http://www.research.chop.edu/blog/finding-new-genetic-syndrome-ends-medical-odyssey-families/
New Genetic Syndrome Found, Arising From Errors in ‘Master Switch’ During Early Development
CHOPS Syndrome Sheds Light on Key Events in Human Biology
Released: 27-Feb-2015 11:00 AM EST
Embargo expired: 2-Mar-2015 11:00 AM EST
Source Newsroom: Children’s Hospital of Philadelphia
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Nature Genetics, online March 2, 2015; HD052860
Newswise — Philadelphia, March 2, 2015 –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.
Note: After the embargo ends, see this blog posting about the “medical odyssey” experienced by families of children with this syndrome: http://bit.ly/1wE6f08
The National Institutes of Health (grant HD052860) supported this study, as did the Cornelia deLange Syndrome Foundation and MEXT, a Japanese government agency.
“Germline Gain-of-Function Mutations in AFF4 Cause a Developmental Syndrome Functionally Linking the Super Elongation Complex and Cohesin,” Nature Genetics, published online March 2, 2015. http://doi.org/10.1038/ng.3229
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www.research.chop.edu/blog/finding-new-genetic-syndrome-ends-medical-odyssey-families.
Finding New Genetic Syndrome Ends Medical Odyssey for Families
Individualized Medical Genetics Center at CHOP, The Children’s Hospital of Philadelphia by Research Communications
LETA_DNA
At 3 foot 8 inches, 66 pounds, Leta Moseley is a tiny teenager with a big personality.
At 3 foot 8 inches, 66 pounds, Leta Moseley is a tiny teenager with a big personality. Seventeen years ago, her family embarked on a medical odyssey in search of a diagnosis for Leta, who has cognitive disabilities, speaks only a few words, and has lung disease and heart irregularities. A bad virus can land her in The Children’s Hospital of Philadelphia (CHOP) for several weeks, at times on a ventilator for breathing support. Yet, when she is healthy, Leta can take over a dance floor with her swirls and smiles.
CHOP medical geneticist and researcher Ian Krantz, MD, has been a tireless detective in his efforts to find out what genetic anomaly could be behind Leta’s constellation of symptoms. She had many characteristics in common with his patients with the rare multi-system disorder Cornelia de Lange Syndrome that Dr. Krantz has long studied. But her clinical features weren’t a perfect fit for this diagnosis, and genetic testing for Cornelia de Lange syndrome was negative. Dr. Krantz, Director of the Individualized Medical Genetics Center at CHOP, took Leta’s clinical history and photos all over the world with him to genetic conferences, in hopes of finding other children who shared Leta’s profile.
Over the past 10 years, Dr. Krantz and his team identified two other unrelated children (who live less than 200 miles away) with clinical features that seemed to match Leta’s. Using samples from all three children, his research team made the groundbreaking discovery “back home” in the genetics lab at CHOP. With the help of a breakthrough in sophisticated gene-sequencing technology that became available two years ago, they analyzed the protein-coding portions of DNA (exomes) and identified mutations in the AFF4 gene in Leta and the other two children. In genetic research, this is the equivalent of finding a needle in a haystack.
“This is a great example of how families and their doctors work together over many years to find answers and advance both science and the care of their children,” Dr. Krantz said. “Although it has been a long road to get to this point, it is really just the beginning, and we still need to work closely with the families to fully understand the significance of this discovery and how best to use this information to take better care of Leta and other children with this diagnosis.”
After years of mystery and misdiagnoses, Leta’s family finally has a name for her disorder — a new diagnosis called CHOPS syndrome. The acronym stands for the group of symptoms seen in the three affected children: Cognitive impairment and coarse facial features, Heart defects, Obesity, Pulmonary involvement, Short stature and skeletal dysplasia (abnormal bone development).
As this novel finding is disseminated in a Nature Genetics report, Dr. Krantz expects that CHOPS syndrome may be the answer for other parents around the world who have been on a hunt for their child’s complex, undiagnosed genetic disorder. They may find reassurance that CHOPS syndrome is a de novo condition — which means that it resulted from a new mutation arising in a single egg or sperm that went on to form the affected child but is not present in the patient’s parents — so it is unlikely to recur in any subsequent children.
“Ending the ‘diagnostic odyssey’ for families has a profound psychological effect, allowing for closure and an understanding of how all of these myriad clinical differences in their child are linked to a single underlying cause,” Dr. Krantz said. “It also ends a very expensive search for an answer often with many unnecessary diagnostic tests and blood draws. It allows us to find other children and adults with the same condition that in turn gives us a better understanding of the clinical issues and best options for management and to provide some idea of prognosis for families. We can more effectively counsel families about recurrence risk for themselves and family members. Most importantly, understanding the underlying molecular basis for the clinical findings in their children is the first step towards identifying targeted therapeutics in the future.”
In this interview, Leta’s mom, Lainey Moseley, described her family’s steadfast love for Leta along their unpredictable journey to the discovery of CHOPS Syndrome:
Q: Tell me about Leta; she seems to have quite a big personality.
A: It blows me away that so much is going on inside that little body of hers. It is so hard to really know what her potential is because we think she is brilliant and understands what is going on all the time. Yet, Leta has cognitive impairment, is nonverbal, has small stature, and she is pretty medically challenged with lung disease and pulmonary hypertension. Having said that, she does have a big personality given all her disabilities, and she endlessly amuses us with her antics. Life with Leta is chaotic and far from normal — the highs and lows are so extreme — but she gives us so much love in return. I cannot imagine our life without her.
Q: When you describe your search for a medical diagnosis for Leta as a “medical odyssey,” what does that mean to you?
A: Like everyone else, we really wanted to have a healthy child. We realized early on that Leta wasn’t hitting her milestones, and at one year old she was diagnosed with lung disease, but for 16 years no genetics doctors were able to give us a definitive genetics diagnosis. After many years, we gave up caring about a diagnosis; a label wasn’t going to alter the course of Leta’s life. But it was still unsettling not knowing how her disabilities were going to unfold. What was her lifespan going to be? Was the lung disease going to be a degenerative condition? We had no idea what her capacity was for learning or speaking. When you don’t have a diagnosis, you don’t know the end game or what to expect.
Q: How did you feel when Dr. Krantz told you that he had found this genetic glitch in Leta’s exome?
A: When Dr. Krantz called and told us that he had identified her gene mutation and that he actually had found two other kids like Leta, it was beyond exciting. I was so curious what these two other little kids, Liam and Nadira, would look like. Leta is so unique. It was hard to imagine that there were two other people in the world just like her. But the discovery also became important for other reasons. On an emotional level, when I found out her dad and I were not carriers of the AFF4 gene mutation, I realized that Leta’s medical issues were not my fault. All those years, I carried the burden that maybe I had done something wrong in my pregnancy that caused Leta’s genetic condition. A diagnosis let me off the hook of blaming myself. There’s nothing that I could have done differently to prevent it. This was just a random act of nature. That was a big turning point for me.
Q: So far, two other families are known to have the same genetic mutations as Leta. Why is it important for you to have this new connection?
A: It is important because we share a medical bond and now have a support group to compare notes about our kids, like what medicines are the doctors prescribing for their lung disease? What kind of communication devices do we each use? Does your child have the same hyperactive personality as mine? They are all so much alike, it is now almost like having triplets. I really am looking forward to getting to know Liam’s and Nadira’s families better. Having them in my life makes me feel so much less alone in my journey with Leta. Liam’s mom and I have become Facebook friends, and she was with me every step of the way praying for Leta when she was in the hospital last month on a ventilator.
Q: Overall, how has your experience been being part of Dr. Krantz’s research team?
A: The whole team has been phenomenal and so wonderful. They have been really supportive by keeping us informed about the ongoing AFF4 research. The genetics team is organizing a lunch next month so that our families can finally get together as a group. We’ve already learned that the research into the condition that Leta, Liam, and Nadira share could be groundbreaking in genetics and possibly lead to understanding roots of other genetic mutations. So that’s pretty exciting when it’s your child who is on the ground floor of that breakthrough. We’ve always thought that Leta is a superstar, but now she is a trailblazer in genetic research, giving other kids the chance to be born healthy.
Editor’s Note: For more information on how CHOPS syndrome sheds light on key events in human biology, read the press release. Also, learn more about Leta by reading the blog http://savingleta.com/written by her mom, Lainey.
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