New neurodevelopmental disorder identified

Wednesday, 20 April, 2022

New neurodevelopmental disorder identified

An international research team, led by the Murdoch Children’s Research Institute (MCRI) in Melbourne, has linked a recognised tumour suppressor gene to a new neurodevelopmental syndrome. The team’s study found variations in the FBXW7 gene were associated with a newly identified condition — which causes mild to severe developmental delay, intellectual disability, hypotonia and gastrointestinal issues — with their results published in the American Journal of Human Genetics.

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 harbouring 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; 62% had decreased muscle tone; 46% noted feeding difficulties and constipation; and 23% had seizures. Brain imaging also detailed variable underlying structural differences affecting the cerebellum, nerve fibres and white matter.

MCRI researcher Dr Sarah Stephenson said because the FBXW7 gene regulates the life cycle of cells, cell growth and survival, the research team speculated that abnormal cell proliferation during brain development may underpin the broad spectrum of brain abnormalities identified in the new disorder. After reducing the gene’s levels in a fly model, the researchers found this affected the flies’ ability to jump in response to a stimulus, supporting 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.

“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,” Stephenson said.

MCRI Professor Tiong Tan, also a clinical geneticist at Victorian Clinical Genetics Services (VCGS), said the team’s 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 personalise 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.”

Tan said the next step will be to test these results in human stem cells, which would be engineered into brain cells for analysis in the lab, and develop a better understanding of how the brain is affected in this condition.

Image credit: © Africa

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