A functional genetic link between distinct developmental language disorders

Sonja C. Vernes, Dianne F. Newbury, Brett S. Abrahams, Laura Winchester, Jérôme Nicod, Matthias Groszer, Maricela Alarcón, Peter L. Oliver, Kay E. Davies, Daniel H. Geschwind, Anthony P. Monaco, Simon E. Fisher

Research output: Contribution to journalArticle

425 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2337-2345
Number of pages9
JournalNew England Journal of Medicine
Volume359
Issue number22
DOIs
StatePublished - Nov 27 2008
Externally publishedYes

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Language Development Disorders
Language
Single Nucleotide Polymorphism
Genes
Language Disorders
Speech Disorders
Neural Pathways
Chromatin Immunoprecipitation
Autistic Disorder
Transcription Factors
Down-Regulation
Phenotype
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Vernes, S. C., Newbury, D. F., Abrahams, B. S., Winchester, L., Nicod, J., Groszer, M., ... Fisher, S. E. (2008). A functional genetic link between distinct developmental language disorders. New England Journal of Medicine, 359(22), 2337-2345. https://doi.org/10.1056/NEJMoa0802828

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 journalArticle

Vernes, SC, Newbury, DF, Abrahams, BS, Winchester, L, Nicod, J, Groszer, M, Alarcón, M, Oliver, PL, Davies, KE, Geschwind, DH, Monaco, AP & Fisher, SE 2008, 'A functional genetic link between distinct developmental language disorders', New England Journal of Medicine, vol. 359, no. 22, pp. 2337-2345. https://doi.org/10.1056/NEJMoa0802828
Vernes SC, Newbury DF, Abrahams BS, Winchester L, Nicod J, Groszer M et al. A functional genetic link between distinct developmental language disorders. New England Journal of Medicine. 2008 Nov 27;359(22):2337-2345. https://doi.org/10.1056/NEJMoa0802828
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. / A functional genetic link between distinct developmental language disorders. In: New England Journal of Medicine. 2008 ; Vol. 359, No. 22. pp. 2337-2345.
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AU - Groszer, Matthias

AU - Alarcón, Maricela

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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.

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