Vol. 16, Issue 6 Sep 2016

Case Management: Role of Genetic Evaluation and Testing in Pediatric Hypertrophic Cardiomyopathy

Contributing Author: Stephanie M. Ware, MD, PhD

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After reading this article, the reader should be able to:
• Identify the potential sequelae of pediatric cardiomyopathies.
• Review the differential diagnosis of pediatric hypertrophic cardiomyopathy (HCM).
• Summarize the benefits of establishing the precise cause of pediatric HCM.
• Discuss the role of genetic testing in children with the clinical diagnosis of HCM.
• Review the establishing guidelines for HCM family screening.
• Describe the management of pediatric HCM

Activity Launch Date: September 2016

Expiration Date: September 2017

This CME activity does not have any commercial support

A seven-year-old male is referred to Riley Cardiomyopathy Program at Indiana University Health for evaluation after a harsh cardiac murmur is detected during a well child visit at his pediatrician’s office. The boy has no complaints of chest pain, shortness of breath, or fatigue. His mother reports his appetite is good but feels his energy level has decreased slightly.

The patient has a history of attention deficit hyperactivity disorder (mother says he did “okay” in first grade) and a family history of sudden death of unknown etiology in a paternal uncle. On physical examination, he measures at the (continued on page 2) fifth percentile for height and 25th percentile for weight. Facial features, hands, and feet are normal in appearance, and a neurologic assessment is unremarkable. A 12-lead electrocardiogram (ECG) is performed and shows sinus rhythm with T wave inversion in the lateral, inferior, and left precordial leads and left ventricular hypertrophy (Figure 1). Asymmetric septal hypertrophy with outflow tract obstruction and systolic motion of the mitral valve are seen on echocardiography (Figure 2). He is diagnosed with hypertrophic cardiomyopathy (HCM). A genetic etiology is strongly suspected, as non-genetic causes are rarely identified in children.

Overview of Cardiomyopathies in Children

Pediatric cardiomyopathies are clinically heterogeneous heart muscle disorders (Table 1 see page 4) that cause systolic or diastolic dysfunction and are associated with significant morbidity and mortality. Among affected children, up to 40 percent progress to transplantation or die within five years of diagnosis.1

“The annual US incidence of cardiomyopathy in children younger than 18 years is 1.13 cases per 100,000,”2 notes Stephanie Ware, MD, PhD, professor of pediatrics and medical and molecular genetics at Indiana University School of Medicine and cardiovascular geneticist at Riley Children’s at Indiana University Health. “Although substantial evidence points to a genetic contribution, with more than 100 genes implicated to date, 60 to 70 percent of cases of pediatric cardiomyopathy continue to be classified as idiopathic. Incorporating evaluation by a geneticist and genetic testing into the diagnostic process may allow the cause of the disease to be successfully identified in up to 70 percent of these patients.”

Pediatric Hypertrophic Cardiomyopathy

HCM is defined as the presence of unexplained left ventricular hypertrophy, a primary myocardial process characterized by myocyte disarray and fibrosis. HCM is the most frequently inherited cardiac disorder, affecting one in 500 adults. Although the disease is rare in the pediatric population, it can develop at any time during childhood, with infancy and adolescence the most common ages of presentation. According to the US Pediatric Cardiomyopathy Registry, HCM occurs with greater frequency in males and affects significantly more blacks than whites or Hispanics. 3

HCM is typically inherited in an autosomal dominant manner, with a subset of cases representing de novo mutations.4 Hundreds of mutations may affect the more than 27 genes thus far identified. In adults, the underlying cause of HCM is usually mutations in genes that encode for two cardiac sarcomeric proteins—MYH7, which encodes beta myosin heavy chain, and MYBPC3, which encodes myosin-biding protein C. Collectively, these mutations account for approximately 80 percent of all adult HCM cases in which a genetic diagnosis is made.5

Differential Diagnosis

“Although sarcomeric gene mutations are an important cause of pediatric HCM, the disease is less straightforward in children and also encompasses conditions with diverse genetic origins and clinical phenotypes,” Dr. Ware explains. “Making the clinical distinction is important, since patients with concomitant inborn errors of metabolism, neuromuscular diseases, or malformation syndromes have additional medical management needs. Establishing the cause of HCM also allows risk stratification for potentially affected family members.”

In the pediatric population, once metabolic, neuromuscular, and syndromic causes are ruled out as etiologies, HCM is considered a familial disease, caused by the same genes responsible for isolated cardiomyopathy in adults.6 HCM genetic testing currently has a very high diagnostic yield, with mutations found in upwards of 60 percent of cases. For this reason, comprehensive or targeted genetic testing is advised for every child with the clinical diagnosis of HCM.7 Additionally, mutation-specific cascade genetic testing is universally recommended for family members, regardless of their clinical status, after a causative mutation is identified in an index case.7

“One of the most feared complications of HCM in children and young adults is disease diagnosis at the time of sudden death,” stresses Dr. Ware. “The potential to avert such catastrophic events relies on diagnosing HCM in asymptomatic individuals.”

In the pediatric population, once metabolic, neuromuscular, and syndromic causes are ruled out as etiologies, HCM is considered a familial disease, caused by the same genes responsible for isolated cardiomyopathy in adults.

The patient’s basic metabolic screen (i.e., lactate, serum amino acids, urine organic acids) is normal, but genetic testing identifies a pathogenic mutation in MYH7. Family-based cardiac screening and mutation-specific genetic testing is performed for the parents and the patient’s four siblings. Echocardiography reveals mild cardiac hypertrophy in the father, and two of the siblings are found to be positive for the MYH7 mutation (Figure 3).

Symptom Management

The goals of HCM management are to reduce symptoms and prolong survival. The mainstay of therapy in children is betaadrenergic blockade or calcium channel blockers (e.g., atenolol, verapamil), which may decrease outflow tract obstruction and relieve chest pain and dyspnea.4

“Avoidance of high-intensity exercise is generally recommended once a child with HCM starts high school,” says Dr. Ware. “The rationale for this recommendation is based on observations that hypertrophy often shows marked progression at adolescence, and sudden death, the usual cause of death in HCM, has a higher than expected association with exercise.”

Some patients with severe outflow tract obstruction and persistent symptoms despite medication may be candidates for septal myectomy. Alternative therapies that occasionally play a role in the management of adult HCM, such as alcohol septal ablation or insertion of an implantable cardioverter defibrillator, are uncommonly used in children.

The pediatric cardiologist prescribes beta-blocker therapy (atenolol 25 mg twice daily). No activity restrictions are recommended, but the parents are advised to beginguiding their child’s interests away from competitive athletics (except golf). Repeat echocardiography is scheduled in six months and will be performed annually thereafter.

Family Screening Recommendations

First-degree relatives (i.e., children, siblings, parents) of individuals with HCM require ongoing cardiomyopathy screening, even when the results of genetic testing are uninformative. Furthermore, owing to incomplete and age-dependent penetrance, repeat screening is necessary after normal evaluations. Screening should include echocardiography, ECG, and evaluation by a cardiologist familiar with the family history of HCM and the guidelines for screening frequency, which vary by age.8 Ongoing cardiac surveillance can be discontinued only when the specific genetic cause of HCM in the family is identified and the at-risk relative does not have the mutation.

“A study of cardiac screening and genetic testing among 302 first- and second-degree relatives at risk for HCM or dilated cardiomyopathy showed a 57 percent uptake rate for testing,”9 states Dr. Ware.“Cardiac screening revealed asymptomatic and previously undiagnosed cardiomyopathy in 25 percent of the identified at-risk family members, and genetic testing was positive in 40 percent of these individuals, indicating the need for ongoing cardiac surveillance.”

Importantly, familial testing in this study also identified 33 not-at-risk relatives, thereby providing reassurance that they could safely discontinue ongoing cardiac monitoring and spare their children cardiac screening and genetic assessment.9 Nonetheless, Dr. Ware cautions that family histories are dynamic, and the indications for testing affected family members change as other relatives are diagnosed with HCM. Consequently, it is essential to address family history at each clinic visit and update screening recommendations accordingly. Genetic counselors can help collect family medical information and appropriately adjust screening recommendations.

Ongoing cardiac surveillance can be discontinued only when the specific genetic cause of HCM in the family is identified and the at-risk relative does not have the mutation.

Because the two siblings who are HCM mutation-positive have a 90 percent chance of developing the disease at some point in their lives, ongoing cardiac surveillance by echocardiography is recommended, with annual screening during puberty. The father undergoes cardiopulmonary stress testing, begins beta-blocker therapy, and will be followed by a cardiologist.


In children with HCM, outcomes primarily depend on cause and age. Children who present before one year of age have the broadest spectrum of causes and the poorest outcomes,10 primarily attributable to the high incidence of inborn errors of metabolism and neuromuscular disease in this patient population.4 Mortality among those diagnosed after infancy is comparable to that for adults. Results from an Australian population-based study of 80 children aged zero to 10 years at diagnosis showed that 83 and 76 percent were alive and had not undergone transplantation five and 10 years after presentation, respectively, and that familial HCM was predictive of survival.11

“HCM can profoundly affect an individual’s quality of life, ” Dr. Ware concludes. “A multidisciplinary approach to diagnosis and management that involves cardiovascular genetics and pediatric cardiology is key to alleviating symptoms and lowering the risk of sudden life-threatening events.”

“HCM can profoundly affect an individual’s quality of life,” Dr. Ware concludes. “A multidisciplinary approach to diagnosis and management that involves cardiovascular genetics and pediatric cardiology is key to alleviating symptoms and lowering the risk of sudden life-threatening events.”

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Stephanie M. Ware, MD, PhD

Cardiovascular Geneticist, Riley Children's Health
Professor of Pediatrics and Medical Genetics, IU School of Medicine Program Leader, Cardiovascular Genetics, IU School of Medicine

Dr. Ware received her medical and doctor of philosophy degrees from the University of Cincinnati (OH) College of Medicine and completed a residency in pediatrics and a fellowship in genetics at Baylor College of Medicine in Houston, TX. As a clinical geneticist and program leader in cardiovascular genetics at IU School of Medicine and Riley Children’s Health, she coordinates clinical genetic services for patients with cardiomyopathy, genetic syndromic conditions, aortopathy and vascular disorders, and inherited arrhythmias. Her research focuses on the genetic and developmental basis of pediatric hear t disease, in particular disorders of cardiac function (cardiomyopathies) and structure (congenital hear t disease).

Dr. Ware is a fellow of the American College of Medical Genetics and Genomics and a member of several other professional organizations, including the American Society for Clinical Investigation and the Society for Pediatric Research. The author of more than 100 peer-reviewed publications and textbook chapters, she serves as the editor of the journal Pediatric Research and has presented at numerous scientific meetings in the United States and abroad.

Dr. Ware is the recipient of several current National Institutes of Health, American Heart Association, and other research grants. In 2013, she received the American Heart Association Established Investigator Award.

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