Variants of the gene CNTNAP2 were significantly associated with the inability of children with typical specific language impairment to process and repeat nonsense words, a heritable behavioral marker of this disorder, reported Simon E. Fisher, D.Phil., of the University of Oxford, and colleagues online in the New England Journal of Medicine.
Because this genetic region coincides with one associated with language delays in children with autism, the researchers said the findings could represent a crucial genetic link between the two disorders.
In an accompanying editorial, Karin Stromswold, M.D., Ph.D., of Rutgers University in New Brunswick, N.J., agreed that these findings were a bold step forward in the search for the genetic underpinnings of language impairment.
"Autistic children often have deficits in nonsense-word repetition, a finding consistent with a role of CNTNAP2 in nonsense-word repetition," she wrote. "Perhaps CNTNAP2 will be implicated in other clinical populations with disorders involving nonsense-word repetition."
The general relevance of this gene to speech dyspraxia remains to be determined, she added.
Specific language impairment -- the most common type of childhood speech disorder -- affects up to 7% of healthy children with many having a family history of the disorder.
However, studies to correlate gene polymorphisms with specific language impairment among affected families have been unfruitful, Dr. Fisher's group noted.
So the researchers decided to search beyond the classically defined genetic region looked at in prior studies, following the trail of a rare mutation of the FOXP2 transcription factor found to cause another kind of severe speech and language disorder.
First, they did genomic screening on human neuron-like cells to isolate genes regulated by FOXP2 in the brain.
One candidate stood out, CNTNAP2 -- a gene that encodes a neurexin and is expressed in the developing human cortex, where it may mediate intercellular interactions during neuroblast migration and laminar organization, and it is a gene that FOXP2 binds to and dramatically down-regulates.
Then, Dr. Fisher and colleagues tested for associations between single-nucleotide polymorphisms (SNPs) in this gene and language deficits in the same well-characterized set of 184 specific language impairment-affected families used by prior studies.
These families included a child with specific language impairment at least 1.5 standard deviations below the normative mean for the child's age on the Clinical Evaluation of Language Fundamentals -- Revised (CELF-R) scale. All their siblings were tested as well.
Children with a nonverbal IQ of less than 80, a clinical diagnosis of an autistic-spectrum disorder, or another known medical or developmental condition that can impair language were excluded.
Nine SNPs located between exons 13 and 15 were significantly associated with nonsense word repetition (P=0.01 to 0.00005).
Of them, the SNP rs17236239 was the strongest predictor of ability to repeat nonsense words, with a P-value of 0.002 even after overly conservative correction for testing of multiple SNPs. It was also the marker with the strongest link to expressive language abilities (P=0.008).
For receptive language abilities, a different SNP -- rs4431523 -- was the strongest marker (P=0.003).
Notably, the same SNP alleles were associated with age at first spoken word in a prior study of the gene in children with autism.
"Therefore, similar CNTNAP2 variants may represent susceptibility factors for language-related deficits in both specific language impairment and autism," Dr. Fisher and colleagues said.
In their study, four combinations of the nine SNPs accounted for 94% of participants.
The most common combination was associated with reduced ability to repeat nonsense words. It was present among 40% of family members with nonsense word repletion ability more than two standard deviations below the population mean compared with a frequency of 29% among those with scores of more than half a standard deviation above the population mean.
The risk did not appear to increase with the number copies of this haplotype were associated with poorer language abilities. Children with one copy or two copies had about a six-point (0.4 SD) lower mean score for nonsense-word repetition than those with no copies of the haplotype (89.7 and 89.4 versus 95.2).
Family-based quantitative association analyses of the haplotypes and nonsense-word repetition scores again indicated a significant association with impaired language performance for the most common combination of the SNPs (P=0.0006).
Gender of the children did not appear to be a significant factor with the genetic markers.
|The study was supported by grants from the Wellcome Trust and Autism Speaks as well as awards from the National Institute of Mental Health, a scholarship from the University of Oxford, a Tourette Syndrome Association fellowship, and a Marie Curie Intra-European Fellowship. Dr. Fisher and several coauthors reported being members of the Specific Language Impairment Consortium.
Zalman S. Agus, MD Emeritus Professor
University of Pennsylvania School of Medicine
New England Journal of MedicineSource Reference: Vernes CJ, et al "A Functional Genetic Link between Distinct Developmental Language Disorders" N Engl J Med 2008; 359: DOI: 10.1056/NEJMoa0802828.
New England Journal of MedicineSource Reference: Stromswold K "The Genetics of Speech and Language Impairments" N Engl J Med 2008; 359.