Sonia Van Dooren
Co-promotors: Willy Lissens, Sara Seneca, Maryse Bonduelle, Pedro Brugada
Unravelling the molecular genetic pathways of Brugada syndrome by a next generation sequencing approach
Cardiac arrhythmias are world-wide one of the leading causes of morbidity and mortality. Although environmental factors clearly contribute to the determinants of arrhythmogenesis, familial and population studies both have proven major evidence of genetic susceptibility. Congenital primary cardiac arrhythmias comprise a distinct group of cardiac disorders that result from defects in electrical properties of the heart. The coordinated cardiac activity includes the process of synchronised and successive opening and closing of ion channels in response to the electrical gradient and mediates the action potential in each cardiac compartment. Mutations in genes that either encode or regulate specific cardiac ion channels underlie different forms of inheritable arrhythmogenic disorders that occur in structurally normal hearts. One of common forms is Brugada syndrome (BrS), inherited as an autosomal dominant trait with variable penetrance and expression. The BrS is characterised by coved type ST elevation on the ECG and increased risk of lethal ventricular arrhythmias. One of the proposed mechanisms underlying the typical saddleback and coved-type ECG morphology is the ionic imbalance between inward sodium and calcium currents (INa and ICa) and transient outward potassium currents (Ito) during phase 1 of the cardiac action potential. Although many functional analyses have aided in better understanding the basic arrhythmogenic mechanism of BrS, genetic studies partly fail to further unravel this. Several research groups describe loss-of-function mutations in the gene encoding the pore-forming ion-conduction -subunit of the sodium channel (SCN5A). However, they account for only 20% of Brugada syndrome patients diagnosed following well established rules. Rare mutations have been reported in 2 of the 4 auxiliary function-modifying -subunits of the sodium channel (SCN1B and 3B) and in a panel of recently associated genes (GPD1L, KCNE3 and HCN4).
The recent technological advances in molecular genomics would allow us to study several proposed and new candidate genes to even the exome in parallel, thereby primarily focusing on proteins involved in INa, ICa and Ito of phase 1 of the cardiac action potential. This next generation sequencing approach has the major advantage of detecting compound and double mutations and/or polymorphisms, which might play a crucial role in the observed reduced penetrance and expressivity. The impact of the discovered mutations and/or polymorphisms will be on the one hand correlated phenotypically and on the other hand further studied in vitro at the transcription and expression level as well on the electrophysiological level.
Clinical practice will greatly benefit from the extrapolation of our mutational analyses and in vitro studies. They will have a substantial impact on patient management, in particular prevention, risk stratification, (presymptomatic, prenatal and pre-implantation) diagnosis and treatment and stratification of subclasses of patients.
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