Elsevier

Heart Rhythm

Volume 9, Issue 1, January 2012, Pages 57-63
Heart Rhythm

Clinical
Genetic
Double or compound sarcomere mutations in hypertrophic cardiomyopathy: A potential link to sudden death in the absence of conventional risk factors

https://doi.org/10.1016/j.hrthm.2011.08.009Get rights and content

Background

Risk stratification strategies employing sarcomere gene mutational analysis have proved imprecise in identifying high-risk patients with hypertrophic cardiomyopathy (HCM). Therefore, additional genetic risk markers that reliably determine which patients are predisposed to sudden death are needed.

Objective

The objective of this study was to determine whether multiple disease-causing sarcomere mutations can be regarded as markers for sudden death in the absence of other conventional risk factors.

Methods

Databases of 3 HCM centers were accessed, and 18 probands with 2 disease-causing mutations in genes encoding proteins of the cardiac sarcomere were identified.

Results

Severe disease progression or adverse cardiovascular events occurred in 7 of these 18 patients (39%), including 3 patients (ages 31, 37, and 57 years) who experienced sudden cardiac arrest but also were without evidence of conventional HCM risk factors; 2 survived with timely defibrillation and therapeutic hypothermia and 1 died. These 3 probands carried distinct and heterozygous disease-causing sarcomere mutations (including a man who inherited 1 mutation independently from each of his parents with HCM)—that is, double MYBPC3 and TNNI3 mutations and compound MYBPC3 mutations—as the only predisposing clinical markers evident to potentially explain their unexpected cardiac event.

Conclusions

These observations support the emerging hypothesis that double (or compound) mutations detected by genetic testing may confer a gene dosage effect in HCM, thereby predisposing patients to adverse disease progression. In 3 families, multiple sarcomere mutations were associated with a risk of sudden death, even in the absence of conventional risk factors.

Introduction

Hypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death (SCD) in the young, is an often unpredictable inherited monogenic cardiac disease caused by a vast array of mutations in genes encoding proteins of the sarcomere.1, 2, 3 The clinical risk stratification algorithm employed in this disease has proved useful in identifying many high-risk patients who subsequently experienced lifesaving interventions from prophylactic implantable cardioverter-defibrillators (ICDs).4, 5 However, it is also apparent that some patients with HCM, but without conventional risk factors, may nevertheless incur SCD,6, 7, 8 thereby promoting the ongoing aspiration to identify additional risk markers that may aid in the selection of patients for ICDs.4, 6 In this regard, the strategy of using single mutations in genes encoding proteins of the cardiac sarcomere as prognostic markers has proved largely unreliable in HCM.9, 10, 11, 12, 13

More recently, a hypothesis has emerged suggesting that patients with HCM who carry more than 1 independent disease-causing gene mutation may be at a greater risk for severe disease expression and adverse outcome.14, 15, 16, 17 Most such patients with HCM reported with multiple mutations also have the conventional disease markers of risk, including some who develop advanced heart failure symptoms with left ventricular remodeling associated with systolic dysfunction.14, 15, 17 However, it is presently unresolved whether 2 (or more) disease-causing sarcomere mutations alone can be considered unique markers of increased SCD risk. In this study, we advance a novel perspective on risk stratification in HCM by presenting asymptomatic patients with double or compound sarcomere mutations, but without conventional evidence for increased risk to explain their cardiac arrest.

Section snippets

Patient selection

The databases of 3 centers (2 in Minneapolis and Boston, USA, and 1 in Sydney, Australia) were assessed. We identified 330 probands with HCM who underwent systematic mutational screening from 2000 to 2010. The clinical diagnosis of HCM was made by 2-dimensional echocardiography or cardiovascular magnetic resonance imaging of a hypertrophied and nondilated left ventricle (LV) in the absence of another cardiac or systemic disease capable of producing the magnitude of hypertrophy evident.3

Mutational analysis

Patients

Study group

Of the 330 probands, 18 (5.5%) had 2 disease-causing sarcomere mutations, including 11 with double mutations—MYBPC3 and MYH7 (n = 5); MYBP3 and TNNI3 (n = 4); MYH7 and TPMI (n = 1); and MYH7 and alpha-actin (n = 1)—and 7 others with compound mutations: MYBPC3 (n = 5), MYH7 (n = 1), and TNNI3 (n = 1; homozygous) (Table 1, Table 2).

Of the 18 probands with double or compound mutations, 11 also had 1 or more conventional HCM risk markers,4, 18 (while the other 7 had no risk factors). Of the 11

Discussion

Many patients with HCM susceptible to SCD from unpredictable ventricular tachycardia/ventricular fibrillation can be recognized by the presence of 1 or more noninvasive clinical risk markers.4, 18 Identification of such high-risk patients is crucial since ICDs have proved effective in preventing SCD in this disease.4, 5 However, recognition that some patients without conventional risk factors may occasionally experience an unanticipated arrhythmic event suggests that the present stratification

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  • Cited by (0)

    Dr. Semsarian is the recipient of a Practitioner Fellowship from the National Health & Medical Research Council, Canberra, Australia. This study was funded in part by a grant from the Hearst Foundations, New York, to Dr. Barry J. Maron. Dr Barry J. Maron is a consultant to GeneDx and receives research support from Medtronic. Dr. Martin S. Maron receives research support from Genzyme.

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