Researchers Discover New Neurodevelopmental Disorder

An international research collaboration has discovered a new neurodevelopmental disorder after uncovering its link to a known tumor suppressor gene. The findings end long diagnostic journeys for 32 families globally and highlight the potential for international data sharing and new genomic sequencing methods.

Led by Murdoch Children’s Research Institute (MCRI), the group found that variations in the FBXW7 gene were associated with the newly identified condition, which causes mild to severe developmental delay, intellectual disability, hypotonia and gastrointestinal issues.

FBXW7 regulates the life cycle of cells, cell growth and survival, which led the team to speculate that abnormal cell proliferation during brain development may underpin the broad spectrum of brain abnormalities identified in this new 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,” says MCRI researcher Dr. Sarah Stephenson.

 The study used cutting-edge diagnostic tools, genomic sequencing and global data sharing platforms to identify 35 people, aged 2–44 years, from 32 families in seven countries harboring the FBXW7 gene, which had variants that were associated with the never-before described neurodevelopmental syndrome. Almost all affected people had developmental delay and intellectual disability, ranging from borderline to severe. Sixty-two percent had decreased muscle tone, 46% noted feeding difficulties and constipation, and 23% experienced seizures. Brain imaging also detailed variable underlying structural differences affecting the cerebellum, nerve fibers and white matter.

The team then reduced the gene’s levels in a fly model, which affected 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 condition. It also further cemented the fundamental role of the gene in development broadly, and the brain, specifically.

MCRI professor Tiong Tan, also a clinical geneticist at Victorian Clinical Genetics Services (VCGS), said the findings highlight the power of undiagnosed diseases programs that use new genomic sequencing technologies and international data sharing and collaboration to bring diagnoses to children and families who have been seeking answers, often for many years.  

“The clinical features are so variable with this neurodevelopmental disorder that in some cases it would have been difficult to diagnose without the genomic tools and associated expertise,” Tan said. “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.”

The findings were published recently in American Journal of Human Genetics.