Abstract
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 = 5.0×10-5 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 language | English (US) |
|---|---|
| Pages (from-to) | 2337-2345 |
| Number of pages | 9 |
| Journal | New England Journal of Medicine |
| Volume | 359 |
| Issue number | 22 |
| DOIs | |
| State | Published - Nov 27 2008 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
A functional genetic link between distinct developmental language disorders. / Vernes, Sonja C.; Newbury, Dianne F.; Abrahams, Brett S.; Winchester, Laura; Nicod, Jérôme; Groszer, Matthias; Alarcón, Maricela; Oliver, Peter L.; Davies, Kay E.; Geschwind, Daniel H.; Monaco, Anthony P.; Fisher, Simon E.
In: New England Journal of Medicine, Vol. 359, No. 22, 27.11.2008, p. 2337-2345.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A functional genetic link between distinct developmental language disorders
AU - Vernes, Sonja C.
AU - Newbury, Dianne F.
AU - Abrahams, Brett S.
AU - Winchester, Laura
AU - Nicod, Jérôme
AU - Groszer, Matthias
AU - Alarcón, Maricela
AU - Oliver, Peter L.
AU - Davies, Kay E.
AU - Geschwind, Daniel H.
AU - Monaco, Anthony P.
AU - Fisher, Simon E.
PY - 2008/11/27
Y1 - 2008/11/27
N2 - 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 = 5.0×10-5 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.
AB - 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 = 5.0×10-5 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.
UR - http://www.scopus.com/inward/record.url?scp=57149090343&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=57149090343&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa0802828
DO - 10.1056/NEJMoa0802828
M3 - Article
C2 - 18987363
AN - SCOPUS:57149090343
VL - 359
SP - 2337
EP - 2345
JO - New England Journal of Medicine
JF - New England Journal of Medicine
SN - 0028-4793
IS - 22
ER -