Neuroanatomical anomalies associated with rare AP4E1 mutations in people who stutter.

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 grey matter volume and white matter fractional anisotropy between a unique group of seven subjects who stutter and carry the same rare heterozygous coding mutations and seven unrelated controls without such variants. The carriers of the mutations are members of a large Cameroonian family in which the association between and persistent stuttering was previously identified. Compared to controls, mutation carriers showed reduced grey 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 is relatively high. Moreover, the pattern of grey matter volume differences was significantly associated with expression across the left supratentorial regions. This spatial congruency further supports the connection between mutations and the observed structural differences.