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Table of Contents
Year : 2021  |  Volume : 11  |  Issue : 1  |  Page : 5-12

Scope of genetic testing for inherited cardiovascular diseases in the clinical practice

Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India

Date of Submission27-Mar-2020
Date of Decision03-Jun-2020
Date of Acceptance21-Jun-2020
Date of Web Publication18-Feb-2021

Correspondence Address:
Dr. Ashwin Dalal
Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Ministry of Science and Technology, Government of India, Opp. Metro Rail Pillar No. NUP.9B, Inner Ring Road, Uppal, Hyderabad - 500 039, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JICC.JICC_15_20

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Inherited cardiac disorders are clinically and genetically heterogeneous group of disorders where sudden cardiac death is mostly the first clinical presentation. The available clinical markers are insufficient to make an accurate diagnosis, and therefore, molecular genetic diagnostics is an important tool for clinical decision-making. The advancements in technology have tremendously improved the affordability of genetic testing. In India, though genetic testing is being largely applied in the pediatric settings for chromosomal abnormalities and metabolic disorders, it is still at a nascent stage in the cardiology practice. Since cardiomyopathies and channelopathies have become actionable because of new interventional therapies, this article highlights the importance and need of genetic testing for inherited cardiac disorders by practicing cardiologists, in-view of the American College of Medical Genetics, American College of Cardiology, European Heart Rhythm Association guidelines. Incorporating cardiovascular genetic testing in the routine clinical practice can take it forward by greatly improving the scope of disease management.

Keywords: Cardiomyopathies, channelopathies, genetic testing, inherited cardiac disorders, next-generation sequencing technology

How to cite this article:
Rangaraju A, Dalal A. Scope of genetic testing for inherited cardiovascular diseases in the clinical practice. J Indian coll cardiol 2021;11:5-12

How to cite this URL:
Rangaraju A, Dalal A. Scope of genetic testing for inherited cardiovascular diseases in the clinical practice. J Indian coll cardiol [serial online] 2021 [cited 2021 Jun 13];11:5-12. Available from:

  Introduction Top

Inherited cardiac disorders comprise a wide and heterogeneous spectrum of diseases broadly categorized based on the pathologies into: Cardiomyopathies and channelopathies. Combined together, they are a major cause of morbidity and mortality in the young, with a prevalence of 3' worldwide. They show varied clinical manifestations with overlapping symptoms, in most of cases sudden death being the first presentation of the disorder.[1] The genetic basis of these disorders has been strongly established by many research groups over the past two decades. Cardiomyopathies result from the variations in genes encoding sarcomeric, cytoskeletal, and desmosomal proteins. Channelopathies are essentially arrhythmic disorders in structurally normal hearts. They are caused by the variations in genes-encoding cardiac ion channels and are classified as long-QT syndrome (LQTS), the short-QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT).[2]

Molecular cardiology has become an important tool to study and understand the etiology, pathogenesis, and development of inherited cardiac disorders and has begun to change clinical practice.[3] With the advent of next-generation sequencing, genetic testing has become largely accessible and affordable and is now becoming an important part in the process of disease diagnosis and management. However, the clinical application of genetic testing for inherited cardiovascular diseases is still at a nascent stage in India. This article will discuss why genetic testing is necessary to integrate in the clinical practice for inherited cardiac disorders, the process of genetic evaluation and interpretation of a genetic test report for an effective clinical decision-making.

  Genetics of Inherited Cardiac Disorders Top


According to the European Society of Cardiology (ESC) classification, cardiomyopathies are divided into hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM).[4]

HCM is recognized by thickening of the left or the right ventricle along with the interventricular septum. It is the most common type of cardiomyopathy with a prevalence of 1:500.[5] The clinical course is varied ranging from being asymptomatic, severe heart failure to sudden cardiac death (SCD). It is an autosomal-dominant disorder; however, in pediatric-onset cardiomyopathies, X-linked, autosomal recessive, and de novo sporadic patterns are more often observed. Variants in genes-encoding sarcomere proteins account for 30'–60' of HCM cases, with MYH7 (encoding myosin heavy chain) and MYBPC3 (encoding cardiac myosin-binding protein C) being highly associated genes.[6] The American College of Medical Genetics (ACMG) has established separate guidelines for MYH7 variants to address the heterogeneity associated with cardiovascular conditions. As per these guidelines, variants in the codons from 181 to 937 are considered as the hotspot region and are classified as pathogenic.[7]

DCM is genetically more heterogeneous than HCM, with more than 50 genes implicated. Genes encoding cytoskeletal, sarcomere, calcium handling, and nuclear lamina proteins have all been implicated in DCM. Variants encoding the A-band region of TTN gene account for 20' of DCM.[8],[9] ARVC is characterized by fibrofatty replacement of myocardial tissue with predominant involvement of the right ventricle and ventricular arrhythmias. It is caused by variants in genes encoding for desmosomal proteins and is also referred to as “disease of the desmosome.”[10] Genes PKP2, DSP, DSG2, DSC2, JUP, TMEM43, and PLN account for 63' of ARVC cases.[11] RCM is often caused by the variants in the same genes as HCM, as well as other genes such as those encoding intermediate filament genes. In some cases of cardiomyopathy, ventricular arrhythmias can precede the development of left ventricular dysfunction, and notably, variants in SCN5A, LMNA (encoding lamin A/C), DES (encoding desmin), FLNC (encoding filamin C), and others have a particularly high arrhythmia risk.[12] [Table 1] gives the list of genes involved in cardiomyopathies.
Table 1: Genes involved in cardiomyopathies

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Influx and efflux of sodium, potassium, calcium, and chloride ions in cardiomyocytes by ion channels are crutial for a normal heart rhythm. Variants in the genes encoding for these ion channels modify the ionic balance of the electrical component of cardiac function and result in a set of clinically and genetically diverse arrhythmic disorders such as BrS, CPVT, and LQTS. These disorders are collectively termed as “Channelopathies.” Conventionally, these patients have structurally normal hearts but are predisposed to syncope, arrhythmias, and SCD, the latter being the first presentation in channelopathies.[13] LQTS is the most common channelopathy with a prevalence of 1:2500 followed by BrS with a prevalence of 1:5000. Other rarer heritable arrhythmias include CPVT, SQTS. These predominantly have an autosomal-dominant mode of inheritance; however, other forms of inheritance have also been noted.[14] Most of the genes are overlapping among these disorders [Table 2].
Table 2: Overlapping genes among different types of channelopathies.

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LQTS is characterized by a prolongation of the QT interval on the electrocardiogram (ECG) (QTc. 480 ms). The clinical presentation can be variable, ranging from asymptomatic to episodes of syncope and SCD due to ventricular tachyarrhythmia (torsade de pointes) in a structurally normal heart. At present, genetic analyses are used for the precise diagnosis for LQTS, where individuals and family members at risk of developing the disease with a normal ECG may be identified through genetic testing. So far, 15 genes have been implicated in LQTS which contribute to approximately 80'–85' of all long QT (LQT) cases. They are KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, CALM1, CALM2, SCN4B, AKAP9, SNTA1, and KCNJ5. Nearly 1200 pathogenic variations been reported in these genes; however, 70'–75' of LQT cases are caused by the variations in only three genes, KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3), with KCNQ1 responsible for around 35' of cases.[15],[16] Genetic testing for LQTS has a major role in the diagnosis of index cases, risk stratification in the family members and therapeutic strategies. The second common arrhythmic disorder after LQTS is BrS with a prevalence of 1:5000. To date, more than 300 pathogenic variations in 16 genes; SCN5A, GPD1-L, SCN1B, SCN2B, SCN3B, KCNE3, KCNE5, KCNJ8, KCND3, CACNA1C, CACNB2b, CACNA2D1, RANGRF, HCN4, SLMAP and TRPM4 have been associated with BrS. Genetic testing identifies the pathogenic cause in 35'–40' of clinically diagnosed cases of BrS and approximately 25'–30' of diagnosed patients carry a pathogenic variation in the SCN5A gene.[17]

CPVT is characterized by severe arrhythmias under adrenergic stimulation, such as exercise or emotional stress with an estimated prevalence of 1/10,000. The resting ECG is usually normal, but exercise testing induces ventricular arrhythmia in 75'–100' of patients. It is associated with a high mortality rate of around 30' by the age of 30 years since the first manifestation of CPVT is sudden death. To date, more than 100 pathogenic variations have been identified in five genes; RYR2, CASQ2, KCNJ2, TRDN, CALM1, and CALM2, contributing to nearly 60' of all clinically diagnosed cases. The RYR2 gene, encoding the ryanodine receptor alone is responsible for nearly 50' of all cases.[2],[18]

SQTS was first reported in the year 2000 and is considered as the most lethal channelopathy. It is characterized by a short-QT interval on the ECG (QTc, 325 ms) with a high-sharp T-wave and has a high familial incidence of palpitations or syncope, and SCD, typically seen during childhood and is often the only phenotypic manifestation. So far, four genes have been implicated KCNQ1, KCNH2, KCNJ2, and CACNA2D1 which account for nearly 50' of clinically diagnosed short QT cases.[19]

  Benefits of Genetic Testing and American college of Medical Genetics/European Society of Cardiology Recommendations Top

Inherited cardiac disorders are genotypically and phenotypically heterogeneous with overlapping clinical symptoms; therefore, it is essential to know if the disease manifestation is sporadic or inherited. A genetic testing firstly helps to differentiate between a genetic and a nongenetic manifestation. In situations where the available clinical markers are not enough for an accurate diagnosis, genetic testing for the proband can help in a definitive diagnosis. It helps in the identification of high-risk mutations/complex genotypes associated with severe disease expression, such as marked hypertrophy and premature heart failure. Identification of a pathogenic variant can facilitate better disease management in the index patient and help to identify asymptomatic affected family members. Presymptomatic carriers of pathogenic variants can undergo interval screening to detect the earliest manifestations of the cardiac disorder. Timely genetic testing can provide options for family planning, including preimplantation genetic diagnosis in first-degree family members as the risk of transmission is 50' in both cardiomyopathies and channelopathies.[20]

  1. Cardiomyopathies and channelopathies are medically actionable with well-established treatments and interventions available to improve survival, reduce morbidity, and enhance the quality of life; hence, ACMG and ESC have laid recommendations for genetic testing for cardiomyopathies and channelopathies broadly summarized below [Table 3][21],[22],[23],[24]
  2. Genetic testing is recommended as a Class I indication in probands with a confirmed diagnosis of cardiomyopathies, channelopathies (specially LQTS and CPVT)
  3. Genetic testing is recommended in at-risk family members of the proband
  4. Testing is recommended in presymptomatic individuals with a strong family history of cardiac disorders
  5. Genetic test is recommended even in diagnosed patients with no family history of inherited cardiac disorders or sudden death, as this may reflect incomplete information of family history and screening, incomplete penetrance, or a de novo mutation in proband.
Table 3: Summary of genetic testing recommendations for cardiomyopathies and channelopathies as laid by the American college of cardiology (ACC), European heart rhythm association (EHRA), Heart rhythm Society (HRS) [21-24]

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  Genetic Testing for Syndromic Disorders with Extracardiac Manifestations Top

Genetic testing is not only beneficial in the diagnosis of isolated cardiac disorders, but also helps in the diagnosis of syndromic disorders with extracardiac manifestations. Genetic evaluation is recommended in individuals with facial dysmorphology, metabolic disorders, chromosomal aberrations, and in neuromuscular disorders which show cardiomyopathy as a secondary manifestation. HCM diagnosis is based on the presence of left ventricular hypertrophy (LVH) with left ventricular myocardial wall thickness ≥15 mm. However, LVH can also be seen in inherited syndromes with extracardiac manifestations suggesting a systemic disorder. Fabry's disease, Noonan syndrome, neuromuscular disorders such as muscular dystrophies are some of the disorders which also show cardiac involvement. Most of these systemic disorders with cardiac manifestations usually have an early onset with recessive pattern of inheritance that typically manifest from birth or infancy. [Table 4] gives a list of systemic disorders with cardiac and extracardiac manifestations. Genetic testing can help to understand the etiology of systemic syndromes.
Table 4: Syndromes with cardiac and extracardiac manifestations

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A recent study reported that the use of extended panels with HCM mimic genes demonstrated a diagnostic yield of a 1' for Fabry disease, 0.3' for familial amyloidosis, and 0.15' for PRKAG2-related cardiomyopathy. In their study cohort, the patients were initially referred for HCM-directed genetic testing but were diagnosed with Fabry's disease only after genetic testing. These patients did not show any extracardiac manifestations, and clinically, cardiac resonance imaging could not clearly differentiate between Fabry's HCM or sarcomeric HCM. Interestingly, in 45' of the patients diagnosed with an HCM mimic, family history of isolated HCM was reported, suggesting that the differential diagnosis of an HCM mimic even in patients with a family history of isolated cardiac disorders cannot be ruled out.[25] Genetic testing can be immensely helpful in such differential diagnosis and identification of a mimic can lead to a major change in the disease management of the patients, disease prognosis, and risk stratification of family members.

On the other hand, mutations in certain genes show a wide phenotypic spectrum, and genetic testing can identify such genes that help in the right prognosis of the condition. For instance, Titin (TTN) gene shows wide phenotypic spectrum of muscular dystrophies with or without cardiac involvement. This variability in the phenotype is attributed not only to the type of TTN mutation but also to the domain on which the mutation exists. DCM causing TTN variants are predominantly restricted to the A band region, while the latest reports indicate that heterozygous M-line mutation cause late-onset dominant disorders predominantly involving the skeletal muscle, while homozygous or compound heterozygous M-line TTN mutations cause recessive early-onset disorders involving both skeletal and cardiac muscle. The term “congenital titinopathy” has been suggested for such severe manifestations that included dystrophy with fatal cardiomyopathy, centronuclear myopathy, and arthrogryposis multiplex congenita that are caused by autosomal recessive TTN mutations.[26]

Most of the genetic testing companies offer large gene panels which include genes that cause genetic syndromes associated with cardiomyopathy. This increases the likelihood of identifying the genetic etiology for the syndromic disorders, especially in patients with overlapping phenotypes and those who do not show pathognomonic features. To make genetic testing cost-effective for the patients, it is beneficial to prefer a large panel which covers most of these genes.

  How Genetic Information is Useful? Top

Patients having a pathogenic or likely pathogenic variant have a two-fold greater risk of heart failure and atrial fibrillation compared to those without a variant.[27] The first evidence of a phenotype can help in early interventions such as introducing lifestyle modifications, medications to slow down disease progression, and using devices to reduce the risk of SCD. Knowing a variant can help to establish genotype-phenotype correlation for better disease prognosis. Of late, medications have been shown to be useful in treating patients carrying certain pathogenic variants. For example, mexiletine, a sodium-channel blocker is reported to be beneficial in patients with Type 3 LQTS secondary to variants in SCN5A gene. In DCM, genetic testing shows better prognostic value for specific genetic findings, such as consideration of implantable cardioverter defibrillator (ICD) for the primary prevention in carriers of LMNA gene pathogenic variants. In ARVC, ICD placement for primary prevention in asymptomatic male carriers of a malignant pathogenic variant showed significant impact on long-term clinical outcome. LQT1 patients with KCNH1 variants are at higher risk during physical activity, but are very well protected by beta-blockers, whereas LQT2 patients with KCNH2 variants are known to be at a higher risk in the presence of sudden noises. Therefore, a genetic test helps in a better disease prognosis in the proband, disease risk assessment in family members, and also help in prenatal diagnosis.[28],[29],[30]

  Steps Involved during a Genetic Test Top

  1. Genetic evaluation should start after a comprehensive clinical examination and diagnosis by the cardiologist, as clinical information is extremely important in deciding the type of genetic test that needs to be performed
  2. After a confirmed clinical diagnosis, a three-generation detailed family history is mandatory. Pedigree helps to determine the mode of inheritance, identify at-risk immediate family members with any medical conditions. Questions related to the details of heart disorders, sudden deaths in the family with reasons known or unknown, symptoms of palpitations, and syncope should be asked to the patient during the pretest genetic counseling session
  3. Select an appropriate genetic test based on the type of disorder and range of symptoms, mostly its either a cardiac panel or whole-exome sequencing (WES)
  4. Genetic counseling: Genetic testing should precede and end with a pretest and posttest genetic counseling sessions, respectively. Genetic counselors help to effectively communicate the result interpretation and limitations of the tests, for the patient to make informed decisions. Even when genetic testing is not recommended, genetic counseling is important to educate the patients about the risk of transmission to future generations. Genetic testing should be offered to index patients who fulfil the diagnostic criteria for an inherited cardiac disorder and cascade genetic testing are recommended in family members after disease-causing variant has been identified [Figure 1].
Figure 1: Flowchart showing various steps involved in the genetic evaluation process

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  How to Choose a Genetic Test Top

Advances in next-generation technology have brought tremendous improvements that have made genetic testing cost-effective and more accessible. Owing to the heterogeneous nature of cardiac disorders with several overlapping genes, a multigene panel (covering 100–170 genes) is usually recommended and is also the standard of practice for cardiovascular genetic testing rather a single-gene testing approach. Multigene panels have the advantage of increasing the probability of identifying a disease-causing variant. They also increase the likelihood of identifying individuals with multiple mutations, and this knowledge is essential for appropriate targeted testing of family members. A slight variation can exist in the composition of gene panels among different laboratories. The decision to order a panel that includes a larger number of genes should be based on the specifics of the patient's medical history, physical examination findings, and family history. It is critical that the ordering physician should have an understanding of the benefits, and limitations of specific test types to be able to select an appropriate test for their patient.

In syndromic cardiac disorders with extracardiac manifestations, WES has proven to be very helpful. With its ability to detect the changes throughout the coding regions of the human genome and being increasingly cost-effective, WES is a valuable diagnostic clinical tool for elucidating the genetic etiology of diagnostic odysseys. However, it also has the chance of identifying variants of unknown significance, which are difficult to interpret and decode clinically. More the number of genes screened higher the numbers of Variant of unknown significance (VUS), thus increasing the complexity of the interpretation. In addition, there are higher chances that a causative variant is classified as a VUS in a newly identified gene due to the lack of supporting scientific evidence.

  Genetic Test Interpretation and Recommendations Top

Large gene panels produce several variants and the entire crux of clinical management lies in how well the variants have been classified and interpreted. As per the ACMG guidelines, there is 5–tier variant classification as “pathogenic,” “likely pathogenic,” “benign,” “likely benign” and VUS. Genetic testing results are probabilistic rather that determinative. Whether a variant is pathogenic or benign primarily depends on the strength of evidence available on different population and disease databases such as gnomAD (, Clinvar (, OMIM (https://www.ncbi.nlm., HGMD (http://www., and dbSNP ( The future course of recommendation with respect to the clinical management in the proband and cascade genetic testing in the at-risk family members greatly depend on variant annotation and classification. The four different scenarios are described below:

Identification of a pathogenic or a likely pathogenic variant

A variant which results in the loss of function of protein is classified as pathogenic or likely pathogenic. Identifying a pathogenic variant confirms the disease diagnosis in the index patient. Further, it also allows the at-risk family members to do targeted genetic testing. Family members who carry the same variant as that of the proband are at a higher risk of developing the same heart condition and should be advised for a regular follow-up and physical examination by a cardiologist. Relatives who do not have disease-causing variant are very unlikely to develop the condition and cannot pass the variant to future generation as well. However, it is important to carefully examine these individuals if the?y develop any symptoms or other changes. Having a familial mutation in a family member means that there is a high risk of developing the disease at some point in life, but it is difficult to predict the actual occurrence or severity of the condition. In case of channelopathies, having the genetic defect means that the disease is confirmed and therefore preventive strategies should be established, for example, having a familial mutation in a LQTS gene would mean being at higher risk of SCD even if the basal ECG shows normal values. Therefore, lifestyle changes should be recommended and beta blocker therapy may be indicated.[20],[28]

Identification of a benign or likely benign variant

When a benign or likely benign variant is identified in the proband, it indicates that such variants are also present in the healthy population, and therefore, it has no role to play in disease causation. In such cases, predictive and cascade genetic testing is not recommended in the at-risk family members. However, there may be chances that the disease-causing variant is present on other genes that are not covered in the test.[20],[28] Most of the clinical laboratories do not report benign variants.

Genetic test with “no variants” detected

If no variants are detected in a genetic test, it does not mean that the cause of the condition is not genetic. It could be possible that variant is present in a gene which was not part of the gene panel, or a variant is identified in a gene not well associated with the condition. When no specific cause of disease is identified, then predictive and cascade genetic testing in unaffected relatives is not warranted either. Rather, family screening using phenotypic evaluations is recommended. Large panels with better coverage of the relevant genes, analysis for deletions, duplications in the genes of interest, or WES may also be considered. Genetic testing may be reconsidered in the future to identify any new associated genes. On the other hand, if the causative variant identified in the proband is not found in the family members, then the risk of recurrence in the family is reduced.[20],[28]

Identification of a “variant of unknown significance”

As mentioned before, large gene panels give rise to several variants whose clinical relevance is unknown at present. In such cases, a genetic test may be inconclusive due to the lack of evidence to classify a variant as pathogenic or benign. Such variants are called as variants of uncertain significance. Targeted testing of VUS in the unaffected family members is not recommended, however, just like a negative result, an inconclusive result does not rule out the genetic basis of the inherited heart condition and physical examination of at-risk family members is still recommended. With growing information in genetics, new evidences from case–control studies may reclassify a VUS to either pathogenic or benign.[20],[28]

  Conclusion Top

With the growing advances in interventional therapies and molecular genetic diagnostics, incorporating genetic testing for inherited cardiovascular diseases by cardiologists can greatly improve the disease management for patients.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4]


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