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Stuttering is a speech disorder characterized by involuntary disruptions of verbal expression. It occurs in about 5 % of pre-school children, where it frequently resolves spontaneously. However, stuttering persists in some individuals and thus about 1 % of the general population remains affected. Although the causes of this disorder remain very poorly understood, there is good evidence for genetic contributions to stuttering. To help elucidate the genetics of stuttering at a molecular level, we studied large families from the African and Pakistani populations in which this disorder occurs. We enrolled 3 large families from the Republic of Cameroon and 6 consanguineous families from Pakistan, all containing multiple members who stutter. Family members were diagnosed using the Stuttering Severity Instrument - 3. We performed a genome wide linkage scan using the Weber 10 microsatellite marker panel on three African families. Single nucleotide polymorphism (SNP) genotyping using the Illumina 6K Chip was also done in the African families, as well as in the five newly ascertained Pakistani families. The program Pedcheck was used to test for proper inheritance within families. One African family was excluded from further analysis due to multiple inheritance inconsistencies. Here we report linkage results from one African family, designated CAMST01 and 5 Pakistani families. No significant linkage was found in family CAMST01 in the initial parametric linkage analysis. Additional non-parametric analysis was performed using the program MERLIN, however CAMST01 was broken into smaller sub-families for analysis to overcome the computational constraints of this program. When this was done, several SNPs on chromosome 15q displayed 2-point LOD scores of more than 3. In this analysis, no LOD scores exceeding 3 were observed at any other loci across the genome. In subsequent multipoint analyses on chromosome 15q, a LOD score exceeding 6 was obtained at this locus. Support for these initial linkage findings was obtained by typing microsatellite markers in this region, which also showed a significant two-point LOD score over 3. In addition, suggestive LOD scores of 2.5 were observed on chromosomes 12 and 6 when SNP linkage analysis was performed on each sub- pedigree alone and in pairs of sub-pedigrees. The region on chromosome 15 that contains markers showing significant LOD scores extends from 15q15.1 to 15q21.3, and is flanked by SNP markers rs1009913 (at map position 42.69 cM) and rs690054 (at map position 51.72 cM). Five consanguineous Pakistani stuttering families (designated PKST families) were also genotyped for 6090 SNPs on the Illumina plateform. Significant linkage, with a LOD score of 3.25 under an autosomal recessive model of inheritance, was observed on chromosome 3q13.13- 3q21.2 in family, PKST77. Analyses under dominant and additive models of inheritance produced no significant evidence for linkage in this family. Further genotyping of microsatellite markers and additional SNPs in this region defined a linkage interval spanning 14.2 Mb. Within this linkage interval, the exons of the candidate gene DRD3 (Dopamine Receptor D3) were sequenced in affected and unaffected individuals, however no novel variation was observed. Our results demonstrate that, in addition to the previously reported linkage to stuttering on chromosome 12 {Riaz, 2005 #96}, additional stuttering genes reside on chromosome 15 and on chromosome 3. Our results also formally prove the existence of genetic heterogeneity in the origins of this disorder.
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