Inherited aortic disease: identification of novel disease genes and functional analysis of the molecular pathogenesis

• Applicant: Privatdozent Dr. Georg Rosenberger, Ph.D.
• Subject Area: Human Genetics
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 308609320

Thoracic aortic aneurysms and dissections (TAAD) account for about 1% of mortality in western countries. TAAD may occur as isolated nonsyndromic form or in conjunction with other clinical features such as in patients with Marfan or Loeys-Dietz syndrome. There is a strong genetic predisposition to TAAD. Individualized risk assessment, application of preventive measures and adequate therapy and aftercare concepts strongly depend on proper diagnosis of the underlying disease. Combined clinical and molecular genetic information is crucial for correct diagnosis. Only about half of the patients show pathogenic mutations in known disease genes, thus further heterogeneity is evident. The central goal of the project is to identify additional disease genes for TAAD. We will perform whole exome sequencing (WES) in 10 patients with TAAD and subsequent multiple exome comparison, thereby generating novel candidate genes by a genetic (but not functional) approach. We will verify novel candidate genes and already uncovered candidate genes (preliminary work) by gene panel sequencing in our cohort of 180 mutation negative patients with TAAD spectrum disorders. This concept enables a deeper view (many patients) in the phenocritical properties of a number of candidate genes. By using various molecular biological, biochemical and cell biological methods, we will analyze the pathophysiological consequences of the novel TAAD-associated mutations. This is essential in order to confirm the pathogenicity of rare sequence variants. Moreover, a better understanding of the molecular pathogenesis of TAAD may enable developing scientifically based treatment options. In our preliminary work, WES of relatives in an affected family identified CDKL1 as a novel TAAD candidate gene. We verified CDKL1 as a disease gene by uncovering another CDKL1 sequence alteration in two affected sibs in a second family. Therefore, we will start immediately with functional assays for the putative pathogenic CDKL1 protein variants. Gradually, we will include yet to be discovered and to be verified pathogenic sequence changes in our functional analyses. These studies will be adapted to the respective classes of proteins. With the ultimate goal to provide an adequate etiology-based care for patients with TAAD spectrum disorders, our proposed project covers the entire spectrum of modern human genetic research including whole exome and gene panel sequencing in clinically detailed characterized patients as well as functional characterization of pathogenic mutations.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Yskert von Kodolitsch