Genetics of stuttering: New developments

By Ehud Yairi, Ph.D.alt text
University of Illinois

For a long period, information on the familiality of stuttering was?ÿprimarily based on data concerning the percent of people who stutter?ÿhaving relatives with histories of stuttering. This figure has varied?ÿfrom 20% to 74%.?ÿ Although it is apparent that stuttering runs in?ÿfamilies, this fact, in-and-by itself, is insufficient to conclude?ÿgenetic underlining. After all, a good number of tendencies, e.g.,?ÿreligious and political affiliations, also run in families.

As research methods improved, family pedigrees (trees) were analyzed?ÿin detail to study the occurrence of stuttering in different classes?ÿof relatives: mothers, fathers, sisters, and brothers, taking into?ÿaccount family size, something that was overlooked in the past.?ÿObviously, a family of 12 with one member who stutters presents a?ÿvery different picture than a family of 4 with one who stutters.?ÿUsing sophisticated computer programs (e.g., segregation analysis),?ÿinvestigators evaluated the transmission of stuttering by matching?ÿthe disorderƒ??s familial distribution against several possible genetic?ÿmodels.?ÿThey were successful in showing that a few alternative?ÿmodels provided a good fit. Professor Kenneth Kidd of Yale University?ÿand his team made an enormous contribution in this respect, e.g.,?ÿ
Kidd, et al. (1978) and Cox, et al. (1984).?ÿ (For a more?ÿcomprehensive review, see Yairi, et al., 1996).

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

The accumulated findings justified a move from behavioral and?ÿstatistical genetics into biological genetics.?ÿTypically, the first?ÿphase in such research is linkage analysis aimed at identifying the?ÿgeneral location of possible genes using DNA extracted from samples?ÿof body tissues. Then, forms of known marker genes are identified on?ÿevery chromosome (or just chromosomes of interest).?ÿWhen a marker?ÿgene form is co-inherited with stuttering (linkage), the indication?ÿis that the gene contributing to stuttering is on the same chromosome?ÿas the marker gene; in fact, very close to it.

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

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

Also very interesting, further analyses revealed two possible?ÿgenetic routs to stuttering.?ÿ First, there was a significant increase?ÿin the evidence for linkage on chromosome 12 for families who had?ÿhigh linkage signal on chromosome 7. The region on Chromosome 12 is?ÿvery close to that reported signal by Riaze and colleagues for the?ÿPakistani families.?ÿSecond, a region on chromosome 2 showed a?ÿsignificant increased linkage signal for families who had high?ÿ linkage signal chromosome 9 or negative signal on chromosome 7.?ÿIncidentally, the region on chromosome 2 has been implicated in?ÿrecent studies of autism.?ÿ We have speculated that such gene?ÿinteractions may provide better insight into stuttering sub-types.

Although it is too early to speculate on what genes might be?ÿinvolved, it appears that the genes in the different chromosomes are?ÿsimilar, having some evolutionary homology. This might be consistent?ÿwith the possibility that related genes affect susceptibility to?ÿstuttering. In summary, we have advanced from simplistic casual?ÿobservations that stuttering runs in families, arriving now at a?ÿpoint where we are within armƒ??s reach of identifying the specific?ÿgene, or genes, underlying stuttering.?ÿOne has to keep in mnd,?ÿhowever, that appreciable portions of the available evidence have?ÿconsistently assigned significant roles to non-shared environmental?ÿ factors.

References
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childhood stuttering.?ÿ Journal of Speech and Hearing Research, 36,?ÿ
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Ambrose, N.G., Cox, N.J., & Yairi, E. (1997).?ÿ The genetic basis of?ÿ
persistence and ecovery in stuttering. Journal of Speech, Language, and Hearing?ÿResearch, 40, 567-580.

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

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

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

Howie, P. M. (1981). Concordance for stuttering in monozygotic and?ÿdizygotic twin pairs.?ÿ Journal of Speech and Hearing Research, 24,?ÿ317-21.

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

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