Brain Communications, 2021
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Abstract Developmental stuttering is a common speech disorder with strong genetic underpinnings. Recently, stuttering has been associated with mutations in genes involved in lysosomal enzyme trafficking. However, how these mutations affect the brains of people who stutter remains largely unknown. In this study, we compared gray matter volume and white matter fractional anisotropy between a unique group of seven subjects who stutter and carry the same rare heterozygous AP4E1 coding mutations and seven unrelated controls without such variants. The carriers of the AP4E1 mutations are members of a large Cameroonian family in which the association between AP4E1 and persistent stuttering was previously identified. Compared to controls, mutation carriers showed reduced gray matter volume in the thalamus, visual areas and the posterior cingulate cortex. Moreover, reduced fractional anisotropy was observed in the corpus callosum, consistent with the results of previous neuroimaging studies of people who stutter with unknown genetic backgrounds. Analysis of gene expression data showed that these structural differences appeared at the locations in which expression of AP4E1 is relatively high. Moreover, the pattern of gray matter volume differences was significantly associated with AP4E1 expression across the left supratentorial regions. This spatial congruency further supports the connection between AP4E1 mutations and the observed structural differences. While gene mutations associated with stuttering have begun to be identified, their effects on human brains remain largely unknown. Chow et al. report that stuttering mutations in the AP4E1 gene are associated with structural differences in the corpus callosum and the thalamus, linking genetics and brain anomalies in stuttering.