Mayo Clinic Proceedings Continuing Medical Education

Mayo Clinic Proceedings Continuing Medical Education

Objectives

On completion of this article, you should be able to:

(1)Summarizeclinical indications for cardiovascular disease genetic testing.

(2)Recognize common pitfalls and current limitations of genomic-aided approaches.

(3)Appraise the current clinical utility of genetic testing to individualize the diagnosis, risk-stratification, and management of patients with an array of cardiovascular diseases.

Questions

A 27-year-old male collapses while running a marathon. Resuscitation efforts are unsuccessful. On post-mortem examination, the ventricular septum appears grossly thickened and histopathology reveals cardiac myofibrils disorganization. Due to concerns for a possible genetic etiology, the patient’s family and medical providers request a whole exome molecular autopsy to facilitate family-based cascade screening. The results of the genetic test return and several rare genetic variants are identified. When interpreting the results of this patient’s genetic test, which of the following criteria is most likely to suggest that an identified rare genetic variant is benign?

(A) Co-segregation of the rare variant with disease in a multi-generational pedigree.

(B) Determination that the rare variant has occurred de novo.

(C) Observation that the rare variant has a minor allele frequency that exceeds the estimated disease prevalence.

(D) Realization that the rare variant results in a nonsense mutation or frame-shift mutation.

(E) Reproducible evidence that the rare variant yields a loss-of-function in vitro phenotype.

Explanation: According to current American College of Medical Genetics and Genomics standards and guidelines for rare genetic variant interpretation a minor allele frequency in the publicly available Exome Aggregation Consortium (ExAC), Exome Sequencing Project (ESP) or 1000 genomes (1KG) databases that exceeds estimated disease prevalence provides strong evidence the identified genetic variant is benign (choice C).1 Furthermore, a minor allele frequency >5% in any of these databases provides stand-alone evidence that an identified genetic variant is benign.1 In contrast, co-segregation with disease (choice A), de novo status (choice B), identification of a nonsense or frame-shift genetic variant (choice D), and reproducible in vitro or in vivo evidence of a functional phenotype (choice E) all provide strong evidence for pathogenicity.

Reference(s): 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;17:405-424.

A 37-year-old male with hypertension, hyperlipidemia, and type II diabetes mellitus presents to his local emergency department for evaluation of dyspnea and substernal chest pain radiating to the back. A CT angiogram is negative for acute pulmonary embolism, but reveals a dissecting aneurysm of the ascending aorta. On physical exam, the patient has an early diastolic decrescendo murmur, but no overt musculoskeletal, ocular, dermatologic, or craniofacial abnormalities. Current medications are amlodipine, atorvastatin, and metformin. Family history is significant for the patient’s 62-year-old father who underwent repair of an aortic aneurysm in his 40’s. The patient undergoes emergent surgical repair. At an outpatient follow-up visit, you are unsure as to whether the patient and his family would benefit from further work-up for potential genetic etiologies given his family history. What is the next best step to evaluate this patient for a potential familial thoracic aortopathy?

(A) Order comprehensive familial aortopathy gene panel to help identify a precise diagnosis.

(B) Initiate genetic testing for ACTA2, MAT2A, MYH11, MYLK, PRKG1, and TGFB2 to help confirm a diagnosis of non-syndromic familial aortopathy.

(C) Initiate genetic testing for COL3A1, FBN1, TGFBR1, and TGFBR2 to rule out vascular Ehlos-Danlos, Marfan syndrome, and Loeys-Dietz syndrome

(D) Referral to Medical Genetics to rule out syndromic forms and for consideration of genetic testing.

(E) No further testing indicated.

Explanation: If there is any doubt in regards to the indication, appropriateness, or selection of a genetic test, the patient should be referred to a Medical Geneticist and/or a cardiovascular sub-specialist with expertise in genetics/genomics to minimize the inappropriate use of genetic testing and likelihood of obtaining misleading results. The patient in this case likely has non-syndromic Familial Thoracic Aortic Aneurysm and Dissection (FTAAD), but syndromic forms such as vascular Ehlos-Danlos Marfan syndrome, and Loeys-Dietz should first be ruled out clinically. The use of genetic testing to rule out any genetic disorder should be avoided as the possibility of genotype-negative disease exists (choice C). According to current European Cardiology Society (ESC) guidelines, genetic testing for syndromic and non-syndromic FTAADs should only be undertaken following evaluation by a geneticist (class I recommendation, choice D).2 Selection of the best genetic test (choices A and B) needs to be individualized on a per case basis given the overlapping natures of the familial aortopathies. As such, choice A represents the next best step in this case.

Reference(s):Erbel R, Aboyans V, Boileau C, et al. 2014 ESC Guidelines On The Diagnosis And Treatment Of Aortic Diseases: Document Covering Acute And Chronic Aortic Diseases Of The Thoracic And Abdominal Aorta Of The Adult. The Task Force For The Diagnosis And Treatment Of Aortic Diseases Of The European Society Of Cardiology (ESC). European Heart Journal. 2014;35:2873-2926.

According to current societal guidelines/recommendations, which of the following clinical scenarios represents a class I recommendation for the initiation of genetic testing?

(A) A 36-year-old asymptomatic female with an incidentally discovered heart rate-corrected QT interval of 472 msec undergoing evaluation for possible congenital long QT syndrome.

(B) A 18-year-old male whose 24-year-old sister was diagnosed recently with arrhythmogenic cardiomyopathy (ACM) secondary to a frameshift mutation in the PKP2 gene.

(C) A 45-year-old male with syncope noted to have borderline ST-elevations in leads V1-V3 on electrocardiogram during a recent febrile illness undergoing work-up for possible Brugada syndrome.

(D) A 38-year-old female with left ventricular dilation on echocardiography, but otherwise negative cardiac work-up including no evidence of cardiac arrhythmia or conduction disturbance on Holter monitor undergoing evaluation of suspected autosomal dominant dilated cardiomyopathy.

(E) A 55-year-old asymptomatic male whose parents and three older siblings all have a history of coronary heart disease who inquires about the usefulness of a genetic risk score given his family history.

Explanation: For most monogenic cardiovascular disorders, targeted family-based cascade testing once a bona-fide mutation is identified in a first-degree relative represents a class I recommendation for the initiation of genetic testing. As such, the 18-year-old male should be tested for his sister’s arrhythmogenic cardiomyopathy-causative PKP2 mutation (choice B). Although the clinical scenarios described in choices A, C, and D may merit genetic testing, due to the strength of the long QT syndrome phenotype (choice A) or current evidence to support genetic testing in Brugada syndrome (choice C) and dilated cardiomyopathy (choice D) genetic testing in these scenarios currently carry class IIa recommendations according to current Heart Rhythm Society/European Heart Rhythm Association guidelines.3 Currently, no clinical guidelines recommend the use of genetic risk scores in polygenic conditions such as coronary heart disease (choice E).

Reference(s): 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). Heart Rhythm. 2011;8:1308-1339.

A 52-year-old male with a history of hyperlipidemia and obesity presents for a general medical exam. Current medications include lisinopril and rosuvastatin. Both of the patient’s parents have hypertension and have been diagnosed with coronary heart disease requiring percutaneous coronary intervention. In addition, the patient’s father and older brother have atrial fibrillation. The patient read a newspaper article on precision medicine and inquires as to whether he should get his “genes tested” to provide a more precise estimate of his risk for a variety of cardiovascular diseases. What is the best response to this patient’s inquiry?

(A) A genetic risk score is available to help determine his risk of atrial fibrillation.

(B) A genetic risk score is available to help determine his risk of coronary heart disease.

(D) Genetic risk scores are available to assess his risk of atrial fibrillation, coronary heart disease, and hypertension.

(E) Genetic risk scores for atrial fibrillation, coronary heart disease, and hypertension exist, but their clinical utility remains under investigation.

Explanation: Several studies have illustrated that the use of genetic risk scores modestly, but statistically significantly, improve the ability to predict the incidence of atrial fibrillation and future adverse events in coronary heart disease compared to conventional clinical variable-based risk-stratification tools4-7 and can prompt patients and providers to address modifiable risk factors in those with a genetic predisposition8. However, large prospective randomized control trials are needed to define the clinical utility of these genetic risk scores in regards to their ability to improve clinical outcomes and lower health care costs. As such, choice E is the best response to this patient’s inquiry.

Reference(s): Tada H, Shiffman D, Smith JG, et al. Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke. Stroke. 2014;45:2856-2862.

Everett BM, Cook NR, Conen D, Chasman DI, Ridker PM, Albert CM. Novel genetic markers improve measures of atrial fibrillation risk prediction. Eur Heart J. 2013;34:2243-2251.

Ripatti S, Tikkanen E, Orho-Melander M, et al. A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet. 2010;376:1393-1400.

Mega JL, Stitziel NO, Smith JG, et al. Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. Lancet. 2015;385:2264-2271.

Kullo IJ, Jouni H, Austin EE, et al. Incorporating a Genetic Risk Score Into Coronary Heart Disease Risk Estimates: Effect on Low-Density Lipoprotein Cholesterol Levels (the MI-GENES Clinical Trial). Circulation. 2016;133:1181-1188.

A 16-year-old female presents for evaluation of several syncopal episodes that occurred during soccer practice. Work-up is significant for a normal electrolyte panel and a 12-lead electrocardiogram displaying a heart-rate corrected QT interval of 505 msec. The patient takes no medications. Family history is notable for a maternal uncle that drowned while swimming with friends in a local rock quarry at age 23. Due to concern for a possible inherited cardiac channelopathy, the patient is referred to a genetic counselor and a genetic cardiologist and long QT syndrome genetic testing is initiated. Use of the patient’s genetic test results can be used to individualize the following elements of her medical care?

(A)Diagnosis only

(B)Risk-stratification only

(C)Diagnosis and risk-stratification

(D)Diagnosis and treatment

(E)Diagnosis, risk-stratification, and treatment

Explanation: Evidence to support the use of genetic testing to further enhance the management/treatment of the proband with a monogenic cardiovascular disorder is limited to a handful of clinical scenarios (ICD implantation for primary implantation in LMNA/SCN5A-mediated dilated cardiomyopathy, enzyme replacement in lysosomal storage disease hypertrophic cardiomyopathy phenocopies, and trigger avoidance/therapy selection in long QT syndrome). Currently, genetically testing is useful in the diagnosis as well as the genotype-/mutation-specific risk-stratification and therapy selection in long QT syndrome (choice E).3, 9 As such, long QT syndrome serves as the prototype for the promise of precision genomic medicine.

Giudicessi JR, Ackerman MJ. Genotype- And Phenotype-Guided Management of Congenital Long QT Syndrome.CurrProblCardiol. 2013;38:417-455.

CME References:

1.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;17:405-424.

2.Erbel R, Aboyans V, Boileau C, et al. 2014 Esc Guidelines On The Diagnosis And Treatment Of Aortic Diseases: Document Covering Acute And Chronic Aortic Diseases Of The Thoracic And Abdominal Aorta Of The Adult. The Task Force For The Diagnosis And Treatment Of Aortic Diseases Of The European Society Of Cardiology (Esc). European heart journal. 2014;35:2873-2926.

3.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). Heart Rhythm. 2011;8:1308-1339.

4.Tada H, Shiffman D, Smith JG, et al. Twelve-Single Nucleotide Polymorphism Genetic Risk Score Identifies Individuals At Increased Risk For Future Atrial Fibrillation And Stroke. Stroke. 2014;45:2856-2862.

5.Everett BM, Cook NR, Conen D, Chasman DI, Ridker PM, Albert CM. Novel Genetic Markers Improve Measures Of Atrial Fibrillation Risk Prediction. Eur Heart J. 2013;34:2243-2251.

6.Ripatti S, Tikkanen E, Orho-Melander M, et al. A Multilocus Genetic Risk Score For Coronary Heart Disease: Case-Control And Prospective Cohort Analyses. Lancet. 2010;376:1393-1400.

7.Mega JL, Stitziel NO, Smith JG, et al. Genetic Risk, Coronary Heart Disease Events, And The Clinical Benefit Of Statin Therapy: An Analysis Of Primary And Secondary Prevention Trials. Lancet. 2015;385:2264-2271.

8.Kullo IJ, Jouni H, Austin EE, et al. Incorporating A Genetic Risk Score Into Coronary Heart Disease Risk Estimates: Effect On Low-Density Lipoprotein Cholesterol Levels (The Mi-Genes Clinical Trial). Circulation. 2016;133:1181-1188.

9.Giudicessi JR, Ackerman MJ. Genotype- And Phenotype-Guided Management of Congenital Long Qt Syndrome. Curr Probl Cardiol. 2013;38:417-455.