HudsonAlpha Institute for Biotechnology researchers, in a cooperative effort with an international team of collaborators from six countries, recently identified a new genetic variant in the EBF3 gene that causes intellectual and developmental delay in children. The research “Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism” was published online December 22 in the American Journal of Human Genetics (AJHG).
“Essentially, we did experiments to understand how variants in the EBF3 gene might change its function during development,” said Drew Hardigan, a graduate student in the Myers Lab at HudsonAlpha and a co-lead author. “The role of EBF3 had been studied in terms of neural development, but had not been previously described as a gene in which mutations cause intellectual and developmental delay. We were able to demonstrate that changes to the gene are the cause of a clinical disorder.”
The finding arose from the lab of HudsonAlpha faculty investigator Greg Cooper, Ph.D., who was the senior author for the report. Through ongoing work under an NHGRI grant for the diagnosis of unexplained intellectual and developmental disabilities, Cooper’s team identified two separate patients via genomic sequencing and analysis that had EBF3 variations.
When the HudsonAlpha team could not find any similar cases or publications to confirm the EBF3 variations were causing the patients’ symptoms, they turned to GeneMatcher, an online tool that acts like a matchmaker for scientists studying specific rare genetic variants. Using GeneMatcher, Cooper’s team was able to contact researchers around the world who were also interested in variations of unknown signficance in EBF3.
Cooper noted that, under the current NHGRI grant, HudsonAlpha has sequenced roughly 400 patients and their parents—so called “trios”—in the search for rare genetic disorders. In the case of EBF3: “We got lucky to have two in just one clinic, based on our estimates of what the worldwide prevalence of EBF3 mediate disease is,” Cooper told Clinical OMICs. “With GeneMatcher, we were able to get 10 different patients worldwide from other researchers, so we couldn’t have done it without that tool as you’d have to be thinking cohorts in the hundreds of thousands of people to get that cohort in a single pipeline.”
Once connected, the international group performed a statistical analysis confirming the gene was very likely the cause of the symptoms for 10 patients. The experiments showed that the genetic changes to EBF3 disrupt important functions required for normal development. They also found that changes in this gene were likely the cause of about one in every 1,000 patients with unexplained neurodevelopmental disorders.
“We were able to combine statistical and computational analyses of genetic data with the results of biological experiments to provide these 10 patients with an answer,” said Cooper.
Despite not having a specific treatment for children with this specific EBF3 variant, Cooper noted that being able to positively diagnose the cause of these children’s condition has benefits. “People perceive a substantial amount of personal benefit even if there is no drug to treat the disease,” he said. More broadly for all types of rare disease diagnosis: there are benefits for family planning depending on whether it is a recessive gene or a de novo variant.
“Another tangible benefit is support groups. Once you make the identification, you can refer families to a support groups [and] online discussion forums where they can share experiences,” Cooper said. “They glean a lot of benefit if they can interact with other families that are going through the same thing.”