Arrhythmogenic Diseases Gene Panel
Dr. rer. nat. Christoph Marschall
Arrhythmogenic diseases include both primary arrhythmia syndromes, i.e. disorders of the ion channels of the heart muscle, and cardiomyopathies with risk of arrhythmia. The three most common ion channel disorders are the Long QT syndrome (LQTS), the Brugada syndrome (BrS) and the catecholaminergic polymorphic ventricular tachycardia (CPVT). Among the cardiomyopathies, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) as well as arrhythmogenic right ventricular cardiomyopathy (ARVD) are of particular significance. Most forms follow an autosomal dominant inheritance pattern with incomplete penetrance and varying severity. The major causative genes have been known for several years. Genetic diagnostics is considered reasonable in most cases (see Ackermann et al, Europace 13:1077, 2011) and is used frequently to confirm diagnosis; however, it may also be of prognostic or therapeutic significance. In the case of ion channel disorders, targeted analysis of relatives is of great use, once the causative mutation has been identified in the index patient. Due to therapeutic consequences, predictive diagnostics is also recommended for minors without restriction. In the case of cardiomyopathies, however, the indication for predictive diagnostics should be considered thoroughly during genetic counseling, especially in the case of minors. It may on the one hand be helpful for the interpretation of some mutations to check the segregation in the family. On the other, the detection of a mutation is rather burdening due to the limited possibilities of treatment (exception: DCM with LMNA mutation).
The molecular diagnostics of all arrhythmogenic diseases available here is based on DNA sequencing of all genes known to cause the diseases. Analysis and evaluation of the results is carried out step-wise and based on indication. During the last few years, the number of genes associated with arrhythmogenic diseases has increased significantly. However, in the case of ion channel disorders (LQTS, BrS, CPVT) and ARVD, 90-95% of all mutations are located in a few major genes. In order to achieve the highest diagnostic sensitivity possible, it may therefore be more reasonable like in the case of LQTS to test the major genes KCNQ1, KCNH2 and SCN5A for large deletions as well instead of analyzing every known gene. In addition, the analysis of rarely affected genes frequently brings about unclear results or incidental findings. As a consequence, the current recommendations for diagnostic procedures frequently focus on the major genes. In contrast to the ion channel disorders, the causes of HCM and DCM are still more heterogeneous. NGS is of value here: it enables the analysis of currently more than 50 cardiologic relevant genes at the same time within one approach. This also includes titin, which is the largest human gene and is thought to be causative for DCM in approx. 25% of all cases. However, interpreting NGS results still represents a significant challenge. For instance, validation of TTN mutations through segregation analysis is currently necessary. Therefore, this gene should possibly only be analyzed in large families with several affected members. The use of NGS is of advantage in some cases of ion channel disorders, if differential diagnosis is difficult and multiple diagnoses are under consideration.
All coding exons and their flanking intronic sequences from the genes in the arrhythmogenic diseases gene panel are analyzed either by Sanger sequencing or by next generation sequencing (NGS).
Abriel et al, Gene 517:1 (2013) / Beckmann et al, pädiat prax 80:31 (2013) / Campuzano et al, J Med Genet 50:280 (2013) / Sikkema-Raddatz et al, Human Mutat online April (2013) / Kaufman et al. JACC 60:1419 (2012) / Herman et al, N Engl J Med 366:619 (2012) / Ackerman et al, Europace 13:1077 (2011) / Tester et al, Am J Cardiol 106:1124 (2010)