PHILADELPHIA, March 2, 2015 /PRNewswire-USNewswire/ --
Analyzing a puzzling multisystem disorder in three children,
genetic experts have identified a new syndrome, shedding light on
key biological processes during human development. The research
also provides important information to help caregivers manage the
disorder, and may offer clues to eventually treating it.
"This syndrome illuminates a very important pathway in early
human development—a sort of master switch that controls many other
genes," said study leader Ian D. Krantz, M.D., co-director of the
Individualized Medical Genetics Center at The Children's Hospital
of Philadelphia (CHOP). Krantz, a medical geneticist, is an
attending physician in CHOP's comprehensive human genetics
program.
Krantz is the senior author of the study, published online today
in Nature Genetics. His co-study leader is Katsuhiko
Shirahige, Ph.D., of the Institute for Molecular and Cellular
Biosciences, University of Tokyo, also
the home institution of first author Kosuke
Izumi.
The investigators named the disorder CHOPS syndrome, with the
acronym representing a group of symptoms seen in the affected
children: cognitive impairment and coarse facies (facial features),
heart defects, obesity, pulmonary involvement, short stature and
skeletal dysplasia (abnormal bone development).
The central research finding is that mutations in the gene
AFF4 disrupt a crucial group of proteins called the super
elongation complex (SEC). The SEC controls the transcription
process by which DNA is copied into RNA, enabling genes to be
expressed in a developing embryo. The timing of this biological
process is tightly regulated, so anything that interferes with this
timing can disturb normal development in a variety of ways.
"Because the SEC involves such a crucial process in cell
biology, it has long been a focus of study, particularly in
cancer," said Krantz. "CHOPS syndrome is the first example of a
human developmental disorder caused by germline mutations in the
SEC."
Originating in the embryo, germline mutations are passed along
to every cell in a developing organism, with harmful effects in
multiple organs and biological systems. The mutated AFF4
gene produces mutated proteins, which then accumulate and cause a
cascade of abnormalities in other genes controlled by
AFF4.
"AFF4 has a critical role in human development,
regulating so many other genes," said Krantz. "When it is mutated,
it can damage the heart and skeleton, and lead to intellectual
disability, among other effects."
The current study sequenced the exomes (the protein-coding
portions of DNA) of three unrelated children treated at CHOP for a
complex developmental disorder. All three patients had some
symptoms similar to those found in patients with Cornelia deLange
syndrome (CdLS), a rare multisystem disease long studied at CHOP.
Krantz led research that discovered the first causative gene for
CdLS in 2004.
The research team's DNA analysis and studies of gene expression
patterns determined that the new syndrome is genetically distinct
from CdLS, even while sharing some common molecular mechanisms.
Although only the three children in the study are known to
definitely have CHOPS syndrome, Krantz expects diagnoses to
increase with the dissemination of this discovery and the ongoing
spread of faster, lower-cost gene-sequencing technology.
The research findings offer practical and emotional benefits for
families, said Krantz. Physicians may now order more appropriate
tests to monitor and manage specific medical issues arising from
CHOPS syndrome. "This also means families and children can end
their 'diagnostic odyssey'—the frustrating procession of tests and
unsuccessful treatments that often occurs in trying to find an
answer for families who have a child affected by a complex,
undiagnosed disorder," he added.
The researchers have shown that CHOPS syndrome is a de
novo condition—being caused by a new mutation arising in a
single egg or sperm that went on to form the affected child, but
not present in the patient's parents. Therefore, doctors can
reassure parents that this illness is extremely unlikely to recur
in any subsequent children.
Like many other rare genetic diseases, CHOPS syndrome does not
yet have an effective treatment; physicians like Krantz can only
manage the symptoms. But the research team's insight into the basic
biology of this disorder may lay the groundwork for future
treatments of this disease, and possibly others.
The National Institutes of Health (grant HD052860) supported
this study, as did the Cornelia deLange Syndrome Foundation and
MEXT, a Japanese government agency.
NOTE: To learn more about the "diagnostic odyssey" that led to
the CHOPS syndrome diagnosis, and to read a family's perspective,
visit:
www.research.chop.edu/blog/finding-new-genetic-syndrome-ends-medical-odyssey-families.
About The Children's Hospital of Philadelphia: The Children's Hospital of
Philadelphia was founded in 1855
as the nation's first pediatric hospital. Through its long-standing
commitment to providing exceptional patient care, training new
generations of pediatric healthcare professionals and pioneering
major research initiatives, Children's Hospital has fostered many
discoveries that have benefited children worldwide. Its pediatric
research program is among the largest in the country. In addition,
its unique family-centered care and public service programs have
brought the 535-bed hospital recognition as a leading advocate for
children and adolescents. For more information, visit
www.chop.edu.
"Germline Gain-of-Function Mutations in AFF4 Cause a
Novel Syndrome and Functionally Link the Super Elongation Complex
and Cohesin," Nature Genetics, published online March 2, 2015. http://doi.org/10.1038/ng.3229
Contact: John Ascenzi
The Children's Hospital of Philadelphia
(267) 426-6055
Ascenzi@email.chop.edu
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SOURCE The Children's Hospital of Philadelphia