations, while a second variant in the ZMAT4 gene on chromosome 8 showed a very suggestive association in African ancestry populations. How these variants might act to affect the products of these genes or cause the clinical features of stuttering remains a fascinating challenge for the future.
The second study was done by the same Vanderbilt, Curtin University, and Wayne State investigators, with additional collaborating investigators from the Irish Stammering Association and the University of North Carolina. It used stuttering cases and controls from multiple sources for a total of more than 2,000 well-studied, independently enrolled stuttering cases and 7,500 normally fluent control subjects. The same GWAS approach was used here, which found one significant association with a variant site near the SSUH2 gene. This variant appears to affect the degree to which the SSUH2 gene is turned on in muscle tissues of the esophagus. Thus, while much remains to be learned about this gene, the findings thus far point to a potentially promising connection to muscle control, a known issue in stuttering.
Jane Fraser, President of the Stuttering Foundation, commended the work saying, “The Stuttering Foundation has long been excited about genetic studies as a way to better understand the underlying causes of stuttering. We are glad to see this additional new work in the area of genetics, which will hopefully lead us to further progress.”
Dr. Drayna received his bachelor’s degree from the University of Wisconsin in 1976, and his Ph.D. from Harvard University in 1981, followed by postdoctoral training at the Howard Hughes Medical Institute at the University of Utah. He joined the NIDCD in 1997, focusing on disorders of auditory pitch perception, variation in human taste perception, and disorders of voice and speech. Dr. Drayna’s work has had a major focus on the genetics and neuroscience of stuttering.
From the Spring 2022 Magazine