Researchers discover new neurodevelopmental disorder

Date:
April 7, 2022
Source:
Murdoch Childrens Research Institute
Summary:
Researchers have discovered a new neurodevelopmental disorder
after uncovering its link to a tumor suppressor gene.



FULL STORY ========================================================================== 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.


========================================================================== Story Source: Materials provided by
Murdoch_Childrens_Research_Institute. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Sarah E.M. Stephenson, Gregory Costain, Laura E.R. Blok, Michael
A. Silk,
Thanh Binh Nguyen, Xiaomin Dong, Dana E. Alhuzaimi, James
J. Dowling, Susan Walker, Kimberly Amburgey, Robin Z. Hayeems,
Lance H. Rodan, Marc A. Schwartz, Jonathan Picker, Sally A. Lynch,
Aditi Gupta, Kristen J.

Rasmussen, Lisa A. Schimmenti, Eric W. Klee, Zhiyv Niu, Katherine E.

Agre, Ilana Chilton, Wendy K. Chung, Anya Revah-Politi,
P.Y. Billie Au, Christopher Griffith, Melissa Racobaldo, Annick
Raas-Rothschild, Bruria Ben Zeev, Ortal Barel, Sebastien Moutton,
Fanny Morice-Picard, Virginie Carmignac, Jenny Cornaton, Nathalie
Marle, Orrin Devinsky, Chandler Stimach, Stephanie Burns Wechsler,
Bryan E. Hainline, Katie Sapp, Marjolaine Willems, Ange-line Bruel,
Kerith-Rae Dias, Carey-Anne Evans, Tony Roscioli, Rani Sachdev,
Suzanna E.L. Temple, Ying Zhu, Joshua J.

Baker, Ingrid E. Scheffer, Fiona J. Gardiner, Amy L. Schneider,
Alison M.

Muir, Heather C. Mefford, Amy Crunk, Elizabeth M. Heise, Francisca
Millan, Kristin G. Monaghan, Richard Person, Lindsay Rhodes, Sarah
Richards, Ingrid M. Wentzensen, Benjamin Cogne', Bertrand Isidor,
Mathilde Nizon, Marie Vincent, Thomas Besnard, Amelie Piton, Carlo
Marcelis, Kohji Kato, Norihisa Koyama, Tomoo Ogi, Elaine Suk-Ying
Goh, Christopher Richmond, David J. Amor, Jessica O. Boyce, Angela
T. Morgan, Michael S. Hildebrand, Antony Kaspi, Melanie Bahlo, Ru'n
Frid- riksdo'ttir, Hildigunnur Katri'nardo'ttir, Patrick Sulem,
Ka'ri Stefa'nsson, Hans To'mas Bjo"rnsson, Simone Mandelstam,
Manuela Morleo, Milena Mariani, Marcello Scala, Andrea Accogli,
Annalaura Torella, Valeria Capra, Mathew Wallis, Sandra Jansen,
Quinten Weisfisz, Hugoline de Haan, Simon Sadedin, Sze Chern Lim,
Susan M. White, David B. Ascher, Annette Schenck, Paul J. Lockhart,
John Christodoulou, Tiong Yang Tan.

Germline variants in tumor suppressor FBXW7 lead to impaired
ubiquitination and a neurodevelopmental syndrome. The
American Journal of Human Genetics, 2022; 109 (4): 601 DOI:
10.1016/j.ajhg.2022.03.002 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220407121608.htm

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