By Ehud Yairi, Ph.D., University of Illinois
Summer 2006

alt textFor a long period, information on the familiality of stuttering was primarily based on data concerning the percent of people who stutter having relatives with histories of stuttering. This figure has varied from 20% to 74%. Although it is apparent that stuttering runs in families, this fact, in-and-by itself, is insufficient to conclude genetic underlining. After all, a good number of tendencies, e.g., religious and political affiliations, also run in families.

As research methods improved, family pedigrees (trees) were analyzed in detail to study the occurrence of stuttering in different classes of relatives: mothers, fathers, sisters, and brothers, taking into account family size, something that was overlooked in the past. Obviously, a family of 12 with one member who stutters presents a very different picture than a family of 4 with one who stutters. Using sophisticated computer programs (e.g., segregation analysis), investigators evaluated the transmission of stuttering by matching the disorder's familial distribution against several possible genetic models. They were successful in showing that a few alternative models provided a good fit. Professor Kenneth Kidd of Yale University and his team made an enormous contribution in this respect, e.g., Kidd, et al. (1978) and Cox, et al. (1984). (For a more comprehensive review, see Yairi, et al., 1996).

Approximately 13 years ago, Ambrose, et al. (1993) at the University of Illinois were the first to report statistically significant evidence for a Mendelian single major locus model (SML) which assumes that there is one, or several major genes responsible for stuttering. Viswanath et al., also supported this finding. If correct, then chances for identifying genes underlying stuttering are brighten. The Illinois group later concluded that a mixed model, incorporating SML, polygenic components (many other genes), as well as environmental factors, had the best fit (Ambrose, et al. 1997). Furthermore, they showed that not only does the initial expression of stuttering have strong genetic components but also its future developmental course. That is, children who stutter and have a familial history of chronic stuttering would tend to follow that same pattern. And vice versa, children who stutter but have a familial history of naturally recovered stuttering, would tend to follow that pattern. Another significant contribution was made by twin studies that consistently demonstrated considerably higher concordance levels of stuttering in identical than in non-identical twin pairs (e.g., Howie, 1981; Felsenfeld, et al., 2000).

The accumulated findings justified a move from behavioral and statistical genetics into biological genetics. Typically, the first phase in such research is linkage analysis aimed at identifying the general location of possible genes using DNA extracted from samples of body tissues. Then, forms of known marker genes are identified on every chromosome (or just chromosomes of interest). When a marker gene form is co-inherited with stuttering (linkage), the indication is that the gene contributing to stuttering is on the same chromosome as the marker gene; in fact, very close to it.

At the beginning of the current millennium, Nancy Cox (2000) reported the results of the first complete standard genome-wide screen of DNA markers for analysis of stuttering for members of the Hutterite population in North Dakota. In this ground-breaking study, areas in chromosomes 1, 3, 5, 9, 13, and 15 had evidence for linkage of stuttering. Since then, four additional promising genome-wide linkage studies have identified several chromosomal regions that appear to be associated with stuttering. Shugart et al. (2004) reported a modest signal for a stuttering locus on chromosome 18 and Riaz et al. (2005), using Pakistani families, found a strong linkage signal on chromosome 12. An NIH team under the leadership of Dr. Drayna studied stuttering in a large Cameroon family and reported a modest evidence for linkage on chromosome 1 (Levis, et al., (2004).

The largest and most recent study on linkage mapping was conducted by the Illinois International Genetics of Stuttering Project under the leadership of Professor Nancy Cox, University of Chicago, using blood samples from families in the USA, Sweden, and Israel. Our team identified moderate evidence for linkage for the broad category of 'ever-stuttered' (including both persistent and recovered stuttering) on chromosome 9 whereas for persistent stuttering only it was on chromosome 15. The strongest signal for males only appeared on chromosome 7 and for females only on chromosome 21.

Also very interesting, further analyses revealed two possible genetic routs to stuttering. First, there was a significant increase in the evidence for linkage on chromosome 12 for families who had high linkage signal on chromosome 7. The region on Chromosome 12 is very close to that reported signal by Riaze and colleagues for the Pakistani families. Second, a region on chromosome 2 showed a significant increased linkage signal for families who had high linkage signal chromosome 9 or negative signal on chromosome 7. Incidentally, the region on chromosome 2 has been implicated in recent studies of autism. We have speculated that such gene interactions may provide better insight into stuttering sub-types.

Although it is too early to speculate on what genes might be involved, it appears that the genes in the different chromosomes are similar, having some evolutionary homology. This might be consistent with the possibility that related genes affect susceptibility to stuttering. In summary, we have advanced from simplistic casual observations that stuttering runs in families, arriving now at a point where we are within arm's reach of identifying the specific gene, or genes, underlying stuttering. One has to keep in mnd, however, that appreciable portions of the available evidence have consistently assigned significant roles to non-shared environmental factors.

References
Ambrose, N.G., Yairi, E., & Cox, N. (1993). Genetic aspects of early childhood stuttering. Journal of Speech and Hearing Research, 36, 701-706.

Ambrose, N.G., Cox, N.J., & Yairi, E. (1997). The genetic basis of persistence and ecovery in stuttering. Journal of Speech, Language, and Hearing Research, 40, 567-580.

Cox, N., Kramer, P., & Kidd, K. (1984). Segregation analyses of stuttering. Genetic Epidemiology, 1, 245-253.

Cox, N. (2000). Genetics of stuttering: Insights and recent advances. Presented at the annual national convention of the American Speech-Language-Hearing Association. Washington, D.C.

Felsenfeld, S., Kirk, K.M., Zhu, G., Statham, D.J., Neale, M.C. & Martin, N.G. (2000). A study of the genetic and environmental etiology of stuttering in a selected twin sample. Behavioral Genetics, 30, 359-366.

Howie, P. M. (1981). Concordance for stuttering in monozygotic and dizygotic twin pairs. Journal of Speech and Hearing Research, 24, 317-21.

Kidd, K.K., Kidd, J.R., & Records, M. (1978). The possible causes of the sex ratio in stuttering and its implications. Journal of Fluency Disorders, 3, 13-23.

Levis, B., Ricci, D., Lukong, J., & Drayna, D. (2004). Genetic linkage studies in a large est African kindred. American Journal of Human Genetics, 75, S2026.

Riaz, N., Steinberg, S., Ahmad, J., Pluzhnikov, A., Riazuddin, S., & Cox, N.J., et al. (2005). Genomewide significant linkage to stuttering on chromosome 12. American Journal of Human Genetics, 76, 647-651.

Shugart, Y.Y., Mundorff, J., Kilshaw, J., Doheny K., Doan, B., Wanyee, J., et al. (2004). Results of a genome-wide linkage scan for stuttering. American Journal of Medical Genetics A, 124, 133-5.

Suresh, R., Roe, C., Pluzhnikov, A., Wittke-Thompson, J., C-Y Ng, M., Cook, E., Lundstrom, C., Garsten, M., Ezrati, R., Yairi, E., Ambrose, N., & Cox, N. (2006). New Complexities in the Genetics of Stuttering: Significant Sex-specific Linkage Signals. American Journal of Human Genetics.

Viswanath, N., Lee, H., & Chakraborty, R. (2004) Evidence for a major gene influence on persistent developmental stuttering. , 76, 401-12. Human Biology

Yairi, E., Ambrose, N. & Cox, N. (1996). Genetics of stuttering: a critical review. Journal of Speech and Hearing Research, 39, 771-84.