Invited paper presented at the EPNS 2011 Cavtat meeting Endophenotypes of FOXP2: Dysfunction within the human articulatory network F. Lie ´geois a, *, A.T. Morgan b , A. Connelly c , F. Vargha-Khadem a a Developmental Cognitive Neuroscience Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK b Murdoch Childrens Research Institute, Melbourne, Australia c Brain Research Institute, Melbourne, Australia article info Article history: Received 8 April 2011 Accepted 17 April 2011 Keywords: Developmental verbal dyspraxia FOXP2 fMRI Articulation abstract 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. Neuro- imaging 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 disor- ders. 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. ª 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. Contents 1. Introduction ............................................................................................... 284 2. Materials and methods ..................................................................................... 285 2.1. Participants .......................................................................................... 285 2.2. fMRI data acquisition ................................................................................. 285 2.3. fMRI data analysis .................................................................................... 286 * Corresponding author. Tel.: þ44 20 7905 2728; fax: þ44 20 7905 2616. E-mail address: F.Liegeois@ich.ucl.ac.uk (F. Lie ´ geois). Official Journal of the European Paediatric Neurology Society european journal of paediatric neurology 15 (2011) 283 e288 1090-3798/$ e see front matter ª 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2011.04.006