Unravelling the genetic architecture of (bicuspid aortic valve-related) aortopathy
17 december 2018
UAntwerp - Campus Drie Eiken - Building O - Auditorium O7 - Universiteitsplein 1 - 2610 WILRIJK (route: UAntwerpen, Campus Drie Eiken
Prof B. Loeys, Prof A. Verstraeten & Prof L. Van Laer
PhD defence Ilse Luyckx - Faculty of Medicine and Health Sciences
Abstract (Presentation in English)
Aortic aneurysms and dissections are a major health problem, accounting for 1-2% of all deaths in the Western population. Although abdominal aortic aneurysms (AAAs) are more prevalent than thoracic aortic aneurysms (TAAs), TAAs have been more exhaustively studied over the past two decades because they have a higher heritability and affect younger individuals. TAA is also prevalent in individuals with a bicuspid aortic valve (BAV), which is the most common congenital heart defect affecting 1-2% of the population. This valve defect is characterized by two aortic valve leaflets instead of the normal three (tricuspid aortic valve, TAV). About 10-20% of the BAV-patients develop thoracic aortic aneurysm at some stage in life and they have an 8-fold increased risk of aortic dissection, typically occurring at young age. Therapies capable of preventing, stopping or reversing TAA formation are not yet available. Hence, an early diagnosis of patients with TAA and the identification of at-risk (BAV/)TAA-individuals is essential. Acquisition of improved insights into the genetic basis of TAA will help by immediately facilitating TAA diagnostics, prognostics and therapy. Moreover, it may reveal novel pathomechanisms which in the long run can advance drug development.
Gene identification in both syndromic and nonsyndromic TAA is proceeding at a rapid pace and has already pinpointed >20 genes associated with familial TAA risk. Whereas these genes explain <30% of all cases of familial TAA, their functional characterization has substantially improved our knowledge of the underlying pathological mechanisms. These new insights enable novel treatment options that are currently being investigated in large clinical trials.
The genetics of BAV-related aortopathy remains largely elusive. At present, mutations in a handful genes have been linked to the disease, explaining less than 5% of BAV/TAA patients. In this thesis, we aimed to further decipher the genetic architecture of BAV-related aortopathy by identifying novel disease genes and/or variants. Insights into the molecular landscape of BAV/TAA were pursued by looking into single nucleotide variants (SNVs), copy number variations (CNVs) and topological associated domains (TADs).
Molecular diagnoses are already being complemented with clinical information to enable the identification of genotype-phenotype correlations. Moreover, together with the advent of next-generation sequencing approaches, these genetic findings are promoting a shift in the management of patients with TAA by enabling gene-tailored interventions. In the second part of this thesis, we expanded the phenotypic spectrum of patients with TAA to improve genotype-phenotype correlations and, hence, aid genetic counselling.