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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 developmenta 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 Childrens Hospital of Philadelphia (CHOP). Krantz, a medical geneticist, is an attending physician in CHOPs 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.

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New Genetic Syndrome Found, Arising From Errors in 'Master Switch' During Early Development