Scientists identify genetic defect responsible for TAR Syndrome

Universitätsmedizin Berlin in collaboration with the Sanger Institute in Cambridge and other cooperation partners in Belgium, the Netherlands and France, were able to identify a genetic defect that is responsible for the development of TAR Syndrome, a congenital malformation of the skeleton and blood. Patients with TAR Syndrome are typically born without radius bones in the forearms; those affected have foreshortened upper arms. An additional characteristic is a blood platelet deficiency. Using modern methods of gene analysis, the team was able to show that TAR Syndrome develops because of a very low concentration of a particular protein. The results of the study have been published in the scientific journal Nature Genetics.

Blood platelets are the smallest and second most common cells in blood. They play an important role in blood clotting by attaching to the tissue surrounding a damaged blood vessel, or rather sticking to each other, in order to close the injury. Additionally, they release clot-enhancing substances. Some children are born with a congenital low platelet count. The consequence is that, in most cases, the children are prone to increased bleeding that is difficult to stop. TAR Syndrome combines the platelet deficiency with a malformation of the skeleton. The genetic background of TAR Syndrome has occupied scientists for 50 years.

In 2007, the work group surrounding Dr. Harald Schulze from the Institute of Transfusion Medicine at Charité, together with the department run by Prof. Stefan Mundlos at the Institute for Medical Genetics and Human Genetics at Charité could prove that all patients with TAR Syndrome are missing a piece of DNA on the first chromosome. "However, a number of healthy parents also had this particularity, so we suspected a second genetic factor. This factor has now been identified in over 50 patients using modern "Next Generation Sequencing" methods and is located in a gene (RBM8A) from the same area that controls the production of a particular protein (Y14)," Schulze explains. Y14 is in turn responsible for the creation of blood platelets, however not for the generation of other blood cells.

Now, scientists can show that the combination of gene deletion on the first chromosome and a variant of the RBM8A gene in the same region results in the inadequate concentration of Y14 protein production in certain cells, which is ultimately the cause of TAR Syndrome development.

This breakthrough enables affected families to receive better genetic consultation. Beyond that, evidence of the mutation offers the possibility to further identify the molecular causes of the disease and to develop better therapeutic options in the future.