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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.
Source Information
From the Wellcome Trust Centre for Human Genetics (S.C.V., D.F.N., L.W., J.N., M.G., A.P.M., S.E.F.) and the Medical Research Council Functional Genomics Unit (S.C.V., P.L.O., K.E.D.), University of Oxford, Oxford, United Kingdom; and the Department of Neurology (B.S.A., M.A., D.H.G.) and the Semel Institute and the Department of Human Genetics (D.H.G.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles.
This article (10.1056/NEJMoa0802828) was published at www.nejm.org on November 5, 2008.
Address reprint requests to Dr. Fisher at the Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Dr., Headington, Oxford OX3 7BN, United Kingdom, or at simon.fisher{at}well.ox.ac.uk.
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