The aim of the project is to research the pathogenesis of rare diseases with new diagnostic methods, which in themselves represent a paradigm shift and added value, since technological progress has fundamentally changed diagnostic efficiency in this field. In line with the goals of the International Rare Disease consortium and through the organisation of the cooperation of excellence, the aim of the project is to continue therapies. One of the main novelties of this research program is that through the synergistic coordination of the Hungarian cutting-edge research capacity it creates opportunities for the customer to further participate in domestic and international cooperation, to publish in leading journals (Q1, D1 quality) in the field and to create a number of new R & D developments. The results will provide an internationally unique opportunity to understand pathogenesis of rare diseases, to develop new diagnostic and therapeutic procedures, to integrate them into the clinic in the long term and thus to ensure the long-term sustainability of the results. A Hungarian clinical exom databank is being developed, which is essential for the design of individualised diagnostics and healing, as well as for the design of modern basic and pharmaceutical research based on genetic basis. In line with the above, the genome-level database created by the project will also support the upcoming paradigm shift of the health system, once the appropriate regulators have been established. According to this, the use of genomic data in daily healing and family planning will greatly increase therapeutic safety and reduce the incidence of serious genetic diseases. Since the intention of health policy is to develop and upload the national health information system, the data obtained from this project serve as a good pilot. In terms of the methodology of the project, the most modern molecular biological, bioinformatics, molecular genetic, biochemical, cell and stem cell biology and in vivo animal model methods, using a wide range of methodological spectrum (e.g. induced pluripotent stem cell technology, beyond the “state of the art” in vitro) achieve the intended objectives. The integration of researchers involved in basic research is also essential for successful collaboration between individual centres (rare disease care network), as their research area fits into the topic and can contribute to the optimal functioning of the clinical network with their expertise. B) A PARTICULATION OF EXECUTIVE REPUBLIC Research activities are based on three key pillars: research on pathogenesis, diagnosis and therapy of rare diseases. The research project will be implemented at the University of Szeged at the Institute of Medical Genetics of SZTE, the Center for Internal Medicine and Cardiology No. 2 of SZTE, the Children’s Clinic and Children’s Centre of SZTE, and also in Szeged at the Institute of Biochemistry and Genetics of the Hungarian Academy of Sciences, the University of Debrecen, the DE Rare Diseases Expert Centre, the Department of Clinical Genetics, and the University of Pécs at the Institute of Medical Genetics, the Institute of Medical Biochemistry and the Neurological Clinic. I. RESEARCH ON PATHOGENESIS OF RARE DISEASES I/1. Task 1: (data in brackets indicate the number of patients to be included) Knowledge of the patho-mechanism of the skin with tumour transformation (n=50) and monogenous diseases leading to sudden cardiac death (n=550). Determination of the specific mutation panel of the Hungarian population of newborn-filtered metabolic diseases (n=30). Functional examination of mutations responsible for the development of Alport syndrome (n=50). Methods: Functional assays in expression systems and in vitro cell lines, mass spectroscopic measurements and next generation sequencing platforms. Implementing institutions: Institute of Medical Genetics of SZTE, Institute of Internal Medicine and Cardiology No. 2, SZTE ÁOK Children’s Clinic and Child Health Centre, and MTA SZBK Sequencing Platform. I/2 Task 1: Functional translational research in rare forms of monogenic diabetes (n=10 mutations), monogenic syndromes (n=3 mutations) and monogenous clotting disorders (n=8 mutations). Methods: functional studies (stability, activity, enzymatics) in recombinant systems and skin fibroblasts. Implementing institutions: But Rare Diseases Expert Centre, Department of Clinical Genetics. I/3 Task 1: It is possible to functionally annotate new genes in neurogenetic diseases. Methods: conventional and new generation sequencing. Implementing institutions: PTE Medical Genetics Institute. II. DEVELOPMENTS IN THE DIAGNOSIS OF RARE DISEASES II/1. Task 1: New generation sequencing diagnostic pa