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.
Vernes
Sonja C
SC
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Newbury
Dianne F
DF
Abrahams
Brett S
BS
Winchester
Laura
L
Nicod
Jérôme
J
Groszer
Matthias
M
Alarcón
Maricela
M
Oliver
Peter L
PL
Davies
Kay E
KE
Geschwind
Daniel H
DH
Monaco
Anthony P
AP
Fisher
Simon E
SE
D002648:Child; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D007805:Language Development Disorders / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
C403049:CNTNAP2 protein, human; C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors; D005819:Genetic Markers; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins