CHOPS Syndrome - New Genetic Disorder Found in Children
Author: Children's Hospital of Philadelphia
Published: 2015/03/03 - Updated: 2026/02/14
Publication Type: Research, Study, Analysis
Category Topic: Pediatric Disabilities - Related Publications
Contents: Synopsis - Introduction - Main - Insights, Updates
Synopsis: This research details the identification of a newly discovered genetic disorder called CHOPS syndrome, published in the peer reviewed journal Nature Genetics. The study was led by Dr. Ian D. Krantz at the Children's Hospital of Philadelphia, with co-leadership from the University of Tokyo, and was funded by the National Institutes of Health, the Cornelia deLange Syndrome Foundation, and MEXT. CHOPS syndrome - an acronym for its key symptoms including cognitive impairment, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia - was identified through exome sequencing of three unrelated children. The central finding is that mutations in the AFF4 gene disrupt the super elongation complex, a group of proteins that controls how DNA is copied into RNA during embryonic development. This is significant for families of children with complex undiagnosed developmental conditions, as it provides a definitive genetic explanation that can end prolonged diagnostic uncertainty and guide more appropriate medical monitoring. The discovery also opens potential avenues for future treatment research into this and related developmental disorders - Disabled World (DW).
Introduction
CHOPS Syndrome: Early Development Genetic Syndrome
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.
Main Content
Krantz is the senior author of the study, published online 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. "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.
Insights, Analysis, and Developments
Editorial Note: The identification of CHOPS syndrome is a good example of what modern genetic sequencing can do for families who have spent years without answers. Before this discovery, the three children in the study presented with a collection of symptoms that overlapped with Cornelia deLange syndrome but did not quite fit, leaving parents and physicians in a frustrating cycle of inconclusive testing. Now there is a name, a known genetic cause, and - importantly - confirmation that the mutation arises spontaneously rather than being inherited, meaning parents can be reassured it is extremely unlikely to affect future children. While there is no treatment for CHOPS syndrome yet, understanding that the AFF4 gene acts as a kind of master regulatory switch during early development gives researchers a concrete target to work with. For the broader rare disease community, this study reinforces a pattern that continues to play out as sequencing technology becomes faster and more affordable: conditions once dismissed as medical mysteries are steadily being given precise genetic identities, and that alone changes the trajectory of care for affected families - Disabled World (DW).Attribution/Source(s): This quality-reviewed publication was selected for publishing by the editors of Disabled World (DW) due to its relevance to the disability community. Originally authored by Children's Hospital of Philadelphia and published on 2015/03/03, this content may have been edited for style, clarity, or brevity.