Scientists in the United Kingdom and Denmark have identified a new genetic disease that causes some children’s brains to develop abnormally, resulting in delayed intellectual development. The majority of patients with the as-yet-unnamed condition have severe learning difficulties that affect their quality of life.
Comprised of frog geneticists, biochemists and clinical geneticists from the Universities of Portsmouth, Southampton and Copenhagen, the team used tadpoles to discover that changes in a protein coding gene called Glutamate Ionotropic Receptor AMPA Type Subunit 1 (GRIA1) caused this rare genetic disorder. The GRIA1 gene helps to move electrical signals around the brain. However, if this process is interrupted or made less efficient, it can cause a reduction in the brain’s capacity to retain information.
The study used tadpoles in which the human gene variants were mimicked using gene editing to show that GRIA1 changes are the underlying cause of the behavior-altering disease. The biochemical analysis of the variants was also performed in frog oocytes.
“Next generation DNA sequencing is transforming our ability to make new diagnoses and discover new genetic causes of rare disorders,” says study co-author Professor Matt Guille, who leads a laboratory in the Epigenetics and Developmental Biology research group at the University of Portsmouth. “The main bottleneck in providing diagnoses for these patients is linking a change discovered in their genome firmly to their disease. Making the suspect genetic change in tadpoles allows us to test whether it causes the same illness in humans.”
Now the variant has been identified, it will help clinicians come up with targeted interventions to help patients and their families and opens the door to screening and prenatal diagnosis. One in 17 people will suffer from a rare disease at some time in their lives. Most of these rare diseases have a genetic cause and often affect children, but proving which gene change causes a disease is a huge challenge.
“This was a transformational piece of work for us; the ability to analyze human-like behaviors in tadpoles with sufficient accuracy to detect genetic disease-linked changes opens the opportunity to help identify a huge range of diseases,” says co-author Dr Annie Goodwin, Research Fellow at the University of Portsmouth. “This is particularly important given that so many neurodevelopmental diseases are currently undiagnosed.”
The findings are published in the American Journal of Human Genetics.