Thoracic aortic aneurysms and dissectionsgenetic analysis of mendelian and complex cases

Zusammenfassung

The present doctoral thesis deals with the still partially unraveled genetic component of thoracic aortic aneurysms and dissections, a frequently asymptomatic but potentially lethal condition and major cause of sudden death. Believing in the relevance of the molecular diagnosis of this disease for an anticipated clinical diagnosis and prognosis, our main objective was to contribute to further elucidate the genetics behind it, from both Mendelian and complex perspectives. The Mendelian cases we analyzed were single and familial, forensic and clinical. We looked for potentially causal genetic variants applying either candidate-gene or whole exome massive parallel sequencing approaches, respectively. When other relatives were available, either affected or unaffected, we demonstrated segregation with the disease through traditional sequencing. We were able to solve approximately 23% of the forensic single cases, and identified two strong candidate genetic variants in TGFB2 and PRKG1 genes in the two non-syndromic familial cases analyzed. For the analysis of complex cases we chose a population-based approach. We selected bicuspid aortic valve patients with and without concomitant thoracic aortic dilation, and faced them against general population controls, seeking a different distribution of risk or protective allele frequencies. We were not able to identify any consistently significant association, though a promising one arose involving HMCN2 and calcium metabolism that should be considered in future studies. Some of the results obtained in this doctoral thesis had direct clinical consequences, supporting molecular diagnosis, reliable genotype-phenotype correlations, and risk stratification as important tools for clinical management of these patients and family members at risk, as well as the need of research to continue.