An international research collaboration, led by the Murdoch Children’s Research Institute and the University of Melbourne in Australia, has discovered a new neurodevelopmental genetic syndrome linked to the tumor suppressor gene FBXW7.
The discovery has helped bring answers to 35 adults and children from 32 families in seven countries around the world, who all have the newly identified syndrome. Symptoms associated with the condition include mild to severe developmental delay, intellectual disability, decreased muscle tone, and gastrointestinal problems.
Previous research has suggested FBXW7 has a tumor suppressor role. The research team behind the new syndrome discovery think that abnormal cell proliferation during brain development could explain the abnormalities observed in those with the disorder.
“FBXW7 now joins a steeply increasing number of intellectual disability/autism spectrum disorder genes that have been implicated in disorders that affect nervous system development, leading to atypical brain function, affecting emotion, learning ability, self-control and memory,” said Murdoch Children’s researcher Sarah Stephenson in a press statement.
Writing in the American Journal of Human Genetics, the researchers report that almost all the 35 individuals tested had developmental delay and borderline to severe intellectual disability. Decreased muscle tone was seen in 62% of the group and 46% had feeding difficulties and constipation, with 23% experiencing seizures.
Genome sequencing and other tests were carried out including brain imaging, which revealed variable abnormalities in the cerebellum, nerve fibres and white matter across individuals with the syndrome.
The team also adjusted gene expression levels of FBXW7 in a fly model, confirming links to neurological function. In a cell line model, the observed genetic variants in the FBXW7 gene also showed impairments in other cell proliferation related proteins.
The variability in phenotype seen with this condition would have made it hard to identify without modern sequencing and genetic testing technologies.
“The diagnosis has given closure and certainty to families, will personalize clinical care of each affected individual and has revealed the genetic and reproductive risks. It’s a dominant condition so an affected person will have a 50-50 chance of passing it on to each of their children. This diagnosis will empower those impacted to make decisions about their reproductive options,” said study lead Tiong Tan, a professor at the University of Melbourne and a clinical geneticist at Victorian Clinical Genetics Services.
The team now plans to express the genetic variations they found in human brain cell lines in the lab to investigate the impact of this condition on the brain further.
