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

doi:10.1056/NEJMoa0802828

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

School of Biology

Research output: Contribution to journal › Article › peer-review

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=5.0x10(-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.

Original language	English
Pages (from-to)	2337-45
Number of pages	9
Journal	New England Journal of Medicine
Volume	359
Issue number	22
DOIs	https://doi.org/10.1056/NEJMoa0802828
Publication status	Published - 27 Nov 2008

Keywords

Child
Chromatin Immunoprecipitation
Down-Regulation
Female
Forkhead Transcription Factors/genetics
Gene Expression Regulation
Genetic Markers
Genome-Wide Association Study
Haplotypes
Humans
Language Development Disorders/genetics
Male
Membrane Proteins/genetics
Nerve Tissue Proteins/genetics
Phenotype
Polymerase Chain Reaction
Polymorphism, Single Nucleotide

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10.1056/NEJMoa0802828

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title = "A functional genetic link between distinct developmental language disorders",

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=5.0x10(-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.",

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author = "Vernes, {Sonja C} and Newbury, {Dianne F} and Abrahams, {Brett S} and Laura Winchester and J{\'e}r{\^o}me Nicod and Matthias Groszer and Maricela Alarc{\'o}n and Oliver, {Peter L} and Davies, {Kay E} and Geschwind, {Daniel H} and Monaco, {Anthony P} and Fisher, {Simon E}",

note = "2008 Massachusetts Medical Society",

year = "2008",

month = nov,

day = "27",

doi = "10.1056/NEJMoa0802828",

language = "English",

volume = "359",

pages = "2337--45",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "22",

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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

N1 - 2008 Massachusetts Medical Society

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=5.0x10(-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.

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=5.0x10(-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.

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KW - Down-Regulation

KW - Female

KW - Forkhead Transcription Factors/genetics

KW - Gene Expression Regulation

KW - Genetic Markers

KW - Genome-Wide Association Study

KW - Haplotypes

KW - Humans

KW - Language Development Disorders/genetics

KW - Male

KW - Membrane Proteins/genetics

KW - Nerve Tissue Proteins/genetics

KW - Phenotype

KW - Polymerase Chain Reaction

KW - Polymorphism, Single Nucleotide

U2 - 10.1056/NEJMoa0802828

DO - 10.1056/NEJMoa0802828

M3 - Article

C2 - 18987363

SN - 0028-4793

VL - 359

SP - 2337

EP - 2345

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 22

ER -

A functional genetic link between distinct developmental language disorders

Abstract

Keywords

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