engleski

Novel arrhythmia-related mutations in Croatian arrhythmia patients

Purpose: Inherited cardiac arrhythmias are life-threatening syndromes that often occur in young people and are characterized by palpitations, syncope, and an increased risk of sudden death. The etiology can be ion-channel dysfunctions as well as structural heart disease. Common features are single gene mutations that produce the dysfunction, an autosomal-dominant inheritance, incomplete penetrance and variable expressivity. Inherited arrhythmias show marked genetic heterogeneity having multiple types and sites of mutation. Common polymorphisms that are usually harmless or result in arrhythmia only under certain conditions (e.g. drug intake) have also been described. Genetic testing is particularly useful as support of the clinical data and in the identification of mutation-carriers that are asymptomatic but may be at risk. We have sought to identify the genetic mutations associated with inherited arrhythmia disorders in a Croatian group of patients and in their relatives in order to identify pathogenic mutations and possible asymptomatic carriers. Methods: We have analyzed the DNA from 13 unrelated Croatian patients (69% male, 30 ±12 years) and close relatives with arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), long-QT-syndrome (LQTS) or Brugada syndrome (BrS). Only definite diagnoses based on clinical data were accepted. Arrhythmia-related genes were analyzed by polymerase chain reaction (PCR) followed by direct sequencing in the exons and exon-intron boundaries. The control population included 200 healthy Croatian individuals. Results: We report a number of novel variants related to disease including: one novel missense mutation in an ARVC case (DSP: E1265X), four novel variants for HCM (MYH7: p.K206E, MYBPC3: p.S1067fsX1073, MYBPC3: c.772+1G>A, MYBPC3: p.Y1251C), and one missense mutation in a BrS patient previously described in atrial fibrillation (KCNE3: p.R53H). The mutations were all absent from the controls. Conclusions: Genetic investigations of arrhythmia patients and the discovery of novel variants are important as they increase our knowledge and understanding of the genetic heterogeneity of arrhythmias, providing us with valuable information for better patient management. The Croatian population is poorly characterized genetically and initial studies might be expected to reveal a particularly high number of novel variants. Indeed, in our study we find that 6 out 10 mutations identified are novel indicating that further investigations might discover a great number of new disease-associated variants.

cardiac arrhythmias; sudden death; gene mutations

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