NEW YORK (GenomeWeb) – A University of Iowa research team has received a $3 million grant from the National Institutes of Health to conduct the first whole-genome sequencing study of children with specific language impairment (SLI).
The project, which is set to run over the next five years, is expected to yield new insights into the genetic causes of language impairment in various developmental and disease contexts. Such findings could potentially lead to the development of tests to identify SLI sooner than currently possible, facilitating early intervention, UI's Jacob Michaelson, who is leading the study, told GenomeWeb.
SLI is a condition in which language does not develop normally in children and cannot be accounted for by other disorders such as autism, intellectual disability, or hearing impairment. According to Michaelson, it is one of the most common developmental disabilities, affecting about seven percent of the population.
While it is known that SLI has a genetic component, past efforts to identify its specific genetic underpinnings have relied on family studies with limited success, and have implicated only a handful of genes, most notably forkhead box protein P2 (FOXP2).
"A lot of people have tried to look at common variants in FOXP2 and look for associations [between those variants] and language ability," Michaelson explained. However, "FOXP2 is a very important gene developmentally, and [so] it's quite unlikely there would be common variation in that gene that is linked clearly" to language impairment.
But with the growing availability of new genomic technologies that can pinpoint even rare variants, Michaelson and his colleagues now aim to delve deeper into the genetics of SLI, kicking off this month a first-of-its-kind study that will sequence DNA from hundreds of male and female children to build a comprehensive catalog of genetic variation in language-impaired and language-proficient individuals.
Michaelson noted that a key aspect to this work is his collaboration with UI's Bruce Tomblin who has collected DNA samples from over 1,000 Iowa school children both with and without SLI over the course of decades studying speech and language disorders. The whole-genome sequencing study, he added, is expected to include samples from about 400 of these children, as well as a similar number of samples from an independent cohort of Australian children.
Once the catalog is complete, Michaelson and his team will computationally determine the functional impact for each variant by grouping them together into pathways and gene sets that may play a role in language impairment, and then test them for enrichment in language-impaired and language-proficient individuals, according to his grant's abstract. The investigators also plan to study the role of potentially functional non-coding genetic variation, looking for positional enrichment of variation near regulatory landmarks such as genomic binding sites of FOXP2.
Given the frequent occurrence of language impairment in individuals with autism, they also aim to perform a gene network analysis comparing network modules — regions of concentrated genetic burden of functional variants — of both language impairment and autism.
"Genes like … FOXP2 that have been classically associated with language impairment … have come up quite frequently in studies of autism," Michaelson said. "We want to do a little more to nail that down and clarify that to see if there is shared genetic liability in those cases."
Beyond its impact on the understanding of SLI, Michaelson hopes that the data from his NIH-funded study will provide clues about language impairment in other disorders.
"Language is affected in various ways in a lot of different psychiatric conditions such as schizophrenia and depression, [as well as in] degenerative diseases and dementia," he said. "We're very interested in using [the NIH study] as a springboard … to compare and contrast the variation in language ability we see in specific language impairment and extrapolating that to other … conditions to see what's shared and what is not."
Down the road, the results of the SLI study may also help in the development of diagnostics that can identify the condition in very young children.
"Ideally, you would know when a child is born … [if they] have a high probability of having difficulties with language," Michaelson said. "If you knew that long before the child could talk, that opens the door for coming up with tailor-made interventions to enrich the child's experience or environment to try to make up for those deficits that are going to be coming because of the genetics of their developmental programing."