Thesis topic proposal
Róbert Sepp


Institute: University of Szeged
theoretical medicine
Graduate School of Multidisciplinar Medical Scienses

Thesis supervisor: Róbert Sepp
Location of studies: 2nd Department of Internal Medicine and Cardiology Center, University of Szeged
Abbreviation of location of studies: ÁOK

Description of the research topic:

Background: Ion channel diseases, or channelopathies, are diseases arising from genetic mutations affecting ion channels of the heart. These diseases are best exemplified by the long QT syndrome (LQTS), Brugada syndrome (BrS) or catecholaminergic polymorphic ventricular tachycardia (CPVT). The prototype of ion channel diseases is the long QT syndrome (LQTS) which is characterized by an abnormally prolonged QT interval and, usually, by stress-mediated life-threatening ventricular arrhythmias. Since the discovery of the primary LQTS genes of potassium (KCNQ1 and KCNH2) and sodium (SCN5A) channels at least 13 LQTS genes have been reported, all encoding different ion channels or ion channel related proteins.
The Cardiology Center, University of Szeged has a long-standing interest in familial cardiac diseases, in ion channel diseases and cardiomyopathies in particular. With regard to ion channel diseases the group described the first congenital long QT syndrome in Hungary back in 1972. Molecular genetics to investigate ion channel diseases has been first applied at this institution in Hungary. We were also the first group in Hungary in establishing a molecular genetic laboratory for successful identification of disease causing mutations in long QT syndrome (KCNQ1, KCNH2, KCNE1 genes) and Andersen-Tawil syndrome (KCNJ2 gene). Parallel to this, foundations of a biobank have been laid down as we have been collecting blood samples from patients with different forms of ion channel diseases and cardiomyopathies. Up to now, the biobank contains blood samples from about 150 families with LQTS or other ion channel diseases, and the number of biobanked samples are increasing continuously.
Aims: We aim to establish genotype-phenotype correlations in a large cohort of genotyped patients with ion channel diseases. Our preliminary results provide evidence that many patients carry more than one rare variant of multiple ion channel genes which may alter clinical phenotype. Analyzing genotype-phenotype correlations, we found trend like differences indicating that the presence of multiple variants or variants with a dominant effect (i.e. definite causative mutation) may lead to more severe form of the disease in LQTS patients. The average corrected QT interval (QTc) showed a trend to increase in mutation carriers with multiple variants and the magnitude of QTc prolongation tended to correlate with the number of identified variants. Also, the average age at the time of first symptoms were lower in carriers of a causative mutation or if they carried multiple variants. Genotype-phenotype correlations will be searched for main clinical variables of ion channel diseases.

Required language skills: English
Number of students who can be accepted: 1

Deadline for application: 2017-04-15

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