TY - JOUR
T1 - Clinical Features and Outcome of Hypertrophic Cardiomyopathy Associated With Triple Sarcomere Protein Gene Mutations
AU - Girolami, Francesca
AU - Ho, Carolyn Y.
AU - Semsarian, Christopher
AU - Baldi, Massimo
AU - Will, Melissa L.
AU - Baldini, Katia
AU - Torricelli, Francesca
AU - Yeates, Laura
AU - Cecchi, Franco
AU - Ackerman, Michael J.
AU - Olivotto, Iacopo
N1 - Funding Information:
This work is supported by Ministero Istruzione Università e Ricerca (PRIN) and the European Union (STREP Project 241577 “BIG HEART,” 7th European Framework Program). Dr. Ho is supported by the National Institutes of Health . Dr. Semsarian is the recipient of a National Health and Medical Research Council (NHMRC) Practitioner Fellowship. Dr. Ackerman is supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program .
PY - 2010/4/6
Y1 - 2010/4/6
N2 - Objectives: The aim of this study was to describe the clinical profile associated with triple sarcomere gene mutations in a large hypertrophic cardiomyopathy (HCM) cohort. Background: In patients with HCM, double or compound sarcomere gene mutation heterozygosity might be associated with earlier disease onset and more severe outcome. The occurrence of triple mutations has not been reported. Methods: A total of 488 unrelated index HCM patients underwent screening for myofilament gene mutations by direct deoxyribonucleic acid sequencing of 8 genes, including myosin binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), regulatory and essential light chains (MYL2, MYL3), troponin-T (TNNT2), troponin-I (TNNI3), alpha-tropomyosin (TPM1), and actin (ACTC). Results: Of the 488 index patients, 4 (0.8%) harbored triple mutations, as follows: MYH7-R869H, MYBPC3-E258K, and TNNI3-A86fs in a 32-year-old woman; MYH7-R723C, MYH7-E1455X, and MYBPC3-E165D in a 46-year old man; MYH7-R869H, MYBPC3-K1065fs, and MYBPC3-P371R in a 45-year old woman; and MYH7-R1079Q, MYBPC3-Q969X, and MYBPC3-R668H in a 50-year old woman. One had a history of resuscitated cardiac arrest, and 3 had significant risk factors for sudden cardiac death, prompting the insertion of an implantable cardioverter-defibrillator in all, with appropriate shocks in 2 patients. Moreover, 3 of 4 patients had a severe phenotype with progression to end-stage HCM by the fourth decade, requiring cardiac transplantation (n = 1) or biventricular pacing (n = 2). The fourth patient, however, had clinically mild disease. Conclusions: Hypertrophic cardiomyopathy caused by triple sarcomere gene mutations was rare but conferred a remarkably increased risk of end-stage progression and ventricular arrhythmias, supporting an association between multiple sarcomere defects and adverse outcome. Comprehensive genetic testing might provide important insights to risk stratification and potentially indicate the need for differential surveillance strategies based on genotype.
AB - Objectives: The aim of this study was to describe the clinical profile associated with triple sarcomere gene mutations in a large hypertrophic cardiomyopathy (HCM) cohort. Background: In patients with HCM, double or compound sarcomere gene mutation heterozygosity might be associated with earlier disease onset and more severe outcome. The occurrence of triple mutations has not been reported. Methods: A total of 488 unrelated index HCM patients underwent screening for myofilament gene mutations by direct deoxyribonucleic acid sequencing of 8 genes, including myosin binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), regulatory and essential light chains (MYL2, MYL3), troponin-T (TNNT2), troponin-I (TNNI3), alpha-tropomyosin (TPM1), and actin (ACTC). Results: Of the 488 index patients, 4 (0.8%) harbored triple mutations, as follows: MYH7-R869H, MYBPC3-E258K, and TNNI3-A86fs in a 32-year-old woman; MYH7-R723C, MYH7-E1455X, and MYBPC3-E165D in a 46-year old man; MYH7-R869H, MYBPC3-K1065fs, and MYBPC3-P371R in a 45-year old woman; and MYH7-R1079Q, MYBPC3-Q969X, and MYBPC3-R668H in a 50-year old woman. One had a history of resuscitated cardiac arrest, and 3 had significant risk factors for sudden cardiac death, prompting the insertion of an implantable cardioverter-defibrillator in all, with appropriate shocks in 2 patients. Moreover, 3 of 4 patients had a severe phenotype with progression to end-stage HCM by the fourth decade, requiring cardiac transplantation (n = 1) or biventricular pacing (n = 2). The fourth patient, however, had clinically mild disease. Conclusions: Hypertrophic cardiomyopathy caused by triple sarcomere gene mutations was rare but conferred a remarkably increased risk of end-stage progression and ventricular arrhythmias, supporting an association between multiple sarcomere defects and adverse outcome. Comprehensive genetic testing might provide important insights to risk stratification and potentially indicate the need for differential surveillance strategies based on genotype.
KW - complex genotypes
KW - genetics
KW - hypertrophic cardiomyopathy
KW - outcome
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U2 - 10.1016/j.jacc.2009.11.062
DO - 10.1016/j.jacc.2009.11.062
M3 - Article
C2 - 20359594
AN - SCOPUS:77949881591
SN - 0735-1097
VL - 55
SP - 1444
EP - 1453
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 14
ER -