Practical Aspects in Genetic Testing for Cardiomyopathies and Channelopathies

Abstract

Genetic testing has an increasingly important role in the diagnosis and management of cardiac disorders, where it confirms the diagnosis, aids prognostication and risk stratification and guides treatment. A genetic diagnosis in the proband also enables clarification of the risk for family members by cascade testing. Genetics in cardiac disorders is complex where epigenetic and environmental factors might come into interplay. Incomplete penetrance and variable expressivity is also common. Genetic results in cardiac conditions are mostly probabilistic and should be interpreted with all available clinical information. With this complexity in cardiac genetics, testing is only indicated in patients with a strong suspicion of an inheritable cardiac disorder after a full clinical evaluation. In this review we discuss the genetics underlying the major cardiomyopathies and channelopathies, and the practical aspects of diagnosing these conditions in the laboratory.

Role of genetic testing in cardiomyopathies: Α primer for cardiologists

“…Whole blood, dried blood spots, or tissue specimens regarding post-mortem examination could serve as acceptable specimens for genetic testing. Conventionally, genetic testing by Sanger sequencing, for individual genes has been per-formed[ 8 ]. Due to the genetically heterogeneous nature of cardiomyopathies and the development and availability of next-generation sequencing (NGS) technique in the clinical setting, a multi-gene panel instead of individual gene-testing is now desirable practice for these diseases.…”

“…Together, these techniques provide excellent precision and accuracy to detect single nucleotide substitutions that produce missense, nonsense, and splice site mutations and small insertion/deletions. A subset of cases with large insertion or deletion variants or other structural DNA changes, whereas the above analyses turn out negative, might benefit from copy number assays using microarray or multiplex ligation-dependent probe amplification[ 8 , 9 ].…”

Sudden Cardiac Death in Young Athletes: Literature Review of Molecular Basis

“…Other rare inherited arrhythmogenic diseases are short QT syndrome (SQTS), sick sinus syndrome (SSS), familial progressive cardiac conduction defect (PCCD), Haïssaguerre syndrome or early repolarization syndrome. [47][48][49] To date, more than 40 genes are implicated in cardiac channelopathies 47,64 (Appendix Table 1): the most common genes encode the cardiac sodium and potassium voltage-gated channels (Na V 1.5, K V 7.1 and K V 11.1), the L-type calcium channel (Ca V 1.2), the cardiac receptor of ryanodine (RyR2). Mutations in these genes may cause loss or gain of channel function, although mixed effects on ion channels are also reported.…”

Next-Generation Sequencing Gene Panels in Inheritable Cardiomyopathies and Channelopathies: Prevalence of Pathogenic Variants and Variants of Unknown Significance in Uncommon Genes

“…Currently, mutations in about 100 different genes are associated to HCM [ 5 , 23 ]. Nevertheless, eight main genes, MYBPC3 , MYH7 , TNNT2 , TNNI3 , TPM1 , ACTC1 , MYL2, and MYL3, account for up to 65–70% of all HCM cases [ 24 , 25 , 26 ], while other uncommon genes seem to be globally involved in about 10% of HCM cases [ 12 , 27 , 28 , 29 , 30 ]. Similarly, 51 curated genes were associated with idiopathic DCM [ 31 ], explaining up to 40–50% of DCM cases [ 24 ].…”

“…Nevertheless, eight main genes, MYBPC3 , MYH7 , TNNT2 , TNNI3 , TPM1 , ACTC1 , MYL2, and MYL3, account for up to 65–70% of all HCM cases [ 24 , 25 , 26 ], while other uncommon genes seem to be globally involved in about 10% of HCM cases [ 12 , 27 , 28 , 29 , 30 ]. Similarly, 51 curated genes were associated with idiopathic DCM [ 31 ], explaining up to 40–50% of DCM cases [ 24 ]. Among these, mutations in TTN gene account for up to 20–25% of DCM cases, while mutations occurring in other genes have rarely been identified [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ].…”