Next-generation sequencing recently revealed that recurrent disruptive mutations 
in a few genes may account for 1% of sporadic autism cases. Coupling these novel 
genetic data to empirical assays of protein function can illuminate crucial 
molecular networks. Here we demonstrate the power of the approach, performing 
the first functional analyses of TBR1 variants identified in sporadic autism. De 
novo truncating and missense mutations disrupt multiple aspects of TBR1 
function, including subcellular localization, interactions with co-regulators 
and transcriptional repression. Missense mutations inherited from unaffected 
parents did not disturb function in our assays. We show that TBR1 homodimerizes, 
that it interacts with FOXP2, a transcription factor implicated in 
speech/language disorders, and that this interaction is disrupted by pathogenic 
mutations affecting either protein. These findings support the hypothesis that 
de novo mutations in sporadic autism have severe functional consequences. 
Moreover, they uncover neurogenetic mechanisms that bridge different 
neurodevelopmental disorders involving language deficits.