Endophenotypes of FOXP2: dysfunction within the human articulatory network.

The identification of the first gene involved in a speech-language disorder was made possible through the study of a British multi-generational family (the "KE family") in whom half the members have an inherited speech-language disorder caused by a FOXP2 mutation. Neuroimaging investigations in the affected members of the KE family have revealed structural and functional abnormalities in a wide cortical-subcortical network. Functional imaging studies have confirmed dysfunction of this network by revealing abnormal activation in several areas including Broca's area and the putamen during language-related tasks, such as word repetition and generation. Repeating nonsense words is particularly challenging for the affected members of the family, as well as in other individuals suffering from idiopathic developmental specific language impairments; yet, thus far the neural correlates of the nonword repetition task have not been examined in individuals with developmental speech and language disorders. Here, four affected members of the KE family and four unrelated age-matched healthy participants repeated nonsense words aloud during functional MRI scanning. Relative to control participants, repetition in the affected members was severely impaired, and brain activation was significantly reduced in the premotor, supplementary and primary motor cortices, as well as in the cerebellum and basal ganglia. We suggest that nonword repetition is the optimal endophenotype for FOXP2 disruption in humans because this task recruits brain regions involved in the imitation and vocal learning of novel sequences of speech sounds.