Journal of Cardiovascular Translational Research

, Volume 2, Issue 4, pp 493–499 | Cite as

Genetic Counseling and Testing for Hypertrophic Cardiomyopathy: An Adult Perspective

  • Cécile Skrzynia
  • Erin M. Demo
  • Samantha M. Baxter


Hypertrophic cardiomyopathy (HCM) is considered to be a genetic disease. As such, multidisciplinary approach is needed to evaluate and treat this condition. We present several patient vignettes to illustrate the complementary skills of cardiologists and genetic counselors in providing comprehensive care. Translational application of research will continue to expand as more genetic causes of HCM will be recognized and more genetic tests will become available. Now is the opportunity to build a strong collaboration between the two disciplines to be prepared for the era of personalized medicine.


Genetic Counseling Hypertrophic Cardiomyopathy Cardiac Genetics 

The first case of hypertrophic cardiomyopathy (HCM) in an adult was described about 50 years ago [1]. At that time, most of the diagnostic and therapeutic techniques which are relied upon today, such as echocardiography, cardiac catheterization, and implantable cardioverter-defibrillators (ICDs) were unavailable. Likewise, our understanding of the genome in general and of cardiac genetics in particular, was almost non-existent.

The first genetic counseling training program opened its doors in 1969 and the National Society of Genetic Counselors (NSGC) was formed 10 years later and the past 40 years have shown continuous growth of this profession. Originally, the role of genetic counselors was confined primarily to the prenatal setting but has gradually expanded to now encompass the pediatric and adult medicine realms. As genetics becomes increasingly important to subspecialties, the need for a combined approach to patients, incorporating the expertise of both the subspecialist MD and the genetic counselor becomes necessary. Nowhere are the opportunities greater than in cardiology, where genetics is rapidly providing insight into a variety of disorders diagnosed and managed by cardiologists.

The most recent testimony to the importance of genetic counseling in cardiology is a set of guidelines addressing the recommended approach to the cardiomyopathies. In these guidelines, the authors consider evaluation, genetic counseling, and genetic testing to be complex processes that warrant referral to experts in genetic evaluation [6]. Even more recent is a publication by JM Bos et al. highlighting the importance of genetic considerations in HCM [2].

This overview of the genetic counseling and testing in adult HCM is based on several typically encountered cases. While each vignette is different, all by definition involve not only the individual, but also members of his/her family, sometimes adult, sometimes children or adolescents. Genetic counseling not only provides information about the pros and cons of genetic testing and the practical aspects of the test, it also addresses the unique psychological impact of cardiac disease and treatment. It should be an integral component of a comprehensive medical evaluation in cardiology when hypertrophic cardiomyopathy is clearly not caused by environment or other non-genetic causes such as athlete’s heart.

Case 1

Same Family, Two Outcomes of Genetic Testing

A 35-year-old woman presents to the cardiology clinic with a family history of hypertrophic cardiomyopathy. Her brother, who was diagnosed 3 years ago, recently died suddenly in his sleep. Her father passed away at 65 of a heart attack, and so did a paternal uncle who died at 70. She has three teenage children who are all very active in sports and she is extremely concerned about them. She had an echocardiogram 10 years ago that was normal but has not been evaluated since. This past month she experienced a syncopal event during the funeral of her brother; she attributed this to not having any food intake that day.

After a full evaluation with an echocardiogram and electrocardiogram she is informed that she has HCM. The option of genetic testing which may give her more information about the etiology of her disease is discussed. This information would also help her children: they could decide if they wanted to know their risk status as well. She is consented for the test and her blood is drawn.

Molecular Analysis was Performed in Lab A on a Panel of 11 Genes Associated with HCM

Scenario A

The report states “DNA sequencing did not detect the presence of any disease-associated variants in the coding regions or splice sites of the ACTC, GLA, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PRKAG2, TNNI3, TNNT2 and TPM1 genes. Variants in these genes have been identified in approximately 52% of individuals with clinical features of hypertrophic cardiomyopathy. Therefore, a negative test result reduces but does not eliminate the possibility that the individual has an underlying genetic cause of cardiomyopathy.”

How to Counsel This Patient

One can start by reassessing the family history for any non-sarcomeric causes of cardiomyopathy: muscular dystrophy, metabolic deficiency, or congenital malformations. The review of family history also serves to provide a background for interpretation of the test result. In this case, the negative test result is uninformative.

This patient has a clinical diagnosis of HCM; the negative test result does not change this diagnosis. Before talking about other family members, the focus should be on the patient herself, specifically her long-term management issues.

If the patient heard about implantable cardioverter-defibrillators (ICDs) she might ask whether she would need one. The question of ICD is the one requiring the most counseling. The risk of sudden cardiac death (SCD) in HCM [4] depends on the following risk factors (excluding known genetic mutations): prior cardiac arrest, recurrent syncope, family history of SCD, severe LV hypertrophy, LV outflow obstruction, abnormal blood pressure during exercise and presence of non-sustained ventricular tachycardia (NSVT). In patients with two or more risk factors ICD should be considered.

The following is recommended:
  1. 1.

    Referral for blood pressure measures during treadmill exercise.

  2. 2.

    Referral to an electrophysiology specialist to discuss pros and cons of an ICD.

The next point that needs to be addressed is the impact of the test result on family members: The patient has a 50% chance of passing onto her children the susceptibility to developing HCM given the autosomal dominant (AD) pattern of inheritance in the family. The children are young and can manifest symptoms and even SCD during teenage years. When the patient asks how to talk to her teenagers about their risk, the referral to a different specialist is needed. This is a long discussion best done by someone knowledgeable about psychological aspects of cardiac diseases; genetic counselors have experience in dealing with children and other family members in similar situations.

For the patient’s younger brother and for her children, a baseline echocardiogram is recommended; since there is a 50% chance that they may also be affected. The echocardiograms need to be repeated every 3 years [10], even if there is no abnormality detected. This is due to age-related penetrance and variable expressivity [14]. Manifestations of HCM depend on which gene is mutated and what particular mutation is present. While the discussion of genotype–phenotype correlation is beyond the scope of this paper, the heterogeneity of HCM dictates a conservative approach to surveillance when the probability of a mutation is 50%.

At this point, there is no reason to test anyone else in the family since the patient is the only person clinically affected in the family and her test was not informative. This situation is not uncommon, since the test sensitivity is 52% and it means not detecting mutation in almost half of patients with HCM. Testing other family members would not give us more information; we already tested the person most likely to have a mutation and did not find any.

However, this situation may change and the patient needs to stay in touch with the practitioner. One likely possibility is that the test sensitivity will improve and re-testing in the future will detect a mutation. Another possibility is emergence of a new technology which would allow detecting hitherto “hidden” mutations. In both cases, testing other family members would become available, which could eventually spare some of the unnecessary monitoring.

Typically, patients who find out genetic test results need more psychological support [5]. One resource that has been very helpful in such situations is the HCMA (Hypertrophic Cardiomyopathy Association Their website offers an opportunity to contact other patients via their chat room. For the patient, a follow-up visit to discuss the ICD is made.

Scenario B

The report states “DNA sequencing of the coding regions and splice sites of the ACTC, GLA, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PRKAG2, TNNI3, TNNT2 and TPM1 genes revealed a heterozygous V178fs variant in exon 5 of the MYBPC3 gene. This variant has not been reported in the literature. However, the V178fs variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 178 and leads to a premature stop codon 7 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. As such, this variant is highly likely to be pathogenic and therefore causative for HCM.”

The patient is informed that her test results are available. The laboratory was able to find the specific genetic change that explains her echocardiogram findings of hypertrophy and also her family history of sudden death and heart attacks. An appointment is scheduled to further discuss this result face to face and the patient is invited to think about the questions she may want to ask.

In preparing for the appointment, one can think of three items on the agenda that would be important for the patient to take home:
  1. 1.

    The genetic test gave very useful information to the patient and her relatives. This result will allow further testing in the family.

  2. 2.

    The risk for her children and siblings is 50/50 for each to have or not have the same mutation. Genetic testing will sort out who in the family is at risk of developing HCM and who is not.

  3. 3.

    There are surveillance and other strategies to reduce risk of sudden death in her and others who may have inherited the familial mutation.

On the day of the appointment, the clinician finds out that the patient is accompanied by her husband and mother. While the patient was on previous occasion very matter of fact and calm, she is now very upset and was obviously crying. Her first question is: “are my children going to die like my brother?”

In an ideal setting, there may be plenty of time and an available genetic counselor, clinical psychologist, and social worker to help deal with this situation. But this is seldom the case. One needs to start by calming the patient, otherwise she will not be able to absorb the information and act upon it. This can be achieved by changing the order of the agenda and starting by reassuring the patient first.

The patient asks to see her test report and reads it. She asks for clarification of the report, particularly of the last sentence: “As such, this variant is highly likely to be pathogenic and therefore causative for HCM.” One way to explain this result in simple terms is to say: this particular gene, the myosin-binding protein C is coding for a part of the cardiac cell that is involved in contracting and relaxing; the gene change found in the patient has not been reported before; however, we know that this type of change called frameshift is always causing a non-functional gene product; we therefore feel that it caused HCM in the patient.

The patient wants to know if it is possible that the lab made a mistake. The laboratory takes great precautions to avoid mistakes, the samples are identified by bar codes, and chance of mixing samples is almost nil. The laboratory also does confirmatory test before releasing results, to be sure of the accuracy.

The patient’s husband is concerned about his wife’s risk of sudden death. For this patient, two risk factors are present: family history and NSVT. You estimate an at least 1% per year risk of SCD [9] and suggest a consultation with an electrophysiologist to make an informed decision about ICD.

The patient’s mother is concerned about her grandchildren’s risk of SCD during competitive sport activities. The first step should be performing single-site testing for the familial mutation in each child. If one child or more happened to inherit the maternal mutation, they certainly could continue to participate in high school athletic programs. It would not be wise, however, to have them train for highly strenuous and competitive, state- or national-level activities.

As presymptomatic testing has many other issues, it requires a separate discussion. This is an area where genetic counselors’ experience is particularly valuable. Parental issues are not always the same as children issues, but children can be involved in decision-making and adolescents should be. Genetic counselors can provide further counseling with or without children, discuss individual decisions, describe options for cardiac screening, help to plan the order of testing and direct to support groups and other resources. They can also address an issue that is of concern to many patients, namely potential for genetic discrimination. As of May 2009, the Genetic Information Non-discrimination Act (GINA) signed previously by former president Bush became law. It prohibits penalizing mutation carriers by health insurance companies and is a first step on a federal level to protect consumers of predictive genetic testing.

Case 2

A Metabolic Condition

A 68-year-old female presents to the cardiology clinic with a recent history of chest pains. Apical left ventricular hypertrophy is noted on echocardiogram and she is given a diagnosis of HCM. This can be caused by environmental and genetic factors. A detailed family history reveals that she has two siblings, a younger 60-year-old brother and an older 70-year-old sister. Her parents died in their late 70s of natural causes. She has three daughters. None of her relatives reportedly had any cardiac problems. Given her age and negative family history, it is hard to determine whether HCM in her case is environmental or genetic.

Two months later, she returns to the clinic with information about genetic testing for HCM that she obtained online. She reports that her three daughters are concerned that this could be hereditary and that she is interested in having genetic testing performed. After a discussion of limitations and benefits of testing, she consents and a blood sample is drawn.

Molecular analysis was performed in Lab A on a panel of genes associate with HCM. The report states “DNA sequencing of the coding regions and splice sites of the ACTC, GLA, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PRKAG2, TNNI3, TNNT2 and TPM1 genes revealed a heterozygous N215S variant in exon 5 of the GLA gene.

This missense variant has been reported in the literature and meets criteria for pathogenicity based upon functional evidence. This variant was identified in four males and one female who presented with atypical Fabry disease with a cardiac specific phenotype and one individual with classic Fabry disease. In summary, this variant is highly likely to be causative for HCM in this individual. This individual could also be at risk for the development of other clinical features associated with Fabry disease.”

Case Discussion

Fabry disease is an X-linked glycogen storage disease and is due to mutations in the alpha galactosidase A gene (α-gal A, GLA gene), which lead to accumulation of globotriaosylceramide (GLA) in vessel walls. The classic symptoms, which include acroparesthesias, corneal clouding, hypohidrosis, and angiokeratomas, often appear in affected males during childhood. Later in life (typically during the fifth decade), cardiovascular disease, renal failure, and strokes develop. [11]. The pattern of inheritance of this disorder is X-linked recessive. It is now recognized that female mutation carriers often manifest aspects of this disease [8, 16].

In this case, the patient did not have any childhood skin or ocular findings, she did not have a history of pain in her extremities, and she did not have reduced sweating. It appears that she had the late onset cardiac variant of Fabry disease [8] with the hypertrophy resulting from sphingolipid deposition in the cardiac tissue. At this point, the practitioner needs to explain the possible extracardiac complications associated with Fabry disease and address the risk of Fabry’s in her relatives, taking into account the complex inheritance pattern produced when an X-linked disorder can manifest in female carriers.

The patient is at risk of renal problems. Specifically, the sphingolipid deposition in podocytes within the kidneys can often cause proteinuria. In general, there is no progression to renal failure [16], but a periodic urinalysis for this patient is prudent. One cannot be completely reassuring regarding risk of strokes later in life, as the variability of the disease is well documented [3].

The patient’s cardiovascular disease may eventually progress to congestive heart failure. Oftentimes, in patients with Fabry disease, the cardiac deterioration includes mitral valve thickening or prolapse and conduction system abnormalities which may lead to fatal arrhythmias. Therefore, a cardiac pacemaker may be needed in some patients [13]. She will definitely need to be followed by a cardiologist on a regular basis to monitor her for these complications.

The patient should be made aware that enzyme replacement therapy (ERT) exists for this condition, but that its use is somewhat controversial in female mutation carriers [8, 17]. There is at this point a paucity of data regarding the efficacy of ERT for cardiac symptomatology in females with Fabry disease, so each case should be considered separately. A referral to metabolic genetics specialist may be useful.

The clinician needs to address the risk of Fabry’s for the patient’s children and siblings. She only has daughters; they each have a 50% chance of having inherited the familial GLA mutation. Typically, we would not expect any of them to manifest the disease, unless there is skewed X inactivation. This phenomenon is tissue-dependent, i.e., skin, white blood cells, heart cells, etc. can have different proportion of their X chromosomes inactivated. Analyzing different tissues is not an efficient and easy endeavor, and would not be useful in this context.

The recommendation therefore, is that the patient’s daughters and both siblings be tested for the known familial mutation. If they are not carriers, their risk of HCM is not increased above the general population risk. However, if one or more relatives are found to carry the GLA mutation; one would recommend a baseline echocardiogram, to be repeated every 3 years [10].

Case 3

Same Family, Individual Variations

A 31-year-old man with a clinical diagnosis of HCM returns to the cardiology clinic for his annual screening. He has been monitored since age 26, after his primary care physician detected a heart murmur and referred him for cardiology evaluation. The idea of genetic testing, which may help screening other family members is discussed. He agrees to go forward with testing, is consented for the test and his blood is drawn.

Molecular analysis was performed in Lab A on a panel of genes associate with HCM. The report states “DNA sequencing of the coding regions and splice sites of the ACTC, GLA, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PRKAG2, TNNI3, TNNT2 and TPM1 genes revealed a heterozygous E258K variant in exon 2 of the MYBPC3 gene.

The E258K variant has been reported in the literature and meets criteria for pathogenicity based upon segregation. In addition, the variant is predicted to cause a splice site alteration. Therefore, the E258K variant is highly likely to be pathogenic and causative for HCM.”

With this result, patient’s relatives, specifically his siblings and children, can be tested. Each of them has a 50% chance of carrying, or not carrying the familial mutation. Mutations in the MYBPC3 gene can cause manifestations in children as well as in adults; testing minors is recommended, certainly before teenage years. The patient reveals that he is no longer with the mother of his son, now 3 years old; she lives in a different state and he has very limited interactions with her. The patient’s siblings are tested and found not to carry the familial MYBPC3 mutation.

One year later, the same man returns to the office with two other test results. He explains that his son, who he has never met, was recently diagnosed with HCM. He understands that his son has some manifestations of the disease that he certainly did not have as a child. Genetic testing was initiated by the child’s cardiologist [12]. The child’s report looks different than his own. It states, “DNA sequencing of the coding regions and splice sites of the ACTC, GLA, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PRKAG2, TNNI3, TNNT2 and TPM1 genes revealed two variants in the MYBPC3 gene: a heterozygous E258K variant in exon 2 and a novel heterozygous L1200P variant in exon 32.”

He also has a copy of the mother’s report which appears to be negative. “DNA sequencing of exons 2 and 32 of the MYBPC3 gene did not detect the presence of the E258K variant or the L1200P variant, both of which were previously detected in the patient's son.”

Case Discussion

This situation, while not very common, is not as rare as to be exceptional (about 10% of pediatric cases have more than one mutation detected (unpublished data from one of the authors and [7])). Bearing in mind that we are diploid organisms, with two alleles of each gene segregating independently, the results of genetic testing in the child and both parents give the following genetic picture:
  • The father has a mutation on one of his MYBPC3 alleles; the other allele is wild type.

  • The mother has no mutations of the MYBPC3 gene; both her alleles are wild type.

  • The child has two mutations of the MYBPC3 gene. There are two possibilities: the mutations are in trans: one mutation on each allele, one inherited from the father, one de novo; or the mutations are in cis, both mutations on the same allele inherited from the father, one from the father, the other de novo, with the second allele being wild type.

The lab would need to do more extensive testing to prove which of the two possibilities happened. Additionally, maternal mosaicism needs to also be considered (see accompanying paper).

While the patient’s HCM diagnosed in his twenties has been so far successfully managed with surveillance and medications, the situation is much more serious for his son ([15], see the case discussion in accompanying paper). The complicated social situation makes it very difficult to provide appropriate psychological resources. The patient has more questions.

He now has a new partner and is considering having another child. He is concerned about this next child having severe HCM as does his previous son. Molecular analysis had demonstrated that the patient’s affected son has HCM due to the presence of an inherited mutation from dad and what appears a new or de novo mutation in the MYPBC3 gene. The risk that the next child will also sustain a new mutation in this same gene is negligible. Thus, barring the presence of gonadal mosaicism (discussed in the accompanying paper), we can be highly reassuring to the couple that subsequent progeny will not be severely affected.

This answer leads to a question about prenatal diagnosis: is it possible? There is technology that allows prenatal diagnosis; the patient needs a referral to prenatal genetic counselors. They can provide not only that information and counseling; they can also refer to preimplantation genetic diagnosis (PGD) centers.

This case illustrates the complexity of genetic testing and need for comprehensive genetic counseling. In this family, genetic testing of a child and his parents clarified the risk for HCM and provided useful information for all other relatives. Indeed, the complex genetics revealed in this case led to the conclusion that neither the paternal nor the maternal relatives required testing for the new mutation found in the affected child. The father’s siblings did benefit from testing for the father’s mutation and the mother’s testing revealed that she carried neither mutation and thus her relatives needed no further testing or screening. The cooperation of this family is not always the norm; often families are dispersed and do not communicate well, crucial affected family members may be unavailable and finally the cost of testing could be prohibitive. The accompanying paper also discusses the complex genetics of this case in detail.


There is a clear trend in the field of cardiology to integrate more genetic testing, as new genes associated with cardiac conditions are being discovered. Only in the past few years, only in the field of hypertrophic cardiomyopathy, we moved from analyzing five genes (Harvard Partners panel A 2005) to adding three more genes (Harvard Partners panel B), to Cardiochip with 11 genes (2007), to 16 available now (GeneDx) and possibly 50 planned for end of 2009 (Correlagen).

In general, genetic testing can confirm the diagnosis and the pattern of inheritance, but will not change the medical management significantly in most cases. However, in some areas it will have a substantial impact: with more genetic testing data available, we will hopefully be able to clarify the genotype–phenotype correlations and with more asymptomatic relatives tested, we will be in a position to establish efficient surveillance and risk reduction measures to prevent heart problems.

One other area is going to be affected: with more genetic testing, the number of patients found to have variations in genes that may or may not be associated with their disease will also grow. These variations called “variants of uncertain significance” (VUS) are usually missense mutations, which do not lead to a truncated protein but change its amino acid composition. When a VUS is detected, testing unaffected family members is not informative. However, testing parents of the proband will indicate which side of the family originated the VUS and, in some cases, provide an indication of the lack of pathogenicity (if the VUS comes from an unaffected side of the family). Conversely, if there are several affected members of the family willing to be tested for presence of the VUS and they all have the VUS, it would indicate a probable statistical causality of HCM.

Some VUS will be reclassified as polymorphisms, some will be found to be deleterious. In the meantime, the patient with VUS would be in a position of having spent considerable effort, time, and resources with an uninformative result. The interpretation of VUS is within a scope of genetic counselors training and they are uniquely qualified to explain this type of result in lay terms. There is a growing demand for those services and many genetic testing laboratories employ genetic counselors to help physicians make the proper test selection and test result interpretation.

The vignettes presented in this and the accompanying paper aim to illustrate the complexity of genetic counseling and testing for hypertrophic cardiomyopathy. In genetics, the “patient” is the whole family: those who share the same genes. Therefore, genetic testing in one individual has implications for all his relatives. Finding a mutation in a patient may be only the beginning of the process of multiple visits, follow-up, and more testing. Not finding a disease-causing mutation is not the end of the process, as blood relatives remain at risk of cardiac problems and need to be followed. Moreover, we expect that with new technologies, more testing will become available and re-testing the proband or other affected relatives is likely to be recommended over the coming years.

As each specialty becomes more focused and divided into further subspecialties, it is particularly important to expand interactions between cardiology and genetics. It is through collaboration of geneticists and genetic counselors with cardiologists that the comprehensive evaluation of HCM can be achieved and provides optimal service for the patient. This collaboration can flourish only when both sides make an effort to reach one to another; these authors have very positive experiences from their outreach efforts and would encourage readers to establish such collaborations in their workplace. To find genetic counselors near you, try the website of the National Society of Genetic Counselors Most major medical centers in US and Canada have genetic counselors staffing their cardiology clinics and the cardiac genetics specialty is growing.

With the technological improvements in cardiac genetics, challenges will grow: there will be patients with more than one mutation in one gene; there will be patients with several VUS and patients with incidental findings not related to the gene we set to analyze. In all those cases, the cardiologist’s and the genetic counselor’s expertise and collaboration will help our patients.


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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Cécile Skrzynia
    • 1
  • Erin M. Demo
    • 2
  • Samantha M. Baxter
    • 3
  1. 1.Departments of Medicine and GeneticsUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.Children’s Healthcare of Atlanta-Sibley Heart Center CardiologyEmory UniversityAtlantaUSA
  3. 3.Laboratory for Molecular MedicinePartners Center for Personalized Genetic MedicineCambridgeUSA

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