Genetics and Genomics by Universidad del Desarrollo

GENETICS AND GENOMICS

MOVING TOWARDS PERSONALIZED GENOMIC MEDICINE

A group of educators from the Faculty of Medicine of the Clinica Alemana – Universidad del Desarrollo, motivated by their vast experience in genetic research, in laboratory, as well as in clinical work, decided to open the Center of Genetics and Genomics (CGG) with the aim of comprehending and utilizing information regarding the genetic contribution to illnesses. The center counts with the a valuable team of specialists, beginning with the director doctor Gabriela Repetto, geneticist and specialist in Chromosome 22 studies, along with Sonia Margarit, genetic counselor that works on breast and ovarian cancer and who joined the team in the year 2004, and nurse María Luisa Guzmán, who has developed a family oriented stimulation program for children with Down Syndrome at the Padre Hurtado Hospital. Currently, the center´s staff consists of more than ten specialists dedicated to investigation, clinical work and molecular diagnosis. The members of the center have raised researching funds through more than twenty projects which have been awarded outside competitive funding. Six correspond to the competitive funding from the National Fund for Scientific and Technological Development (Regular Fondecyt), three of which are in course of execution, one project awarded competitive funding from the National Fund for Health Research and Development (FONIS) and two NIH (Hantavirus and deletion 22q11). In addition, the center collaborates with an Inter-Faculty project and a Anillo en Ciencias Sociales, with investigators from the Universidad del Desarrollo`s Faculty of Government. These competitive funds represent a total amount of US$2.5 million. The results of these investigations have been published in approximately 40 indexed scientific journals, reaching an ISI impact factor of over 180 points.

STATE OF THE ART RESEARCH STATE OF THE ART RESEARCH

The first project awarded to the center corresponds to the Regular Fondecyt, aimed at identifying the modifying factors that take part in the manifestations product of the loss of chromosomal material, from chromosome 22, also known as Velocardiofacial Syndrome. Chromosome 22q11 Deletion Syndrome is the most common chromosomal defect after the Down Syndrome. In Chile, an estimated 4,000 people are affected by Chromosome 22q11 Deletion Syndrome, but only an approximate 10% of the expected cases have been diagnosed. Some of the manifestations of this genetic disorder include congenital heart disease and the submucous cleft palate, learning disability and recently, it has been found that 25% of these persons can develop schizophrenia. Research dealing with the psychiatric and cognitive aspects of this genetic disorder is being executed by an International Consortium of twenty two centers that are principally located in Europe and North America, and the UDD Center of Genetics and Genomics is among these centers and represents the sole South American participant. The investigators at the CGG also participate with clinicians from the Luis Calvo Mackenna Hospital, Roberto del Río Hospital and the Gantz Foundation, among others. The center periodically organizes scientific meetings and the dissemination of information for the families that have a member with this genetic condition, and in this way inform them of the latest worldwide developments and results of research in this area. The year 2008, the center already counted with a laboratory implemented with leading edge devices and instruments, and a qualified staff specialized in different areas. This permitted them to open a new field of genetic exploration focused on cancer. With the arrival of new researches like doctors Annemarie Ziegler and Rebeca Graumann, a new line of investigation concerning biomarkers for cancer began. On the other hand, doctors Ziegler and Mario Fernandez (urologist at

the Clinica Alemana and a collaborator at the center) are establishing common lines of cancer research with the University of Heidelberg in Germany. Another important investigation that is being executed since the year 2010 by Doctor Cecilia Vial and the Hantavirus Program, involves the study of the genetic factors of the virus and the human host. The center is also developing studies that intend to detect the loss or profit of genetic material that could be causing cognitive impairment or congenital disorders. This project, headed by Doctor Guillermo Lay-Son in collaboration with investigators from the Faculty of Medicine of the UDD and the Pontifical Catholic University, includes the cost-efficiency study of the new genomic diagnostic tools. The center also collaborates with the Debra Foundation, dedicated to treating children with Epidermolysis Bullosa, otherwise known as “Crystal Skin Children” in South America. The projects, headed at the foundation by Doctor Ignacia Fuentes, are designed to improve the disease`s diagnostic methods.

BIOSOLUTIONS, GENETIC LABORATORIES SERVICES Today, genetic testing services provide diagnostic and predictive capacity for some diseases. Thanks to the solid experience achieved by the laboratory staff (Karena Espinoza and Felipe Benavides), as well as the availability of advanced equipment in this matter, the Center of Genetics and Genomics participates in BioSolutions, an entity created by the Faculty of Medicine of the Clinica Alemana – Universidad del Desarrollo, that offers diverse testing services in this area. During the year 2013, over 700 tests of this type were performed. This laboratory studies conditions like myotonic dystrophy, cystic fibrosis, lactose intolerance and Huntington disease,

among others. For the moment, the tests do not count with health insurance coverage and must be paid by the persons that are interested, this being a very important limitation that affects the access to this service.

NATIONAL AND INTERNATIONAL NETWORKS

PROGRESS IN BIOINFORMATICS In order to be able to make a thorough and agile analysis of the genetic data and to handle the great amount of information generated by these genomic studies (“Big Data”), information technology support is required. For example, a specialized tool that is able to integrate computer and biological knowledge at the same time. For this reason, in the year 2012, the investigator Luis León, biochemist with a solid experience and specialization in bioinformatics, joined the center´s staff. He has led the difficult task of connecting the biological data and computers.

The Center of Genetics and Genomics of the Universidad del Desarrollo`s Faculty of Medicine collaborates and interchanges information with different internationally relevant centers. Among these are the Institute for Molecular Systems Biology, Zurich; the Albert Einstein College of Medicine and the International Consortium on 22q11 deletion. The specialists additionally participate in directories of national scientific societies: The Chilean Pediatrician Society and the Chilean Genetic Society. In synthesis, the center established and developed itself as a “bedside – to – bench - to bedside” research center, where clinical questions converge from the treatment of patients and laboratory investigations related to genetic illnesses. This interaction later returns to the clinic in the form of diagnostic or predictive tests, or as contributions to the comprehension of the mechanisms of these diseases.

LINES OF INVESTIGATION

· Chromosome 22 Microdeletion Syndrome or Velocardiofacial Syndrome: clinical characterization to optimize the supervision of the health of patients and to search for modifying factors that can explain the ample phenotypic variability of this condition. · Cystic Fibrosis: identification of the mutations that cause this illness in Chile, in order to optimize the molecular diagnosis of the Chilean patients and their families. · Genetic Counseling in hereditary cancer: characterization of the impact and motivations of the high cancer risk families in relation to the pre-symptomatic diagnose and the options of prevention. · Down Syndrome: the study of incidence, morbidity and mortality of patients at the Padre Hurtado Hospital, and the impact of a family-centered stimulation program. · Tumor Biomarkers: the identification and study of the biology of potential candidates for an early diagnosis of ovarian cancer. Genetic susceptibility to develop bladder cancer. · Genetic factors that are modifying genetic factors for common illnesses: study of genetic variants that increase the susceptibility to or the severity of an illness, as in the case of infection by Hantavirus. · Assessment of the cost-effectiveness of new genomic tests for persons with congenital disorders and cognitive disability. For more information visit: http://medicina.udd.cl/centro-genetica-genomica/

The center established and developed itself as a research center, where clinical questions converge from the treatment of patients and laboratory investigations related to genetic illnesses.

RESEARCH TEAM DIRECTORA Gabriela Repetto, M.D, Genetic and Metabolic Diseases subspecialist, Children’s Hospital Boston, Harvard University. INVESTIGATORS - Annemarie Ziegler, PhD in Biochemistry University of Basilea and Freidrich Miescher Institute in Switzerland. - Rebecca Graumann, PhD in Biomedical Sciences, Universidad de Chile. - Cecilia Vial, PhD in Biological Sciences, Pontificia Universidad Católica de Chile. - Luis León, PhD in Biological Sciences, Pontificia Universidad Católica de Chile. - Ignacia Fuentes, PhD in Molecular Physiology, University of Potsdam and Max Planck Institute in Germany.

CLINICAL INVESTIGATORS - Sonia Margarit, Master in Human Genetics for the Sarah Lawrence College of Nueva York. - María Luisa Guzmán, Nurse Midwife, Pontificia Universidad Católica de Chile. - Guillermo Lay-Son, M.D., Master in Medical Sciences, Universidad de Chile. - Mario Fernández, M.D., PhD in Medicine, University of Heidelberg in Germany. CLINICAL INVESTIGATORS - Karena Espinoza - Felipe Benavides - Christina Liao. CENTER ASSISTANTS Medical, Dentistry and Medical and Clinical Laboratory Technology students.

Back row, from left of right: María Cecilia Vial, Annemarie Ziegler, Rebecca Graumann, Mario Fernández, Sonia Margarit, Gabriela Repetto. Middle row, from left of right: Jimena Ovalle, Karena Espinoza, Felipe Benavides, Ruth Pérez, María Luisa Guzmán, Guillermo Lay-Son. Bottom row: Ignacia Fuentes, Luis León.

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UNIVERSIDAD DEL DESARROLLO The UDD`s concept of research is the academic activity that searches for new knowledge that will meaningfully impact the discipline, subject or specific area that is being investigated. The hallmark of the investigations performed at the UDD is the realization of studies with a scientific base; oriented towards the comprehension and resolution of relevant and current problems affecting society; associated to undergraduate and postgraduate teaching with emphasis on the specific fields of knowledge. We believe that the formation of research centers should be the foundation for the development of meaningful investigations that generate expert competence and relevant outcomes. For these reasons, the research funding policy prioritizes the formation of solid lines of investigation or the development of specific topics. The quality of our investigations is supported by the constant increase of external funding awarded to our projects by national and international competitive funding agencies, and also with the increasing volume of indexed scientific publications, as well as the publication of books and book chapters in highly specialized editorials.