We have shown that FOXP2, which is mutant in people with a rare speech and language disorder, directly regulates expression of the CNTNAP2 gene. We went on to demonstrate that variants of CNTNAP2 are associated with deficits in common forms of language impairment. In so doing, we provide an example of how knowledge of the genetic cause of a rare single-gene disorder provides an entry point into the causes of a more complex phenotype. Further analyses of the relevant regulatory networks — including the FOXP2-CNTNAP2 pathway identified here — may lead to a better understanding of neurogenetic mechanisms involved in typical language disorders.
The FOXP2-bound fragment of CNTNAP2
lies outside the classically defined regulatory regions of the genome represented on available promoter-based microarrays. It therefore escaped detection in recently published efforts in which chromatin immunoprecipitation with FOXP2 antibodies was coupled to screening of such microarrays.18,40
Indeed, large-scale surveys of transcription-factor binding have indicated that functional regulatory sequences often lie far from known promoters, with many of such sequences mapping within introns.41
Thus far, CNTNAP2
is the only FOXP2 target that we have tested for association in specific language impairment. Of all FOXP2 targets identified to date,18,40
we prioritized CNTNAP2
for association testing in common language disorders because it represented the most compelling of candidates, with converging support from multiple lines of independent investigation. That these first association analyses were positive illustrates the promise of our function-based approach. In future work, we will go on to assess other neural targets of FOXP2 in a similar manner.
There is considerable debate over the existence of shared causes of neurodevelopmental syndromes that are treated as diagnostically distinct, such as autism and specific language impairment.2,42,43
In this study, we observed an association between the endophenotype of nonsense-word repetition and polymorphisms in the exon 13-15 region of CNTNAP2
in children with specific language impairment. A study of the gene in children with autism37
showed an association between polymorphisms in the exon 13-15 region (similarly centered on tagging-SNP rs2710102) and the age at the first spoken word. The same SNP alleles were associated with susceptibility in both studies (Table S3
in the Supplementary Appendix). Therefore, similar CNTNAP2
variants may represent susceptibility factors for language-related deficits in both specific language impairment and autism.
The CNTNAP2 associations we describe here for specific language impairment are not simply a replication of those reported previously for patients with autistic-spectrum disorders. We made a rigorous effort to exclude persons with autistic-spectrum disorders from our analysis. Although diagnostic boundaries are not always clear, it is unlikely that persons who received a misdiagnosis of autistic-spectrum disorder remained in such numbers that they accounted for the strength of the association that we observed. Moreover, we used a quantitatively defined endophenotype previously proposed to underlie typical specific language impairment, rather than a categorical designation of affected status.
Instead, our findings are compatible with the idea that different components of autistic-spectrum disorders (communication deficits, impaired social interaction, and rigid or repetitive behaviors) may be under different genetic influences.44
In this view, language impairments are observed in relatively pure form in specific language impairment, but when they occur in association with other social and behavioral deficits, such impairments can result in a diagnosis of autism.45
Thus, altered CNTNAP2
function or regulation could represent a shared mechanism contributing to language-related endophenotypes in both specific language impairment and autism. These findings illustrate the value of using endophenotypes for the genetic dissection of such disorders.
In conclusion, by integrating functional genomics and quantitative trait analyses, we have identified a shared neurogenetic pathway that is disturbed in distinct forms of language impairment. This work represents a move away from isolated studies of individual genes and toward an understanding of molecular networks that may go awry in neurodevelopmental disorders affecting language.