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Review
. 2011 Mar 8;123(9):1021-37.
doi: 10.1161/CIRCULATIONAHA.109.914838.

Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice

David J Tester  1 , Michael J Ackerman
Affiliations
Review

Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice

David J Tester et al. Circulation. .
No abstract available

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest: Dr. Ackerman is a consultant for PGxHealth with respect to the FAMILION™ genetic test for cardiac ion channel mutations. Intellectual property derived from MJA’s research program resulted in license agreements in 2004 between Mayo Clinic Health Solutions (formerly Mayo Medical Ventures) and PGxHealth (formerly Genaissance Pharmaceuticals).

Figures

Figure 1
Figure 1. Nucleotide Substitutions
Compared to the depicted normal DNA, amino acid (single letter abbreviation) sequence and resulting peptide sequence are examples of nucleotide substitutions and deletion mutations. The amino acids of the peptide sequence are color coded to represent their unique biophysical properties where yellow represents nonpolar hydrophobic amino acids, green are polar hydrophilic, pink are negatively charged acidic residues, and blue represents positively charged basic amino acid residues. A nucleotide change resulting in a new codon that encodes for: A) the same amino acid as the normal sequence is a silent mutation, B) a different amino acid is a missense mutation, and C) for a termination codon is a nonsense mutation. Illustrated in D) is a deletion of a single nucleotide (G) that results in a shift of the open reading frame of the transcript thus representing a frameshift mutation. Note how the sequence of amino acids has been altered from this point forward. Although not illustrated here, frameshift mutations as a result of a deletion or insertion of nucleotides often lead to a premature stop codon and thus a truncated protein. Illustrated in E), the deletion of three nucleotides (GAC) produced an in-frame deletion of a single amino acid (aspartic acid, Asp) in the protein. The remaining amino acid sequence is unaltered. Three nucleotide insertions (not shown) can have a similar affect whereby an amino acid is inserted into the protein product. Figure adapted from Tester and Ackerman
Figure 2
Figure 2. Indications for Genetic Testing
Provided is a table of possible indications for genetic testing for hypertrophic cardiomyopathy (HCM), long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS). LVH = left ventricular hypertrophy, TdP = torsade de pointes, SUD = sudden unexplained death. The + symbol represents a positive indication for genetic testing. The − symbol represents an indicator that does not warrant for genetic testing for the specific disorder. The +/− symbol represents an indicator that may or may not warrant genetic testing.
Figure 3
Figure 3. Possible Indicators for Genetic Testing in Exercise-Induced Syncope
Depicted for illustrative purposes is a work flow decision tree for indicating which genetic test would be appropriate to order based on the clinical evaluation of an individual manifesting with exercise-induced syncope. The blue boxes represent specific clinical evaluation tests. The yellow boxes represent specific genetic testing panels. The + symbol represents a positive evaluation and the − symbol represents a negative evaluation for the respective clinical test. The key point is that genetic testing for these disorders should be phenotype-guided, NOT universal.
Figure 4
Figure 4. Utility of Genetic Testing
Shown is the current diagnostic, prognostic, and therapeutic utility of genetic testing for hypertrophic cardiomyopathy (HCM), long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS). The + symbol indicates the test has utility, the − symbol indicates no current measurable utility, and +/− indicates the test may have some utility.
Figure 5
Figure 5. Probabilistic Nature of LQTS Genetic Testing
Depicted are the three major ion channels causative for LQTS with areas of probability of pathogenicity shown for mutations localizing to these respective areas. While “radical” mutations have a greater then 90% probability of being a true pathogenic mutation, the level of probability for missense mutations vary depending on their location for each channel protein. Missense mutations residing in red shaded areas have a high probability (>80%) of being pathogenic, those in blue are possibly (51–80%) pathogenic, and those in yellow shaded areas truly represent variants of uncertain significance (VUS, ≤50% probability) clinically. Figure adapted from Tester and Ackerman.
Figure 6
Figure 6. Genotype-Phenotype Correlations in Long QT syndrome
Seventy-five percent of clinically strong LQTS is due to mutations in three genes (35% KCNQ1, 30% KCNH2, and 10% in SCN5A) encoding for ion channels that are critically responsible for the orchestration of the cardiac action potential. Genotype-phenotype correlations have been observed, including swimming/exertion and LQT1, auditory triggers/postpartum period and LQT2, and sleep/rest and LQT3. The bar graphs represent genotype-phenotype data from reference . Also illustrated is the relative gene-specific effectiveness in β blocker therapy where β blockers are extremely protective in LQT1 patients, moderately protective in LQT2, and may not provide sufficient protection for those with LQT3. The late sodium current blockers like mexiletine, ranolazine, and propranolol may be protective in LQT3.
Figure 7
Figure 7. Catecholaminergic Polymorphic Ventricular Tachycardia: a Disorder of Intracellular Calcium Handling
A) Perturbations in key components of the calcium-induced calcium release (CICR) mechanism responsible for cardiac excitation-contraction coupling are the pathogenic basis for CPVT. At the center of this mechanism is the RYR2-encoded cardiac ryanodine receptor/calcium release channel located in sarcoplasmic reticulum membrane. Mutations in RyR2 are clustered and distributed in three “hot-spot” regions of this 4967 amino acid (AA) protein; Domain I or N-terminal Domain (AA 57-1141), Domain II or the Central Domain (AA 1638-2579), and Domain III or Channel Region (AA 3563-4967). B) Because of this clustering of mutations, a tiered strategy for genetic testing of the 105 exon RYR2 gene has been proposed. C) Illustrated is the percent yield of RYR2 mutation detection in cases of strong CPVT, possible CPVT, and LQT1-3 gene-negative “LQTS” referral cases manifesting with exercise-induced cardiac events.
Figure 8
Figure 8. Sodium Channelopathies
Depicted is the linear topology of the 2016-amino acid containing cardiac sodium channel isoform with mutation location and their associated disorders. Circles denote missense mutations and squares represent “radical” mutations including, frame-shift insertion/deletion mutations, in-frame insertions/deletions, nonsense, and splice-site mutations. Figure adapted from Tester and Ackerman.
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