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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.

Original publication

DOI

10.1056/NEJMoa0802828

Type

Journal article

Journal

N Engl J Med

Publication Date

27/11/2008

Volume

359

Pages

2337 - 2345

Keywords

Child, Chromatin Immunoprecipitation, Down-Regulation, Female, Forkhead Transcription Factors, Gene Expression Regulation, Genetic Markers, Genome-Wide Association Study, Haplotypes, Humans, Language Development Disorders, Male, Membrane Proteins, Nerve Tissue Proteins, Phenotype, Polymerase Chain Reaction, Polymorphism, Single Nucleotide