A functional genetic link between distinct developmental language disorders.

Background: Rare mutations affecting the FOXP2 transcription factor cause a monogenic speech and language disorder. We hypothesized that neural pathways downstream of FOXP2 influence more common phenotypes, such as specific language impairment.

Methods: We performed genomic screening for regions bound by FOXP2 using chromatin immunoprecipitation, which led us to focus on one particular gene that was a strong candidate for involvement in language impairments. We then tested for associations between single-nucleotide polymorphisms (SNPs) in this gene and language deficits in a well-characterized set of 184 families affected with specific language impairment.

Results: We found that FOXP2 binds to and dramatically down-regulates CNTNAP2, a gene that encodes a neurexin and is expressed in the developing human cortex. On analyzing CNTNAP2 polymorphisms in children with typical specific language impairment, we detected significant quantitative associations with nonsense-word repetition, a heritable behavioral marker of this disorder (peak association, P=5.0x10(-5) at SNP rs17236239). Intriguingly, this region coincides with one associated with language delays in children with autism.

Conclusions: The FOXP2-CNTNAP2 pathway provides a mechanistic link between clinically distinct syndromes involving disrupted language.