Marcelo Kauffman He is a specialist in Molecular Genomics and a member of the Scientific Research Programs at CONICET (National Council for Scientific Research) and the Health Research Council of the Government of the City of Buenos Aires. He earned his doctorate and master's degrees from the University of Buenos Aires and the Pablo de Olavide University in Spain.
He directs the Neurogenetics Clinic and Laboratory at the JM Ramos Mejía Hospital, units he created 10 years ago, and since last year, he has directed the Precision Medicine Program and Service at the Austral University Hospital. He is also a visiting researcher at the James J and Joan A Gardner Center for Parkinson's Disease and Movement Disorders at the University of Cincinnati, where he is a consultant for the neurogenetic diagnostic program for movement disorders.
He has actively worked in the diagnostic assistance of hundreds of patients with rare neurogenetic disorders and, together with his research group, has developed different molecular genetic diagnostic strategies based on classic and new generation techniques that have allowed the etiopathogenic individualization of hundreds of patients affected by these disorders, as well as the communication of diverse etiologies for the first time in our country.
Adjunct Professor of Clinical Genomics at the Faculty of Biomedical Sciences of the Universidad Austral and Authorized Professor of Neurology at the Faculty of Medicine of the University of Buenos Aires, has received clinical and scientific awards and is the author of more than 40 articles in international journals, mainly in the field of neurogenetic diseases and has received funding from public and private science and technology sources.
Numerous human health disorders are caused by genetic defects. In the last 30 years, the monogenic causes of approximately 5000 diseases have been identified. Notable developments in the field of genomics have occurred in the last five years. This has made it possible to obtain complete human genome sequences almost routinely at numerous centers and laboratories on both sides of the Atlantic and the Equator. Advances in clinical genomics over the last five years have allowed for the identification, week after week, of dozens of new genes as etiological factors in numerous disorders. Although each of these monogenic disorders should be considered within the realm of rare or infrequent diseases, it is plausible to postulate that the knowledge derived from the pathophysiological mechanisms that can be recognized by identifying these rare genetic causes could be common and useful in the research and therapeutic development of the more prevalent non-familial variants of these pathologies.
On the other hand, Medicine is moving towards the personalization of healthcare practice. In particular, in complex cases in diagnostic terms, it is worth considering the development of an individual diagnostic/therapeutic algorithm for that patient, not in terms of what studies to request, but in terms of the interpretation of the vast information obtained, if, as seems to be the case, genomic studies constitute a first diagnostic step to follow in the near future and not a final or distant one as could be considered in the recent past.
The Research and Assistance Program in Precision Medicine and Clinical Genomics aims to position itself as an interdisciplinary group of excellence and advancement in the country and the region, dedicated to the diagnostic assistance of a group of patients affected by pathologies that, due to their low prevalence, have often been neglected, being able to bring to these patients and their families the highest and most individualized diagnostic technology available in the field of genomic medicine.
To achieve this, our working group proposes to:
Studying the causative agents of epilepsy is important for global public health. Cortical developmental malformations (CDMs) are a prominent cause of treatment-resistant epilepsy. Many of these are caused by germline mutations, and somatic mosaicism has also been described.
However, detecting genetic mosaicism in MDCs is difficult to observe in all tissues, making the development of specialized methodologies crucial. Furthermore, somatic mutations have been described in genes belonging to the rapamycin-regulated pathway (mTOR), whose aberrant activation can cause dramatic effects on cortical development. This could present a significant translational opportunity, given that rapamycin use appears to attenuate the epileptic phenotype in a murine model of mTOR pathologies.
Objectives: The aim of this project is to identify etiopathogenic somatic mutations in brain tissue and leukocytes, in genes involved in neurodevelopment, in a population of patients with epilepsy secondary to MDC. Furthermore, we propose to explore the use of genomic, bioinformatic, and single-cell sequencing techniques for the characterization of somatic mutations in neuronal cells.
Activities and methodology: Patients with hemimegalencephaly, megalencephaly, focal cortical dysplasia, periventricular heterotopia, band heterotopia, polymicrogyria, and lissencephaly will be included. Peripheral blood and brain tissue samples will be obtained. A panel of candidate genes (including mTOR pathway genes) will be designed and studied to identify somatic mutations with mosaicism greater than 5% using high-coverage next-generation sequencing (NGS). Various bioinformatics tools will be used to process the genomic information. Mosaicisms less than 30% or greater than 70% will be validated by subcloning.
Finally, we will explore the cellular characterization of mosaic cells using single-cell NGS. To do this, we will isolate individual neuronal nuclei by FACS, obtain sufficient genomic DNA through whole-genome amplification by MDA, and construct sequencing libraries. Originality: This study, which employs genomic tools to search for therapeutic targets for pharmacology, will be pioneering since there are no reports of somatic mutations in MDC in a Latin American population.
Hereditary ataxias are a clinically and genetically heterogeneous group of neurodegenerative diseases that cause severe disability and, together, represent one of the most frequent reasons for consultation in Clinical Neurogenetics.
More than 50 subtypes of hereditary ataxias are known, defined by the etiopathogenic molecular defect, and are not always distinguishable in their phenotypic characteristics, even among those that share alterations in the same gene. This genetic heterogeneity explains why their molecular diagnostic approach is not simple, while the phenotypic variability suggests that other factors, beyond the monogenic etiology, may play a modifying role.
On the other hand, although numerous genes involved in the etiopathogenesis of Ataxias have been recognized, various epidemiological studies agree in estimating that in no less than 40% of Hereditary Ataxias, the etiology is still unknown.
Recent years have shown how new massive DNA sequencing techniques have revolutionized the practice and medical possibilities of genetics. In particular, these methodologies make multigene studies feasible for diagnosing heterogeneous disorders, discovering new etiopathogenic candidates in a fraction of the time and cost that similar approaches required not long ago, and decoding regions of the genome inaccessible to previous techniques.
Following a working hypothesis that posits that the use of novel genomic sequencing techniques will be useful to facilitate the recognition of the etiologies and genetic modifying factors of Hereditary Ataxias, we propose as the general objective of the project, then, to contribute to the knowledge of the mechanisms involved in the genesis of Hereditary Ataxias, particularly, achieving the identification of etiopathogenic mutations and genetic modifying factors in a population of patients affected by them, through the synergy of advanced technologies in the fields of genomic sequencing and bioinformatics applied in a health center for the development of Translational Genomics and Bioinformatics in the Country.
