Australian researchers have discovered a new neurodevelopmental disorder after uncovering its link to a tumor suppressor gene.
The international research collaboration led by the Murdoch Children’s Research Institute (MCRI) and published in American Journal of Human Geneticshas linked a recognized tumor suppressor gene to a new neurodevelopmental syndrome, completing the diagnostic journey for 32 families around the world.
The study found that variations in the FBXW7 gene have been linked to the newly identified condition, which causes mild to severe developmental delays, intellectual disability, hypotension and gastrointestinal problems.
Murdoch Children’s researcher, Dr. Sarah Stephenson, said because the FBXW7 gene regulates cell life cycle, cell growth and survival, the research team speculated that abnormal cell proliferation during brain development could underpin the broad spectrum of brain abnormalities identified in this new disorder.
“FBXW7 now joins a rapidly growing number of intellectual disability/autism spectrum disorder genes involved in disorders that affect the development of the nervous system, resulting in atypical brain function and affecting emotions, learning, self-control and memory” , she said.
The study used state-of-the-art diagnostic tools, genome sequencing and global data-sharing platforms to identify 35 individuals aged 2 to 44 years from 32 families in seven countries harboring the FBXW7 gene, which had variants linked to the never-before-described one were brought to neurodevelopmental syndrome.
Almost all affected had developmental delays and intellectual disabilities ranging from borderline to severe, 62 percent had decreased muscle tone, 46 percent noted feeding difficulties and constipation, and 23 percent had seizures. Brain imaging also details variable underlying structural differences affecting the cerebellum, nerve fibers, and white matter.
The team then reduced levels of the gene in a fly model, affecting the flies’ ability to jump in response to a stimulus. This supported the observation that the 28 variants in FBXW7 were the cause of the disease. It has also further cemented the gene’s fundamental role in development in general and in the brain in particular.
Tiong Tan, professor of Murdoch children, also a clinical geneticist at Victorian Clinical Genetics Services (VCGS), said the results underscored the power of undiagnosed disease programs that use new technologies for genome sequencing and international data sharing and collaboration to help Providing diagnoses to children and families who have been seeking answers, often for many years.
Drawing on the research and clinical expertise of the MCRI and VCGS, Rare Diseases Now (RDNow) has established a pathway for children undiagnosed after a genomic test such as exome sequencing.
“The clinical features are so varied in this neurodevelopmental disorder that in some cases it would have been difficult to diagnose without the genomic tools and expertise that come with it,” Professor Tan said.
“The diagnosis has brought closure and reassurance to families, will personalize clinical care for each affected individual and will reveal the genetic and reproductive risks. It is a dominant condition, so an affected person has a 50/50 chance of passing it on to any of their children. This diagnosis will empower those affected to make decisions about their reproductive options.”
Professor Tan said the next step is to test these findings on human stem cells, which would be converted into brain cells for analysis in the lab, and to gain a better understanding of how the brain is affected in this condition.