A 36-year-old Caucasian woman was referred to the Cardiovascular Genetic and Genomic Medicine Clinic for genetic evaluation due to her diagnosis of idiopathic dilated cardiomyopathy (DCM) at 31 years of age. At that time she had presented emergently to cardiology care in advanced heart failure (HF) having had progressive dyspnea on exertion for several weeks. There was no known trigger to her symptom onset. Her echocardiogram revealed a left ventricular end-diastolic dimension (LVEDD) of 7.2 cm and a left ventricular ejection fraction (LVEF) of 10% to 15%. She underwent cardiac magnetic resonance imaging, which showed a dilated left ventricle, severe global hypokinesis, LVEF of 19%, biatrial enlargement, minimal midwall fibrosis with gadolinium enhancement, and no iron overload. She underwent emergent ventricular assist device (VAD) placement, was treated medically, and improved to the point where her VAD was explanted 1 year later. Since her VAD explant, she has continued with full medical therapy and has received close cardiovascular surveillance with her HF cardiologist. An implantable cardioverter defibrillator (ICD), placed after her VAD was removed, has delivered no shocks. A follow-up echocardiogram revealed an LVEDD of 5.8 cm with a LVEF of 30% to 35%.

During the Cardiovascular Genetic and Genomic Medicine Clinic appointment, which included consultation with a HF/heart transplant cardiologist with genetics expertise and a genetic counselor in a multidisciplinary team approach, the genetic counselor constructed a 4-generation pedigree for the proband, the person who serves as the starting point for the genetic evaluation of a family (Figure 5-1). The family history was significant for nonischemic cardiomyopathy (NICM) and heart transplant in a maternal first cousin once removed. A paternal grandfather was reported who died suddenly at 49 years of age. The proband’s father and mother were 62 years of age with no reported heart disease. The proband also had 3 siblings, none of whom had undergone cardiovascular screening to date. She also had multiple nieces and nephews. No other relatives were reported with a concerning history.

Genetic testing was discussed with the patient as a useful tool to investigate the underlying etiology of her cardiomyopathy. She had been assigned the diagnosis of idiopathic DCM, acknowledging that no plausible cause had been found. Also informing this discussion was the proband’s severe DCM at a young age of onset, and her remote family history of NICM requiring transplant, as well as sudden death in her paternal grandfather. Informed consent was obtained and a blood sample was collected for genetic testing. A comprehensive cardiomyopathy genetic testing panel was ordered that included sequence analysis and deletion/duplication testing of more than 70 genes known to be associated with different types of cardiomyopathy.

The patient tested positive for three variants (Table 5-1). These included a novel, likely pathogenic variant in TNNC1, a gene known to be relevant for DCM; a previously reported pathogenic/likely pathogenic variant in MYBPC3, a well-established hypertrophic cardiomyopathy (HCM) gene with this specific variant having been identified in HCM patients; and a novel variant of unknown significance (VUS) in LAMA4. The genetic testing results were discussed and interpreted by the cardiovascular genetics and genomics team. This thorough assessment included critical review of the available data on each variant, starting with the level of evidence for whether the gene itself has strong, or limited, evidence for association with the patient’s phenotype. Specifically, pathogenic variants in MYBPC3 are a common cause of HCM; however, the role of MYBPC3 variants in DCM is uncertain and still evolving. At the variant level, the adjudication included whether the variant had previously been reported in the scientific literature, whether it segregated with a cardiomyopathy phenotype, the minor allele frequency of each variant in large databases, as well as whether each variant had a ClinVar entry. The ClinVar entry for the previously reported MYBPC3 variant stated that it has been reported in 4 individuals with HCM tested across 4 studies, and that it has been identified in 3 probands with HCM and 2 affected relatives tested by 1 large commercial genetic-testing laboratory. It had also been reported in both a proband and an unaffected parent, suggesting incomplete penetrance.¹

The genetic counselor telephoned the proband to inform her of the results and to present the following plan: (1) Recommend clinical cardiology screening to all first-degree relatives (her parents and siblings). (2) Recommend parental genetic testing for the genetic variants identified in the proband to determine whether they were inherited from 1 parent, both parents, or whether 1 or more were de novo (arose new in the patient).

When the genetic counselor called the proband with her results, remarkably, the proband informed the genetic counselor that her older sister had just been diagnosed with peripartum cardiomyopathy (PPCM). In addition, her father, being prompted by the proband’s questioning of possible family history of heart disease for her initial genetics appointment, had recognized that he had been having shortness of breath, fatigue, and pretibial and pedal edema. He informed his primary care physician, who ordered an echocardiogram that showed a reduced LVEF of 25%. Based on this new family history information, the cardiovascular genetics team modified their recommendations to also include full panel cardiomyopathy genetic testing for the sister with PPCM in order to determine whether she had the same variants as the proband, and/or additional variants that may be underlying her PPCM. The sister presented to the clinic, underwent full evaluation, including genetic testing, and was also found to have the novel TNNC1 variant, not the MYBPC3 or LAMA4 variants, and no additional variants. We hypothesize that the MYBPC3 variant, established as a cause of HCM, may have modified the pathogenicity of the TNNC1 variant. This may explain the dramatic variability of severity of onset between the 2 sisters, 1 with only the TNNC1 variant identified, and the other with the TNNC1 variant in addition to 2 other potentially associated variants.

These additional genetic data allowed us to determine that the proband’s TNNC1 variant was almost certainly inherited from 1 of her parents, because both the proband and her sister with PPCM were found to have this same TNNC1 variant. Referrals were made for the sister’s 6 at-risk children to the local children’s hospital’s cardiac genetics clinic for both clinical cardiology screening and targeted genetic testing for the TNNC1 variant. It was also recommended that both of the sisters’ parents undergo genetic evaluation, including targeted genetic testing, in order to determine which parent had the TNNC1 variant, and whether the other 2 variants identified in the proband were inherited from 1 parent, both parents, or were de novo. It is possible that this pedigree represents bilineal inheritance, meaning that the proband inherited cardiomyopathy-predisposing genetic variants from each of her parents that contributed to her phenotype. Parental testing is also indicated to determine whether 1, or both, of her parents may also have underlying genetic predispositions to cardiomyopathy, and in turn, whether the proband’s paternal, maternal, or both sides of her family may also be at risk.

CASE COMMENTARY

The heritable cardiomyopathies are relatively common conditions that can lead to HF and sudden cardiac death (SCD). DCM may be the most common heritable cardiomyopathy, estimated to occur in 1 in 250 individuals,² and HCM occurs in 1 in 500 individuals.³ Research discoveries and rapidly dropping costs of DNA sequencing technologies have resulted in the availability of multiple cardiomyopathy genetic testing panels.⁴ Genetic testing not only helps in determining the underlying etiology of idiopathic and familial cardiomyopathies, but is also a powerful tool in the determination of which relatives may be at risk, or not, in the preclinical phase. Both pretest and posttest genetic counseling are imperative components of genetic testing, as the many benefits and limitations of genetic testing need to be discussed with each patient undergoing this process.

Position and international consensus statements, as well as practice guidelines, regarding genetic evaluation, including genetic testing and counseling of cardiomyopathy patients, have been published.^5-7 The Heart Failure Society of America practice guideline on genetic evaluation of cardiomyopathy recommends: (1) a careful family history for ≥ 3 generations for all patients with cardiomyopathy; (2) clinical screening for cardiomyopathy in asymptomatic first-degree relatives; (3) genetic and family counseling for all patients and families with cardiomyopathy; and (4) consideration of referral to centers with expertise in the complex processes of genetic evaluation, genetic counseling, genetic testing, and family-based management.⁵

The multidisciplinary clinical cardiovascular genetics evaluation for the proband and her family in the above case presentation resulted in the following:

1. 
   

   Confirmation of a familial cardiomyopathy with an underlying, identifiable, genetic etiology;

   
   
2. 
   

   Determination that the proband’s DCM may be due to bilineal inheritance of multiple variants inherited from both her father and mother;

   
   
3. 
   

   Diagnosis of at-risk relatives with cardiomyopathy;

   
   
4. 
   

   Determination of additional at-risk relatives’ risk status through both clinical screening and cascade, family-specific genetic testing;

   
   
5. 
   

   Receipt of information regarding the inheritance pattern of the variants predisposing to familial cardiomyopathy and recurrence risk;

   
   
6. 
   

   Provision of counseling regarding future reproductive options; and

   
   
7. 
   

   Receipt of psychosocial support and resources.

Genetic forms of cardiomyopathy are often the cause of unexplained, or idiopathic, cardiomyopathy that may lead to HF or SCD. For any cardiomyopathy deemed to be of unknown cause, a genetic basis should always be considered. The types of genetic, or inherited, cardiomyopathies most commonly encountered in the clinical setting include DCM, HCM, and less commonly, arrhythmogenic right ventricular cardiomyopathy (ARVC) and restrictive cardiomyopathy (RCM). Left ventricular noncompaction (LVNC), named as a primary cardiomyopathy by a U.S. consensus panel,⁸ was not considered a cardiomyopathy by a European panel as it is a developmental variant observed in all cardiomyopathies and other cardiovascular conditions.⁹ Because of improved cardiovascular imaging methods, particularly cardiac magnetic resonance (CMR) imaging, LVNC is now more commonly identified and referred to for genetic evaluation. Whether LVNC drives increased risk for development of cardiomyopathy remains unanswered.

The genetic variants predisposing to the various types of familial cardiomyopathies are usually inherited in an autosomal-dominant Mendelian pattern and display both variable expressivity and age-related penetrance. The term penetrance defines whether any evidence of the clinical phenotype is discernable, whereas variable expressivity refers to the degree, variability, and/or severity of the clinical phenotype.²

The genetic cardiomyopathies have had many genes (termed locus heterogeneity) identified in causing disease, and in most genes multiple different pathogenic variants have been implicated (termed allelic heterogeneity).^6,10 There is also significant genetic overlap between the different cardiomyopathy phenotypes, both with each other, and with other heritable cardiovascular conditions including channelopathies, congenital heart disease, and neuromuscular disorders (Figure 5-2).² For example, pathogenic variants in genes encoding sarcomere proteins have been shown to be associated with variable presentations of cardiomyopathy, including hypertrophic, dilated, restrictive, and left ventricular noncompaction phenotypes.^11-13 Most families have their own unique, pathogenic variant(s), colloquially labeled “private,” meaning that they have never been reported in the publicly available databases or in the research literature, which can lead to difficulty in genetic variant interpretation due to lack of data on multiple probands and families with the same variant.

The heritable cardiomyopathies (DCM, HCM, ARVC, RCM) are in most cases nonsyndromic, that is, they exhibit clinical features that are specific to myocardial structure and function (eg, dilatation, hypertrophy). However, syndromic forms of cardiomyopathy also exist, and it is imperative to diagnose these syndromic conditions because of the important implications for therapeutics (eg, enzyme replacement therapy in Fabry disease, which can masquerade as HCM) as well as differences in inheritance patterns and risk to family members (eg, women with DCM due to mutations in the X-linked DMD gene associated with Duchenne and Becker muscular dystrophies). The syndromic forms of cardiomyopathy have been discussed in detail.^14-16 Nonsyndromic DCM, HCM, and ARVC will be discussed below.

DILATED CARDIOMYOPATHY (DCM)

Idiopathic DCM is the most common condition that leads to cardiac transplantation in the United States. Idiopathic DCM is characterized by left ventricular dilatation and systolic dysfunction, with the most common underlying etiologies excluded, including most importantly coronary artery disease, and other causes such as toxin exposure, iron overload, infectious causes such as Chagas disease, and infiltrative disease.¹⁷ Familial DCM can be assigned when 2 or more closely related family members have met stringent criteria for idiopathic DCM diagnoses, or when a first-degree relative of a DCM patient has had unexplained sudden death at 35 years of age or younger.¹⁸ Regarding “apparently sporadic” idiopathic DCM, the true extent of its genetic etiology is uncertain, as family history is often insensitive and affected family members can be asymptomatic and remain undiagnosed unless clinical evaluation commences.¹⁷ Furthermore, prior large clinical series searching for familial DCM by clinically screening large cohorts of family members have not provided comprehensive genetic information. Clinical screening of first-degree relatives of patients with idiopathic DCM revealed familial disease ranging from 20% to 35%.^2,18,19 Family-based DCM studies have implicated genetic etiology with mutations in more than 30 genes of diverse ontology including those encoding the sarcomere, components of the cytoskeleton, ion channels, and others.^2,18,20-22 The current clinical sensitivity of DCM genetic testing reaches approximately 40%,²³ with truncating variants of TTN estimated to account for 15% to 25% of familial DCM.^24-26 Variants of uncertain significance are identified in a high percentage of cases.²³

HYPERTROPHIC CARDIOMYOPATHY (HCM)

HCM is characterized by left ventricular hypertrophy (LVH), myocyte disarray, and fibrosis and has a prevalence of approximately 1 in 500 individuals in the general population.³ Cardiac sarcomere mutations are identified in approximately 50% of HCM patients with a family history of HCM and in approximately 30% of unselected probands.²⁷ The majority of cases are due to mutations in the cardiac myosin-binding protein C (MYBPC3) and beta-myosin heavy chain (MYH7) genes, with more than 15 additional genes identified as rare causes of this condition.^10,27 Similar to DCM, there is a high level of variability of HCM disease expression observed in families; a large cohort study of families with MYBPC3 mutations¹ found ages at diagnosis ranging from 5 to 80 years, all morphological variants of HCM observed, as well as a significant degree of incomplete penetrance. These findings stress the importance of the role of additional genetic, epigenetic, and environmental modifiers in the pathogenesis of the HCM phenotype within and between families and also highlight our current inability to provide specific prognostic information to family members who test positive for an HCM-predisposing variant.

ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY (ARVC)

The prevalence of ARVC is estimated to be 1 in 1000 to 2000, with >50% of cases being familial.²⁸ Although ARVC itself is rare, ARVC commonly presents with arrhythmia, presyncope, syncope, or SCD in young adults (≤35 years), although it may also present in later life.²⁹ The diagnosis of ARVC is made in patients who meet major and minor diagnostic Task Force criteria, revised in 2010.³⁰ In addition to an arrhythmia presentation, classic manifestations include characteristic electrocardiographic parameters, fibrofatty replacement of the right ventricle, and right ventricular enlargement and dysfunction. Structurally, ARVC is classically described as a disease of the desmosome, the cellular structure for cell-to-cell adhesion and electrophysical communication, which is especially essential in the myocardium. However, both desmosomal and more rarely, nondesmosomal, gene variants have been found in association with ARVC.²⁹ Left-dominant and biventricular subtypes have also been described and molecularly classified.³¹ The yield of genetic testing in probands meeting revised Task Force criteria has been shown to be approximately 50%, with more than 1 desmosomal variant identified in 28% of probands; relatives harboring more than 1 desmosomal variant had a 5-fold increased risk of developing ARVC clinical signs and symptoms.³²

It is recommended that a careful family history for at least 3 generations be taken on all patients with cardiomyopathy.^5,18 Guidelines regarding the collection of family history information in the cardiovascular medicine setting exist.³³ Collection of family history is imperative in aiding diagnosis, identifying at-risk relatives, selecting the most informative family member for genetic testing initiation, and determining inheritance pattern.

While most genetic risk variants predisposing to cardiomyopathies are inherited in an autosomal-dominant pattern, there are important exceptions and this information is necessary for the provision of accurate recurrence risks. Also complicating matters is the fact that many inherited cardiomyopathies display both incomplete and age-related penetrance and variable expressivity of clinical signs and symptoms. Small, or limited, family structures may also mask a genetic pattern of disease (eg, smaller sibships including only children may limit the number of affected individuals in the family, higher number of female relatives in a family can hide an X-linked disease). Because patients’ self-reported family history information can have both reduced sensitivity and specificity, it is important to collect medical records, including autopsy reports, whenever possible so that diagnoses can be confirmed. In many cases, it is not until clinical screening commences through a family that a familial, or genetic, condition is able to be diagnosed.³⁴ Also, family history is not static, but changes over time, and should therefore be updated periodically.