Medical Professional Publications

Genotype-Phenotype Model Sheds Light on Language Impairment

Using a model that combines genetic evidence across multiple behavioral disease characteristics may be more powerful for understanding disease than using only single symptoms at a time, especially in the case of specific language impairment. These are the findings from a study involving the Battelle Center for Mathematical Medicine.

Specific language impairment (SLI) is a neurodevelopmental disorder characterized by a significant delay in learning or using language, despite adequate education and normal neurological and psychiatric development. SLI occurs in approximately 7 percent of children entering school and is associated with later difficulties in learning to read.

Studies have indicated that SLI is heritable.  Yet, like many complex conditions, the characteristics of SLI can’t be clearly tied to a single genetic culprit.    

Still, the concept of modeling deterministic relationships could be valuable when studying SLI says Christopher Bartlett, PhD, principal investigator in the Battelle Center for Mathematical Medicine at The Research Institute at Nationwide Children’s Hospital. “Employing specific models of the genotype-phenotype relationship can be useful in complex diseases for which chromosomal issues have been implicated,” he said.

In 2002, Dr. Bartlett and colleagues identified a region on chromosome 13 (13q21) that contains an allele associated with SLI susceptibility. This region was identified as the team examined people with a family history of SLI and who were reading-impaired. However, when they examined those who were only language-impaired (and who had no reading issues), 13q21 was not strongly implicated. “It was unclear why reading impairment would provide stronger evidence for deficits in chromosomal linkage than language impairment would in a study population selected for SLI,” added Stephen Petrill, PhD, a co-author from The Ohio State University.  

In a study appearing in the October 14, 2010 issue of Human Heredity, Dr. Bartlett and colleagues from Rutgers University, The Ohio State University and the University of Toronto sought ways to model this complex genotype-multiple-phenotype relationship.  “We wanted to better understand if the 13q21 locus is related primarily to language, primarily to reading or some combination thereof,” said Dr. Bartlett.  “We hypothesized that the reading deficit was a result of a language deficit.”  

In the study, the group describes the PPL framework, a flexible genetic modeling platform that allowed them to examine the genotype-phenotype relationship of language impairment in a collection of large extended families that had a history of language or reading impairment.

They found that the 13q21 locus was related to poor reading ability due to poor language ability.  “These data are consistent with language processes being involved in the 13q21 linkage,” said Dr. Bartlett.  “The reading impairment phenotype appears to be the most relevant trait.  It appears that 13q21 has an interesting effect on non-word reading ability through effects on global language.”

Although the data do not suggest that a reading impairment phenotype is universally better for finding SLI susceptibility alleles, Dr. Bartlett says this model shows an example of how behavioral biomarkers can clarify the role of genetic biomarkers and vice versa. “We believe this is the first study of its kind to so dramatically increase the strength of evidence for linkage to a cognitive trait in humans,” said Dr. Bartlett.

Simmons TR, Flax JF, Azaro MA, Hayter JE, Justice LM, Petrill SA, Bassett AS, Tallal P, Brzustowicz LM, Bartlett CW. Increasing Genotype-Phenotype Model Determinism: Application to Bivariate Reading/Language Traits and Epistatic Interactions in Language-Impaired Families. Hum Hered. 2010 Oct 14;70(4):232-244.

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