A Functional Genetic Link between Distinct Developmental Language Disorders

By S. Vernes, D. Newbury, B. Abrahams, L. Winchester, J. Nicod, M. Groszer, M. Alarcón, P. Oliver, K. Davies, Daniel H. Geschwind and 2 more. New England Journal of Medicine, 2008

691 citations recorded by the source corpus.

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.

Subfields: Cognitive Neuroscience, Developmental and Educational Psychology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a0ea62a62a6af45bc7219212e7b96f0281eb4ee5

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cognitive Neuroscience

In Developmental and Educational Psychology

In Molecular Biology

Citations in the corpus

Altered Structural Brain Connectivity in Healthy Carriers of the Autism Risk Gene, CNTNAP2 (2011, positive): “However, Scott-Van Zeeland’s study supports a dominant effect of the CNTNAP2 SNP. Vernes et al. (2008) found that a haplotype of nine SNPs, including this CNTNAP2 SNP, had a dominant effect, but no other studies have produced evidence on the dominance of CNTNAP2 rs2710102 by itself.”
The myth of language universals: language diversity and its importance for cognitive science. (2009, background): “& Fisher, S. E. (2008) A functional genetic link between distinct develop-”
Comprehension of reflexive and personal pronouns in children with autism: A syntactic or pragmatic deficit? (2012, background): “Mapping out a detailed linguistic profile in the population with autism is crucial to both establishing reliable differences between autism and other developmental disorders, such as SLI, as well as understanding the heterogeneity of the grammatical abilities of individuals on the autism spectrum.”
Interneuron dysfunction in psychiatric disorders (2012, background): “Since then, several genetic studies have provided additional evidence for the involvement of CNTNAP2 in autis”
Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations (2011, positive): “CNTNAP2 is directly downregulated by FOXP2 35 and has been independently associated with ASD and specific language impairment 34–37 .”
Functional and Evolutionary Insights Into Human Brain Development Through Global Transcriptome Analysis (2009, background): “These include CNTNAP2, which is not only related to language delay in autism, but is a target of the language-related transcriptional repressor FOXP2, and has a more general role as a susceptibility factor for specific language impairment (Vernes et al., 2008).”
FOXP2 as a molecular window into speech and language. (2009, methodology): “Further experiments in transfected human neuron-like cells indicated that FOXP2 downregulates CNTNAP2 expression [21] .B oth genes are expressed in the developing human cerebral cortex [10,13,23], where they show complementary patterns; cortical layers with the highest FOXP2 expression have the lowe”