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- Posted Thursday April 9, 2015
TGen scientists find likely genetic source of muscle weakness in six previously undiagnosed children
Simple genetic test by TGen reveals likely causes of disease, after other extensive testing failed; one child's case produces discovery
PHOENIX, Ariz. - April 9, 2015 - Scientists at
the Translational Genomics Research Institute (TGen),
using state-of-the-art genetic technology, have discovered the
likely cause of a child's rare type of severe muscle
weakness.
The child was one of six cases in which TGen sequenced - or
decoded - the genes of patients with Neuromuscular Disease (NMD)
and was then able to identify the genetic source, or likely genetic
source, of each child's symptoms, according to a study published
April 8 in the journal Molecular Genetics & Genomic
Medicine.
"In all six cases of myopathy, or muscle weakness, these children
had undergone extensive, expensive and invasive testing - often
over many years - without a successful diagnosis, until they
enrolled in our study," said Dr. Lisa Baumbach-Reardon, an
Associate Professor of TGen's Integrated Cancer Genomics Division
and the study's senior author.
This is a prime example of the type of "precision medicine" TGen
uses to zero in on diagnoses for patients, and to help their
physicians find the best possible treatments.
"Our results demonstrate the diagnostic value of a comprehensive
approach to genetic sequencing," said Dr. Baumbach-Reardon. "This
type of next-generation sequencing can greatly improve the ability
to identify pathogenic, or disease-causing, genetic variants with a
single, timely, affordable test."
In one of the six cases, TGen researchers found a unique
disease-causing variant, or mutation, in the CACNA1S gene
for a child with severe muscle weakness in addition to
ophthalmoplegia, or the inability to move his eyes. Properly
functioning CACNA1S is essential for muscle movement. More
specifically, CACNA1S senses electrical signals from the
brain and enables muscles to contract.
"To our knowledge, this is the first reported case of severe
congenital myopathy with ophthalmoplegia resulting from pathogenic
variants in CACNA1S," said Dr. Jesse Hunter, a TGen Senior
Post-Doctoral Fellow, and the study's lead author.
Learning the specific genetic cause of symptoms is a key step in
finding new therapeutic drugs that could treat the patient's
disease.
In another closely related case, TGen's genetic testing found a
pathogenic variant in the RYR1 gene in a case of calcium
channel myopathy. When the brain sends an electrical signal,
CACNA1S opens the RYR1 calcium channel flooding
muscles with calcium and causing them to contract. When either
partner of this duo doesn't function correctly, devastating muscle
weakness results.
Five of the six cases involved patients under the care of Dr.
Saunder Bernes, a neurologist at Barrow Neurological Institute at
Phoenix Children's Hospital. Dr. Bernes referred all five cases to
TGen for genetic sequencing in an effort to find the causes of the
children's muscle weakness.
A sixth patient, under the care of Dr. Judith Hall at the
University of British Columbia, also underwent genetic sequencing
at TGen.
"Without this type of deep genetic analysis, we might never have
discovered the source of each of these children's disease," said
Dr. Bernes, whose young patients' previous tests included muscle
biopsies, EMG, MRI, EKG and limited gene sequencing. "Now we are in
a much better position to find new treatments for these and other
children with similar symptoms."
In three of the six cases, the children had Collagen 6 myopathies,
or weaknesses. Collagen is essential to holding together muscles,
tendons, skin, cartilage and the disks between vertebras. In all
three cases, TGen researchers identified a pathogenic variant, or
disease-causing mutation, in the COL6A3 gene, or likely
pathogenic variants in the COL6A6 gene.
In still another case, TGen testing identified the genetic culprit
of the child's muscle weakness as a pathogenic EMD variant
associated with Emery-Dreifuss muscular dystrophy. EDMD usually
results in slowly progressive weakness and muscle wasting in the
arms and legs, and causes contractures of the elbow, neck muscles,
and the Achilles tendon.
"Reporting these cases raises awareness about how often each child
with muscle disease is unique, requiring personalized medical
treatment beginning with genetic diagnosis through sequencing like
we perform at TGen." Dr. Hunter said. "This study provided answers
to families with these difficult-to-treat and rare
illnesses."
Genetic sequencing was performed at TGen's Collaborative
Sequencing Center and confirmed in federal CLIA certified clinical
laboratories.
Also contributing to this study was Barrow Neurological
Institute.
Funding for this study - Novel pathogenic variants and genes
for myopathies identified by whole exome sequencing - was
provided by the Muscular Dystrophy Association (Grant #186435), the
Flinn Foundation, the Helios Education Foundation, and the
Freeport-McMoRan Copper & Gold Foundation. This study will
continue for the next three years through a grant from the Arizona
Biomedical Research Commission.
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About TGen
Translational Genomics Research Institute (TGen) is a Phoenix,
Arizona-based non-profit organization dedicated to conducting
groundbreaking research with life changing results. TGen is focused
on helping patients with cancer, neurological disorders and
diabetes, through cutting edge translational research (the process
of rapidly moving research towards patient benefit). TGen
physicians and scientists work to unravel the genetic components of
both common and rare complex diseases in adults and children.
Working with collaborators in the scientific and medical
communities literally worldwide, TGen makes a substantial
contribution to help our patients through efficiency and
effectiveness of the translational process. For more information,
visit:www.tgen.org.
Press Contact:
Steve Yozwiak
TGen Senior Science Writer
602-343-8704
[email protected]