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Cardiovascular genetics: the role of genetic testing in diagnosis and management of patients with hypertrophic cardiomyopathy
  1. Monica Ahluwalia,
  2. Carolyn Y Ho
  1. Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
  1. Correspondence to Dr Carolyn Y Ho, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA; cho{at}


Genetic testing in hypertrophic cardiomyopathy (HCM) is a valuable tool to manage patients and their families. Genetic testing can help inform diagnosis and differentiate HCM from other disorders that also result in increased left ventricular wall thickness, thereby directly impacting treatment. Moreover, genetic testing can definitively identify at-risk relatives and focus family management. Pathogenic variants in sarcomere and sarcomere-related genes have been implicated in causing HCM, and targeted gene panel testing is recommended for patients once a clinical diagnosis has been established. If a pathogenic or likely pathogenic variant is identified in a patient with HCM, predictive genetic testing is recommended for their at-risk relatives to determine who is at risk and to guide longitudinal screening and risk stratification. However, there are important challenges and considerations to implementing genetic testing in clinical practice. Genetic testing results can have psychological and other implications for patients and their families, emphasising the importance of genetic counselling before and after genetic testing. Determining the clinical relevance of genetic testing results is also complex and requires expertise in understanding of human genetic variation and clinical manifestations of the disease. In this review, we discuss the genetics of HCM and how to integrate genetic testing in clinical practice.

  • hypertrophic cardiomyopathy
  • clinical genetics
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Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder characterised by unexplained left ventricular (LV) hypertrophy in the absence of pressure overload, storage/infiltrative processes or other conditions that may result in increased LV wall thickness. The estimated population prevalence of HCM is 1:500 and there is an important genetic component.1 Disease-causing (pathogenic) variants in sarcomere genes are found in ~30% of patients with HCM overall and over 60% with familial disease.2–4 As such, HCM is the most common inherited cardiomyopathy.

Genetic testing can be a valuable tool in managing patients and families with HCM by improving diagnostic accuracy and definitively identifying at-risk relatives.5–7 However, successfully integrating genetic testing with patient care requires understanding of its unique complexities. The purpose of this review is to describe the genetic basis of HCM and discuss how genetics can be used to care for our patients and families.

Genetics of HCM

Pathogenic variants in genes encoding the sarcomere apparatus are the most common genetic aetiology of HCM (table 1). The yield of genetic testing ranges from ~30% to over 60%, with the highest yield in patients with a family history of HCM and therefore a higher a priori likelihood of genetic disease. There are eight core sarcomeric genes with definitive evidence for causing HCM—MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2 and MYL3—and currently four genes with moderate evidence supporting their causal role in HCM—CSRP3, TNNC1, ACTN2 and JPH2.4 7–10 Variants in MYH7, encoding cardiac β-myosin heavy chain, and MYBPC3, encoding myosin-binding protein C, account for the majority of cases of sarcomeric HCM.4 HCM mimickers or genocopies include Fabry disease (caused by variants in GLA), familial amyloidosis (caused by variants in TTR), Noonan syndrome and other rasopathies (caused by variants in genes in the Ras/mitogen-activated protein (MAP) kinase pathway), Danon disease (caused by variants in LAMP2), and glycogen storage disease (including disease caused by variants in GLA and PRKAG2). Variants in ACTN2 can cause a primary cardiomyopathy with variable phenotypes, including HCM, dilated cardiomyopathy and LV non-compaction.11 12 The list of intrinsic cardiomyopathy genes and syndromic genes associated with isolated LV hypertrophy will continue to expand as knowledge evolves. Although these diseases classically have distinguishing clinical features, signs can be subtle and overlapping cardiac-predominant phenotypes occur. As such, genetic testing can provide critical information to clarify diagnosis.13

Table 1

Major genes implicated in hypertrophic cardiomyopathy and genocopies

Patients in whom genetic testing does not identify any clinically significant variants (negative genetic testing results) are broadly categorised as having non-sarcomeric HCM. Patients with negative genetic testing and no family history of HCM are termed as having non-familial HCM.14 Non-familial HCM has been associated with older age at presentation and less severe clinical course, including lower risk of mortality, compared with other patients with HCM.14 15 As greater experience is gained, there could be important clinical implications, as relatives of patients with non-familial HCM would be considered at lower risk because genetic disease is less likely and consequences may be less severe. Thus, longitudinal screening to monitor for disease development may not be required except for the initial evaluation to establish that non-familial disease is present.

Genetic testing

Currently, the main benefits of genetic testing are to (1) identify the molecular aetiology of disease, thus clarifying diagnosis and facilitating appropriate management13 16; and (2) inform family management. Optimal provision of genetic testing requires recognising that a particular cardiovascular disease may be genetic in aetiology, determining the best genetic testing strategy, agreeing that the variant classification provided by the genetic testing laboratory is appropriate (or seeking further consultation if results are challenging), and providing appropriate pretest and post-test counselling to effectively communicate the results and their implications to the patient and their family.17 An important first step is for the provider to obtain a three-generation family history in pedigree format to detail family structure, medical diagnoses and causes of death. Such systematic review allows the provider to determine if familial disease is potentially present, establish the inheritance pattern and identify relatives who may be at risk of developing the disease. Obtaining a thorough family history provides a unique opportunity to not only develop a relationship with the patient, but also better understand family dynamics and potential barriers that may impact family communication.

Genetic counselling

The goal of genetic counselling is to help people understand and adapt to the medical, psychological and familial implications of genetic disease. As such, genetic counselling involves knowledgeable and trained health professionals such as genetic counsellors, genetic nurses and/or medical geneticists with appropriate expertise. If genetic testing is being considered, pretest counselling is essential to discuss the goals, anticipated yield, benefits, limitations and implications for the family. Since family history and age of presentation can influence the yield and interpretation of genetic testing, counselling should be tailored accordingly. Careful attention to the patient’s psychosocial needs is also required. For instance, young patients may encounter challenges as they transition into adulthood or consider starting a family, and additional psychological, emotional, social and cognitive support may be needed. Overall, patients should be prepared for all the possible scenarios of testing, including receiving ambiguous results that are not currently actionable but may be reclassified in the future as more evidence becomes available, and understanding that negative results (failing to identify a clinically significant variant) do not exclude the possibility that genetic disease is present.

Engaging families to pursue recommended screening can be challenging. At-risk relatives who do not yet have diagnostic phenotypic features should be informed about their risk of developing HCM and passing it on to their children. In this case, genetic counselling and testing would help inform longitudinal screening for the relative and cascade screening for other family members. Ultimately, it is the responsibility of the proband (index patient) to communicate with their family regarding the potential for familial disease, results of genetic testing (if available) and recommendations for screening. Due to privacy restrictions, providers ordering genetic testing on the proband cannot directly contact relatives; however, they play an important role in helping their patients communicate with the family by providing support, advice on how to educate relatives and access to resources.18

Family screening

Family screening is performed to identify affected relatives and follow relatives at risk of developing clinical disease. The goals are to provide timely cardiac surveillance and initiate early treatment that may help attenuate adverse outcomes, notably sudden death and symptomatic heart failure.10 The systematic process of identifying relatives at risk for a genetic condition is termed cascade testing and may incorporate clinical screening and predictive genetic testing (figure 1). If the genetic aetiology has not been identified or relatives do not wish to pursue genetic testing, the process begins with clinical screening in the first-degree relatives of an individual with HCM (figure 1A). Due to the variable penetrance and expressivity of HCM, at-risk relatives may not manifest symptoms or signs until early or middle adulthood; thus, longitudinal clinical evaluation is recommended for relatives who are genetically susceptible or have unknown genetic risk (no genetic testing or no definitive variant identified in the family). The frequency of serial clinical evaluation (physical examination, electrocardiogram and, echocardiogram) is determined by age: consider initial screening in early childhood, then every 12–18 months in children and adolescents, and every ~5 years in patients >21 years of age (American College of Cardiology/American Heart Association guidelines5), or every 1–2 years between 10 and 20 years of age, and every 2–5 years thereafter (European Society of Cardiology guidelines6). If additional relatives are identified as having HCM during screening, their first-degree relatives are evaluated, and so forth.

Figure 1

Family screening using a clinical (A) or genetic (B) approach is described. (A) Clinical screening: All family members are at risk of developing HCM (red arrows). Current guidelines recommend that all first-degree relatives (blue stars) of an affected individual undergo serial, longitudinal clinical screening to monitor for disease development. If any of those relatives are found to have HCM (or develop HCM), their first-degree relatives should be screened, a process referred to as cascade screening. The frequency of longitudinal screening varies by age and is outlined in the 2011 ACC/AHA and 2014 ESC guidelines.5 6 (B) Predictive genetic testing is recommended for all members of families in whom a pathogenic variant has been identified to definitively determine which relatives are and are not at risk of developing HCM. Based on these results, family screening can evolve from broad, longitudinal screening of all potentially at-risk relatives (A) to focused longitudinal screening of relatives who are definitively at risk for the disease by inheriting the family’s pathogenic variant (B; red plus sign). Relatives who have not inherited the family’s pathogenic variant (red minus sign) and their children are not at risk of developing HCM. Longitudinal follow-up is not required unless there is a change in clinical status. The black arrow indicates the family proband who underwent genetic testing and was found to carry a pathogenic sarcomeric variant. Squares indicate male and circles indicate female. The filled shapes indicate an individual who has been clinically diagnosed with HCM and the unfilled shapes denote a clinically unaffected relative. ACC, American College of Cardiology; AHA, American Heart Association; ESC, European Society of Cardiology; HCM, hypertrophic cardiomyopathy.

Relatives who have negative predictive genetic testing and do not carry the causative variant can be reassured that they, and their children, are not at increased risk of developing HCM. They can be released from longitudinal screening, but with a low threshold for evaluation if there is any clinical change.

Diagnostic and predictive genetic testing

The purpose of genetic testing is to (1) help provide a definitive diagnosis in patients with known or suspected HCM and (2) guide management of at-risk or undiagnosed relatives.17 There are two basic types of genetic testing: diagnostic and predictive (variant confirmation in relatives).19 Diagnostic testing is performed on an affected individual to attempt to identify the genetic aetiology of disease, typically by using a multigene panel including at least the eight core sarcomeric genes, HCM-associated genes and genocopies (table 1 and further details below). This information can clarify diagnosis and identify the underlying disease process, including differentiating HCM from other genocopies, including metabolic, storage and infiltrative disease. These distinctions critically impact clinical management. The family member with the most definitive diagnosis and the most severe disease expression (based on age of onset and clinical manifestations) is the ideal genetic testing proband for the family as the yield of genetic testing will be highest. Testing the most severely affected relative also provides the greatest likelihood of capturing rare instances when multiple pathogenic variants are present in a single family.20 However, genetic testing may not provide a definitive diagnosis and must be interpreted in conjunction with the clinical presentation and family history.

If a definitive pathogenic variant is identified by diagnostic genetic testing in the family proband, predictive or variant confirmation genetic testing can be offered to relatives (figure 1B). Predictive testing involves focused testing on relatives to determine if they inherited the specific pathogenic variant identified as the cause of disease in their family. Relatives confirmed to carry the pathogenic variant are at risk of developing the disease and should be counselled regarding symptoms and signs of HCM. They should also undergo serial clinical screening to assess for phenotypic evolution and disease development. The penetrance of pathogenic variants (the likelihood that an individual who carries the pathogenic variant develops the disease) is variable and incomplete. Additionally, there is variable expressivity (phenotypic expression associated with the variant).21–23 Moreover, it is not possible to predict when, how severe, or even if disease will develop, highlighting the need for longitudinal follow-up. In comparison to pathogenic variants, variants classified as likely pathogenic do not have definitive evidence that they are disease causing. As such, more caution is required with family management and both genotype-positive and negative relatives should seek attention if there are clinical changes. In contrast, relatives who have negative predictive genetic testing and do not carry their family’s pathogenic variant can be largely reassured that they are not at increased risk of developing HCM and that their children are not at risk. They can be dismissed from longitudinal screening, although they should undergo prompt evaluation if there are any clinical changes (figure 1). Overall, predictive testing can inform families about their risk of developing HCM and passing it on to their children and identifies at-risk relatives who require longitudinal screening.

It is important to recognise that predictive testing should not be pursued if there is any doubt that the variant identified is the cause of HCM in the family.19 In this situation, when genetic testing is not definitive, at-risk relatives should undergo serial clinical follow-up to assess for disease development. A common scenario is identifying a variant of uncertain significance (VUS) with diagnostic genetic testing. These variants are not clinically actionable as there is insufficient knowledge to determine whether they are pathogenic or benign. Since VUS are not reliable markers of disease, they cannot be used for predictive testing in relatives. However, segregation analysis can be performed in the family in an attempt to further assess the clinical significance of the variant (figure 2). With segregation analysis, affected relatives with HCM undergo predictive/variant confirmation testing to determine if they carry the variant of interest. The greater the number of affected relatives found to carry the variant (co-segregation), the more evidence accumulates to support that it is the cause of the disease in the family. In addition to other criteria, definitive evidence of pathogenicity requires that ~10 meioses carry the variant.24–26 In contrast, the absence of the variant in a single relative with a confident diagnosis of HCM (non-segregation) indicates that the variant is unlikely to be pathogenic. Variant confirmation is not pursued in unaffected relatives because their clinical status is not clearly defined (eg, they could be non-penetrant at the time of evaluation but develop HCM in the future, or they may be unaffected and not at risk). Such analyses can provide evidence to help reclassify VUS into a more actionable category as pathogenic or benign. This exercise is most effectively performed in coordination with the genetic testing laboratory so that all may benefit from the knowledge gained. Figure 3 summarises the process of genetic testing in the proband and family.

Figure 2

Segregation testing in a proband with a variant of unknown significance. Segregation testing can help determine if a VUS is disease-causing in a family. (A) All affected individuals undergo testing for the variant and are found to carry the variant (red plus sign). This finding demonstrates that the variant segregates with the disease across four meiotic events and increases the likelihood that the variant may be pathogenic. (B) Although the proband has a VUS, the variant is not present in the affected relative (blue circle). This finding suggests that the variant does not segregate with the disease (non-segregation) and is therefore unlikely to be the cause of disease in this family. Squares indicate male and circles indicate female. The black arrow indicates the proband who has a VUS. The filled shapes indicate an individual who has been clinically diagnosed with hypertrophic cardiomyopathy and the unfilled shapes denote a clinically unaffected relative. VUS, variant of unknown significance.

Figure 3

Schematic for employing genetic testing in the proband (index patient) and family. ACC, American College of Cardiology; AHA, American Heart Association; ESC, European Society of Cardiology; HCM, hypertrophic cardiomyopathy; LVWT, left ventricular wall thickness; VUS, variant of unknown significance.

Patients with confirmed genetic HCM have a 50% chance of transmitting the pathogenic variant, and therefore disease risk, to each offspring. In discussing reproductive planning, preimplantation genetic diagnosis can be considered. This is a process in which in vitro fertilisation is employed and genetic testing is performed on early-stage embryos.27 Only embryos that are determined not to carry the pathogenic variant are implanted, thus minimising the likelihood of transmitting disease risk.27 28

How to test

Diagnostic genetic testing uses multigene panels that have been tailored for specific phenotypes. Core sarcomeric genes that are included on all HCM genetic testing panels are MYH7, MYBPC3, TNNT2, TNNC1, TNNI3, TPM1, MYL2, MYL3 and ACTC1 (table 1).19 Additionally, panels typically include genes with less robust support for causing HCM and genes implicated in other conditions that cause increased LV wall thickness, including glycogen storage disease and lysosome storage diseases, metabolic disease, and other genetic syndromes such as Noonan syndrome. Most panels include >26 genes; however, the yield of clinically actionable results has not increased substantially by increasing panel size.4 29 DNA can be extracted from blood, saliva or previously banked tissue. Costs are variable, and some healthcare systems may provide coverage for genetic testing.

There has been concern that genetic testing may result in genetic discrimination for individuals found to have disease-causing variants. In the USA, the Genetic Information Nondiscrimination Act of 2008 was implemented to provide protection against discrimination regarding health insurance and employment30; however, these protections do not extend life insurance, long-term care or disability. Laws vary from country to country; hence, patients and providers should understand current policies and potential implications prior to undergoing genetic testing. Typically, determining the genetic aetiology of disease does not meaningfully impact individuals with a clinical diagnosis, but implications may be greater for at-risk relatives.

Interpretation of genetic testing and classification of variants

The most challenging and critical aspect of genetic testing is interpreting the results and determining the clinical relevance of a variant. Variant classification is a complex process that requires expertise in understanding of human genetic variation, disease manifestations and weighing available evidence. Although firm evidence exists to support classifying some variants as being definitively pathogenic, uncertainty remains in classifying many variants due to lack of data or ambiguous, even conflicting, results. Further, communication of these results to the patient and family is key, and misinformation can lead to potential harm. Inaccurate interpretation of an uncertain variant can lead to overtesting and unnecessary worry if the variant is incorrectly classified as pathogenic, or alternatively can lead to false reassurance to patients and their families if incorrectly classified as benign.

Originally, variant classification was at the discretion of individual genetic testing laboratories, leading to non-standardised and sometimes discrepant interpretations of the same variant.31 In 2015, the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) published guidelines to provide a conservative and standardised framework for variant interpretation to help minimise the risk of false-positive results (classifying a variant as pathogenic when it is benign) or false reassurance (classifying a variant as benign when it is pathogenic).24 The current guidelines apply to all Mendelian diseases and incorporate eight different types of evidence (including loss-of-function mechanism of disease, established pathogenic variants, functional studies, variant frequency in cases and control population, segregation with disease, and computational evidence).24 Based on these criteria, a five-tier classification is used to classify variants as benign, likely benign, unknown significance, likely pathogenic or pathogenic. Although variant classification is a critical aspect of genetic testing, it is an imperfect science that attempts to estimate the probability that a variant is disease-causing based on limited data. Classifying a variant as pathogenic or likely pathogenic variant indicates that the variant is considered capable of causing disease, whereas classifying as benign or likely benign indicates that the variant is not thought to be disease-causing. If there is insufficient evidence to determine disease causality, the variant is classified as a variant of unknown significance. Table 2 outlines the five-tier variant classification and clinical implications of these results for the patient and family.

Table 2

Variant classification and clinical implications

More recently, important resources have been developed to improve variant interpretation (table 3). Population-based databases of genetic variation from large-scale whole exome and genome sequencing initiatives have been aggregated and made publicly available (Genome Aggregation Database, gnomAD).32 This information provides key insights to help determine if variants are too common to cause rare disease, accounting for ethnic/racial background. Ongoing web-based tools and collaborative efforts aim to create gene-specific recommendations, establish allele frequency cut-offs, define applicable functional studies, weigh evidence of co-segregation of variants, establish evidence for loss-of-function disease mechanism and create quantitative scores to estimate the likelihood of variant pathogenicity.25 31 ClinVar, a resource of the National Center for Biotechnology Information, aggregates available variant-level information, notes when there are conflicting interpretations from different testing agencies and periodically updates listing. Additionally, the Cardiovascular Clinical Domain Working Group of the Clinical Genome Resource applied the ACMG/AMP framework and additional resources to provide systematic, expert curation of variants in MYH7 associated with cardiomyopathies.33 The results of this and additional ongoing efforts are documented in ClinVar.

Table 3

Database resources for interpretation of gene variants

Studies have recently proposed using a quantitative approach to further classify variants in HCM cohorts in a large data set of over 6100 patients.25 In efforts to improve diagnostic yield of genetic testing of Mendelian diseases and enhance variant interpretation, the authors used population frequency thresholds and detection of pathogenic clusters in disease-causing genes and were able to estimate the probability of pathogenicity of a rare variant.25 34 The authors noted that this novel framework resulted in ~14%–20% increase in cases with HCM variants that could be reclassified as pathogenic or likely pathogenic.25 As genetic testing continues and expands to include larger gene panels and whole genome and whole exome sequencing, improved interpretation of variants will be imperative.15

Future directions

Whole genome and whole exome sequencing

Whole genome sequencing (WGS) and whole exome sequencing (WES) will be increasingly used in lieu of targeted gene panel testing as availability increases and costs decrease. Using WGS/WES as a single test has theoretical benefits of being able to provide greater insights for gene discovery, identify modifier genes, reanalyse non-diagnostic cases over time and create large genome data sets for future study in validating polygenic risk scores.35 36 However, the clinical role has not yet been well established. One study compared targeted HCM genetic testing with WGS in patients with HCM and demonstrated similar clinical diagnostic yield.37 Incidental findings unrelated to the genetic testing indication may be identified and trigger further testing. For example, monogenic variants may be detected in genes associated with diseases such as cancer and thrombophilia.37 Carrier states for recessive disease were also identified, which can have important implications regarding reproductive planning.37 Although WGS/WES provides the potential for new gene discovery, interpreting the data can be challenging and unanticipated findings should be expected, further emphasising the importance of pretest counselling and multidisciplinary team approach in defining the relationship between genotype and phenotype.


Genetic testing plays an important role in the management of patients with HCM and their families. Genetic testing can help provide a molecular diagnosis and differentiate HCM from other conditions that also lead to increased LV wall thickness, thus impacting the clinical management of the patient and their family. If a pathogenic variant is detected, predictive testing can definitively identify at-risk relatives and guide longitudinal family screening. However, understanding the clinical relevance of genetic testing is complex and variant classification may be ambiguous. As such, pretest and post-test counselling is essential to help establish appropriate expectations and assist the patient and family in understanding the results. Further expertise and consultation should be sought if genetic testing results are challenging. As comprehensive WES and WGS panels become more readily available, ongoing research efforts are key to expand our knowledge in variant interpretation.


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  • Contributors MA planned, wrote the initial draft of the manuscript and revised it critically for important intellectual content. CYH made substantial contribution to revising the manuscript critically for important intellectual content and writing of the final version of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; externally peer reviewed.

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