The field of Cardiovascular Genomics has advanced tremendously over the past two decades, having a significant clinical impact and changing the perception of the role and scope of genetic testing in several cardiovascular domains.  To kickstart the Cardiovascular Genomics series, CardioNerds Dr. Sara Coles (FIT at Duke University), Dr. Colin Blumenthal (CardioNerds Academy faculty and FIT at UPenn), and Dr. Karla Asturias (CardioNerds Academy fellow and medicine resident at Pennsylvania Hospital) have a great discussion with Dr. James Daubert, a clinical electrophysiologist at Duke University, with a particular interest in inherited arrhythmia syndromes and sports cardiology. In this episode, we review basic concepts of cardiovascular genomics and genetics in electrophysiology while discussing when to (and when not to!) test our patients and their families and how to approach those results. Audio editing by CardioNerds academy intern, Pace Wetstein.

This episode was developed in collaboration with the American Society of Preventive Cardiology and is supported with unrestricted educational funds from Illumina, Inc. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds.

This CardioNerds Cardiovascular Genomics series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs.

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1. The first step is identifying the right phenotype! Getting the right phenotype is crucial, as genetic testing done in a patient without a clear phenotype (or an incorrect one) would lead to significant anxiety, unnecessary tests and interventions, and potentially misleading and dangerous conclusions for patients and their families. Genetic testing typically should be reserved for patients with a confirmed or suspected diagnosis of an inherited disease or for individuals with a previously diagnosed pathogenic variant in a first-degree relative.¹
   
2. Discuss with your patient! Genetic counseling is essential and recommended for all patients before and after genetic testing. It should include a thorough discussion of risks, benefits, and possible outcomes, including variants of uncertain significance.²
   
3. Cardiovascular genetics is a dynamic and rapidly evolving field. New information can cause a variant of uncertain significance to be reclassified as a pathogenic or likely pathogenic variant or to be downgraded to benign or likely benign as variant databases expand. Another possibility is that new research might identify novel genes for a particular disease, which could warrant retesting, particularly for phenotype-positive and genotype-negative patients.¹
   
4. Brugada syndrome is an inherited arrhythmogenic disorder characterized by ST-segment elevation in the right precordial leads and malignant ventricular arrhythmias, with occasional conduction disease and atrial arrhythmias. It is diagnosed in patients with ST-segment elevation ≥ 2 mm in ≥ 1 lead among the right precordial leads, with a type I morphology (J-point elevation with slowly descending or concave ST segment elevation merging into a negative T wave), shown in the image below. This pattern can be observed spontaneously or after provocative drug testing (e.g., procainamide). Pathogenic genetic variants in SCN5A that result in loss of function of the cardiac sodium channel are identified in approximately 20% of cases.^3,4
   

5. Measure the QT interval yourself! A correct determination of the QT interval is essential. Although automatic measurements are widely available, the interval can be underestimated or overestimated, particularly in atrial arrhythmias or complex T-wave morphologies. Determining the end of the T-wave can be challenging in this setting, and can be assessed through the tangent method, which determines the end of the T-wave by the intersection between the baseline (U-P segment) and the “tangent” drawn to the steepest last limb of the presumed T-wave.^5,6
   

6. When encountering a patient with prolonged QT, it is essential to exclude secondary causes like QT-prolonging drugs and electrolyte imbalances. As the acute cause is removed and the acute illness resolves, “see what happens while the dust is settling” and reassess the QT.
   

Notes were developed by Dr. Karla Asturias:

What are some key basic concepts in clinical genetics?

• A mutation is defined as a permanent change in the nucleotide sequence, while a polymorphism is a mutation that occurs in more than 1% of a particular population. While both terms are often used, it can lead to confusion due to incorrect assumptions of pathogenicity. Therefore, both terms have been replaced by the term genetic variant, which we now encounter in the literature and guidelines.
  
  • Proband is the first presenting person in a family that serves as a starting point for a genetic study.
    
  • The phenotype refers to the clinical syndrome observed in our patients, while the genotype relates to the genetic composition, including the presence or absence of any genetic variants.
    
    • In the case of Brugada syndrome, the phenotype includes the type I Brugada pattern on ECG and the presence of ventricular arrhythmias. In many cases, the genotype consists of genetic variants in SCN5A that result in the loss of function of the cardiac sodium channel.
      
    
    
  • While particular genotypes can cause disease, the expression of the clinical phenotype can vary, leading to incomplete penetrance, where only a proportion of individuals carrying a specific genetic variant manifest the phenotype.
    
    • In patients with Brugada syndrome, there is variability in the frequency of ECG abnormalities, even with the same pathogenic variants. Among individuals with an SCN5A pathogenic variant, only 20-30% have an ECG diagnostic of Brugada syndrome, and approximately 80% manifest the characteristic ECG changes when challenged with a sodium channel blocker.⁴
      
    • Additionally, the Brugada phenotype has been reported to be 8 to 10 times more common in men than in women.⁷
      
    
    
  • Most cardiovascular diseases exhibit genetic heterogeneity, with mutations in multiple genes causing the same condition, meaning multiple genotypes can cause a similar phenotype.
    
    • In the cases of congenital long QT syndrome and hypertrophic cardiomyopathy, multiple genes have been implicated in these conditions.
      
    
    
  
  

How do we classify genetic testing results according to the American College of Medical Genetics and Genomics (ACMG) guidelines?

• The American College of Medical Genetics and Genomics (ACMG) guidelines are internationally accepted and describe standard terminology and methods in clinical genetic testing.⁸ They classify genetic variants into five different tiers:
  
  • Pathogenic
    
  • Likely pathogenic
    
  • Variant of uncertain significance (VUS)
    
  • Likely benign
    
  • Benign
    
  • It should be noted that, at present, we have no data to support a quantitative assignment of variant certainty to any of the five categories given the heterogenous nature of most diseases.
    
  • A variant of uncertain significance does not provide a definitive genetic etiology of disease and should not be used for clinical decision-making nor to determine risk for disease in unaffected relatives. ⁹
    
  • Variant interpretation is a dynamic process, and classification may change over time as additional evidence about the variants becomes available. A negative result does not exclude the possibility of genetic disease but indicates that a causative variant could not be identified with the currently available technology and knowledge.
    
  
  

What types of genetic testing are available, and when do we use them?³

• Sanger sequencing Method of DNA sequencing for a single geneHigh accuracy and low cost, compared to broader genetic testingUsed during cascade family evaluation
  
  • Panel sequencing
    
    • Tests for a pre-specified “set” of genes related to a particular phenotype or clinical condition
      
    • First-line diagnostic test for the proband
      
    • Usually, tests for exons only
      
    • Larger panels may be warranted for overlap or ambiguous phenotypes, with the recognition that larger panels may lead to the identification of more variants of uncertain significance
      
    • For unequivocal phenotypes, targeted panels are preferred, as larger panels are unlikely to increase clinical yield and may introduce ambiguous results
      
    
    
  • Whole-exome and whole-genome sequencing
    
    • Comprehensive genetic characterization of coding regions only (exome) or entire genome
      
    • Typically reserved for research settings, but can be considered in the evaluation in proband in very heterogenous conditions
      
    
    
  • Non-sequencing testing is also available through PCR for pre-specified variants
    
  
  

What is the role of genetic testing in the management of inherited cardiovascular diseases? ⁹

• Genetic testing is used to identify the underlying genetic etiology in a patient with a known or suspected inherited cardiovascular disease. 
  
  • Genetic testing is beneficial when the result alters the treatment, informs about the prognosis, and leads to testing in immediate family members.
    
  • Common inherited cardiovascular diseases include Brugada syndrome, long QT syndrome, arrhythmogenic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia, Marfan syndrome, and familial hypercholesterolemia, among others.
    
  
  

How do we approach patients with a confirmed or suspected diagnosis of an inherited cardiovascular disease? ^1,3

• A thorough and detailed disease-appropriate phenotyping and a comprehensive family history with at least three generations should be performed. Genetic testing should be considered if these elements strongly suggest an inherited cardiovascular disease.
  
• The patient should undergo pretesting genetic counseling, after which the patient and provider can make a shared decision as to whether to proceed with testing. As with any medical procedure, the patient should understand potential benefits, risks, and limitations before consenting, including the potential uncertainty related to the results.
  
• If the decision is made to proceed with genetic testing, the next step is to decide the scope of genetic testing. The choice of testing ranges from single genes to large gene panels, knowing that the broader the test, the bigger the risk of finding more variants of unknown significance. For the proband, a panel of genes is usually the first approach.The discussion of any genetic testing results should be accompanied by post-testing genetic counseling to help the patients understand the implication of the results for themselves and their family members.If a pathogenic or likely-pathogenic variant is found, cascade testing should be offered to first-degree relatives to assess their genetic predisposition for a known variant. Cascade testing is usually done by testing for the particular variant that was found in the proband.
  
• If variants of uncertain significance were found, a periodic review of the results should be performed to manage patients appropriately in light of new evidence and developments.
  

1. Musunuru K, Hershberger RE, Day SM, et al. Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association. Circ Genomic Precis Med. 2020;13(4):E000067. doi:10.1161/HCG.0000000000000067
   
2. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Hear Rhythm. 2011;8(8):1308-1339. doi:10.1016/J.HRTHM.2011.05.020
   
3. Wilde AAM, Semsarian C, Márquez MF, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the State of Genetic Testing for Cardiac Diseases. Hear Rhythm. 2022;19(7):e1-e60. doi:10.1016/J.HRTHM.2022.03.1225
   
4. Batchvarov VN. The Brugada Syndrome – Diagnosis, Clinical Implications and Risk Stratification. Eur Cardiol Rev. 2014;9(2):82. doi:10.15420/ECR.2014.9.2.82
   
5. Postema PG, De Jong JSSG, Van der Bilt IAC, Wilde AAM. Accurate electrocardiographic assessment of the QT interval: teach the tangent. Hear Rhythm. 2008;5(7):1015-1018. doi:10.1016/J.HRTHM.2008.03.037
   
6. Postema PG, Wilde AA. The Measurement of the QT Interval. Curr Cardiol Rev. 2014;10(3):287. doi:10.2174/1573403X10666140514103612
   
7. Benito B, Sarkozy A, Mont L, et al. Gender differences in clinical manifestations of Brugada syndrome. J Am Coll Cardiol. 2008;52(19):1567-1573. doi:10.1016/J.JACC.2008.07.052
   
8. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi:10.1038/GIM.2015.30
   
9. Cirino AL, Harris S, Lakdawala NK, et al. Role of Genetic Testing in Inherited Cardiovascular Disease: A Review. JAMA Cardiol. 2017;2(10):1153-1160. doi:10.1001/JAMACARDIO.2017.2352
   

Supplementary bibliography:

1. Eifling M, Razavi M, Massumi A. The Evaluation and Management of Electrical Storm. Texas Hear Inst J. 2011;38(2):111. Accessed April 16, 2022. /pmc/articles/PMC3066819/
   
2. Lahrouchi N, Raju H, Lodder EM, et al. Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome. J Am Coll Cardiol. 2017;69(17):2134-2145. doi:10.1016/J.JACC.2017.02.046
   
3. Honarbakhsh S, Providencia R, Garcia-Hernandez J, et al. A Primary Prevention Clinical Risk Score Model for Patients With Brugada Syndrome (BRUGADA-RISK). JACC Clin Electrophysiol. 2021;7(2):210-222. doi:10.1016/J.JACEP.2020.08.032
   
4. Towbin JA, McKenna WJ, Abrams DJ, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Hear Rhythm. 2019;16(11):e301-e372. doi:10.1016/J.HRTHM.2019.05.007
   
5. Seidelmann SB, Smith E, Subrahmanyan L, et al. Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults. Circ Cardiovasc Genet. 2017;10(1). doi:10.1161/CIRCGENETICS.116.001573
   
6. Nafissi NA, Abdulrahim JW, Kwee LC, et al. Prevalence and Phenotypic Burden of Monogenic Arrhythmias Using Integration of Electronic Health Records With Genetics. Circ Genomic Precis Med. Published online September 22, 2022. doi:10.1161/CIRCGEN.121.003675
   
7. Grondin S, Davies B, Cadrin-Tourigny J, et al. Importance of genetic testing in unexplained cardiac arrest. Eur Heart J. 2022;43(32):3071-3081. doi:10.1093/EURHEARTJ/EHAC145
   
8. Monasky MM, Micaglio E, Locati ET, Pappone C. Evaluating the Use of Genetics in Brugada Syndrome Risk Stratification. Front Cardiovasc Med. 2021;8. doi:10.3389/FCVM.2021.652027
   
9. Tadros R, Tan HL, El Mathari S, et al. Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores. Eur Heart J. 2019;40(37):3097-3107. doi:10.1093/EURHEARTJ/EHZ435