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Genetics of Specific Language Impairment

A downstream target of the FOXP2 gene was associated with a common language disorder in this study of affected families.

Specific language impairment is a disorder that occurs in up to 7% of children aged 5 to 6 years. Typical specific language impairment involves both comprehension and production deficits and is associated with deficits in repeating nonsense words. Although no gene has been implicated in most cases of this disorder, mutations in the gene for the forkhead box P2 (FOXP2) transcription factor are associated with a rare autosomal dominant form that affects approximately 2% of all cases.

In this study, the authors focused on a downstream target of FOXP2: the contactin associated protein-like 2 gene (CNTNAP2), which encodes a neurexin expressed in the cerebral cortex and previously linked to autism. The researchers studied the association of the FOXP2 transcription factor with CNTNAP2 gene expression in cells engineered to express FOXP2. They also looked for associations between single nucleotide polymorphisms (SNPs) in CNTNAP2 and language deficits in 184 families affected by specific language impairment not associated with other developmental disorders.

The researchers found that FOXP2 binds to and downregulates CNTNAP2 expression. Moreover, certain SNPs of CNTNAP2 were associated with problems in nonsense word repetition in family members with specific language impairment. The authors conclude that the FOXP2–CNTNAP2 pathway provides a mechanistic link between clinically distinct syndromes that include disrupted language, such as specific language impairment and autism.

Comment: This study shows that endophenotypes shared among distinct clinical syndromes might share genetic mechanisms. Thus, polymorphisms of CNTNAP2 involved in some cases of autism interact with FOXP2, which is linked to specific language impairment. FOXP2 is expressed primarily in cerebral cortex in areas associated with language function and in striatum; impairments in these areas are consistent with the language and speech symptoms seen in specific language impairment. Sequencing studies have shown that FOXP2 has been a target of selection in recent human evolution (Nature 2002; 418:869). However, the FOXP2 protein also appears to play a role in vocalization in mice and in birdsong. One puzzle remains: CNTNAP2 itself has not been associated with specific language impairment in any genetic study thus far (N Engl J Med 2008; 359:2381). More work must be done to clarify the range of effects that emerge from mutations in these genes.

— Albert M. Galaburda, MD

Dr. Galaburda is Professor of Neurology and Neuroscience, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston.

Published in Journal Watch Neurology March 3, 2009

Citation(s):

Vernes SC et al. A functional genetic link between distinct developmental language disorders. N Engl J Med 2008 Nov 27; 359:2337.

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