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 the American Journal of Human Genetics, has linked a recognised tumor suppressor gene to a new neurodevelopmental syndrome, ending the diagnostic journey for 32 families around the world.

The study found 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.

Murdoch Children's researcher Dr Sarah Stephenson said because the FBXW7 gene regulated 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 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," she said.

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 per cent had decreased muscle tone, 46 per cent noted feeding difficulties and constipation and 23 per cent had seizures. Brain imaging also detailed variable underlying structural differences affecting the cerebellum, nerve fibres 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.

Murdoch Children's Professor Tiong Tan, also a clinical geneticist at Victorian Clinical Genetics Services (VCGS), said the findings highlighted 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. 

Drawing on the research and clinical expertise at MCRI and VCGS, Rare Diseases Now (RDNow) has established a pathway for children who remain undiagnosed after a genomic test such as exome sequencing. 

"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," Professor 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."

Professor Tan said the next step was 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 was affected in this condition.        

Publication: 'Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome,' American Journal of Human Genetics. DOI: 10.1016/j.ajhg.2022.03.002

*The content of this communication is the sole responsibility of MCRI and does not reflect the views of the NHMRC.

Available for interview:

Dr Sarah Stephenson, MCRI Team Leader, Neurogenetics

Professor Tiong Tan, MCRI and VCGS clinical geneticist

Media Contact:

Bridie Byrne
MCRI media manager
+61 457 365 848

About MCRI

The Murdoch Children's Research Institute (MCRI) is the largest child health research institute in Australia committed to making discoveries and developing treatments to improve child and adolescent health in Australia and around the world. They are pioneering new treatments, trialling better vaccines and improving ways of diagnosing and helping sick babies, children and adolescents. It is one of the only research institutes in Australia to offer genetic testing to find answers for families of children with previously undiagnosed conditions.


UDP-Vic acknowledges financial support from the Murdoch Children's Research Institute and the Harbig Foundation. The Rare Disease Flagship acknowledges financial support from The Royal Children's Hospital Foundation, the Murdoch Children's Research Institute, and the Harbig Foundation. The research conducted at the Murdoch Children's Research Institute and Baker Heart and Diabetes Institute was supported by the Victorian Government's Operational Infrastructure Support Program. Sequencing and analysis of Individual 1 were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (BroadCMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 to Daniel MacArthur and Heidi Rehm. The research pertaining to Individual 18 was supported by Telethon Undiagnosed Diseases Program (TUDP, GSP15001). Sequencing of Individual 31 was funded by CREGEMES and Sanger validated by Claire Feger. The research conducted at The Hospital for Sick Children (Canada) was supported in part by the Norm Saunders Complex Care Initiative, SickKids Centre for Genetic Medicine, and University of Toronto McLaughlin Centre. The Chair in Genomic Medicine awarded to J.C. is generously supported by The Royal Children's Hospital Foundation. This work was in part supported by a grant awarded under the Australian National Health & Medical Research Council (NHMRC) Centre for Research Excellence Scheme (APP1117394) to L.E.R.B., A.S., T.R., K-R.D., C-A.E. and by a personal Vici grant (09150181910022) from The Netherlands Organization for Scientific Research (NWO) to A.S. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number T32CA136432.  D.B.A, T.B.N. and M.S. were supported by an Investigator Grant from the National Health and Medical Research Council (NHMRC) of Australia (GNT1174405). This publication was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1TR001873. M.S.H., M.B. and A.T.M. are funded by a National Health and Medical Research Council (NHMRC) Centre of Research Excellence Grant (1116976). M.B. was funded by an NHMRC Senior Research Fellowship (ID:1102971).