DO: 0060243;
Cytogenetic location: 12q24.1 Genomic coordinates (GRCh38): 12:108,600,001-113,900,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.1 | Stuttering, familial persistent, 2 | 609261 | 2 |
Stuttering is a speech disorder characterized by the presence of syllable repetitions, syllable prolongations, and interruptions in the smooth flow of speech known as blocks (summary by Riaz et al., 2005).
For a general phenotypic description and a discussion of genetic heterogeneity of familial persistent stuttering, see 184450.
Riaz et al. (2005) stated that approximately half of stutterers have a family history of the disorder, and twin and adoption studies support a genetic contribution.
In a linkage study of stuttering, Riaz et al. (2005) collected families in the city of Lahore, Pakistan, and surrounding areas. These families were highly inbred, with stuttering occurring in 2 or more generations, and were chosen with preference for a high number of affected individuals. A genomewide linkage scan was performed in 44 families. Initial nonparametric analysis gave evidence of linkage on chromosomes 1, 5, 7, and 12. Additional genotyping was performed on chromosome 12 to a 5-cM level of resolution, and 16 additional individuals were then included, bringing the number of families to 46. Analysis of the enlarged data set provided consistent evidence of linkage on chromosome 12 with a nonparametric lod score of 4.61 with PAH (612349), and a lod score of 3.51 by another approach. The results suggested that a locus on 12q may contain a gene with a large effect on stuttering in this population.
In a large consanguineous Pakistani family with stuttering, Kang et al. (2010) refined the STUT2 locus to a 10-Mb region between D12S101 and D12S1597, on chromosome 12q24.
Associations Pending Confirmation
For discussion of a possible role of variation in the NAGPA gene in familial persistent stuttering-2, see 607985.0001-607985.0003.
In affected members of a large consanguineous 6-generation Pakistani family with stuttering showing linkage to chromosome 12q (Riaz et al., 2005), Kang et al. (2010) identified a glu1200-to-lys (E1200K) variant in the GNPTAB gene (607840). Thirteen affected individuals were heterozygous, and 12 were homozygous. However, the variant did not completely segregate with the disorder: 3 noncarriers were affected, and 2 homozygous E1200K carriers and 9 heterozygous E1200K carriers were unaffected. Kang et al. (2010) suggested nonpenetrance in these individuals. The authors identified 3 additional variants in the GNPTAB gene in 4 additional individuals with stuttering. None of the individuals had features of mucolipidosis. By studying other genes in the lysosomal enzyme-targeting pathway, Kang et al. (2010) found 3 variants each in the GNPTG (607838) and NAGPA (607985) genes that were found in 11 of 270 patients with stuttering, but not in 276 controls. Kang et al. (2010) concluded that variations in genes governing lysosomal metabolism may be susceptibility factors for nonsyndromic stuttering. Kang et al. (2010) performed no functional studies on any of the identified mutations.
By haplotype analysis of 8 unrelated individuals who were heterozygous or homozygous for the E1200K variant in the GNPTAB gene, Fedyna et al. (2011) determined that it arose as a founder allele 572 generations, or 14,300 years ago. Haplotype analysis identified a common 6.67-kb haplotype containing the variant.
Barnes et al. (2016) engineered mice to carry a homozygous glu1179-to-lys mutation in the Gnptab gene, which is homologous to the glu1200-to-lys mutation in human GNPTAB. Compared with wildtype pups, pups with the mutation emitted fewer vocalizations per unit time when separated from their dam. They also showed longer pauses between vocalizations and were more stereotyped in their vocalizations than wildtype littermates. Gnptab missense pups were similar to wildtype on an extensive battery of nonvocal behaviors. Speech from people who stutter showed similar abnormalities when compared with control speech.
Barnes, T. D., Wozniak, D. F., Gutierrez, J., Han, T.-U., Drayna, D., Holy, T. E. A mutation associated with stuttering alters mouse pup ultrasonic vocalizations. Curr. Biol. 26: 1009-1018, 2016. [PubMed: 27151663] [Full Text: https://doi.org/10.1016/j.cub.2016.02.068]
Fedyna, A., Drayna, D., Kang, C. Characterization of a mutation commonly associated with persistent stuttering: evidence for a founder mutation. J. Hum. Genet. 56: 80-82, 2011. [PubMed: 20944643] [Full Text: https://doi.org/10.1038/jhg.2010.125]
Kang, C., Riazuddin, S., Mundorff, J., Krasnewich, D., Friedman, P., Mullikin, J. C., Drayna, D. Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering. New Eng. J. Med. 362: 677-685, 2010. [PubMed: 20147709] [Full Text: https://doi.org/10.1056/NEJMoa0902630]
Riaz, N., Steinberg, S., Ahmad, J., Pluzhnikov, A., Riazuddin, S., Cox, N. J., Drayna, D. Genomewide significant linkage to stuttering on chromosome 12. Am. J. Hum. Genet. 76: 647-651, 2005. [PubMed: 15714404] [Full Text: https://doi.org/10.1086/429226]