End-stage hypertrophic cardiomyopathy (ES-HC) has an ominous prognosis. Whether genotype can influence ES-HC occurrence is unresolved. We assessed the spectrum and clinical correlates of HC-associated mutations in a large multicenter cohort with end-stage ES-HC. Sequencing analysis of 8 sarcomere genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, and ACTC1) and 2 metabolic genes (PRKAG2 and LAMP2) was performed in 156 ES-HC patients with left ventricular (LV) ejection fraction (EF) <50%. A comparison among mutated and negative ES-HC patients and a reference cohort of 181 HC patients with preserved LVEF was performed. Overall, 131 mutations (36 novel) were identified in 104 ES-HC patients (67%) predominantly affecting MYH7 and MYBPC3 (80%). Complex genotypes with double or triple mutations were present in 13% compared with 5% of the reference cohort (p = 0.013). The distribution of mutations was otherwise indistinguishable in the 2 groups. Among ES-HC patients, those presenting at first evaluation before the age of 20 had a 30% prevalence of complex genotypes compared with 19% and 21% in the subgroups aged 20 to 59 and ≥60 years (p = 0.003). MYBPC3 mutation carriers with ES-HC were older than patients with MYH7, other single mutations, or multiple mutations (median 41 vs 16, 26, and 28 years, p ≤0.001). Outcome of ES-HC patients was severe irrespective of genotype. In conclusion, the ES phase of HC is associated with a variable genetic substrate, not distinguishable from that of patients with HC and preserved EF, except for a higher frequency of complex genotypes with double or triple mutations of sarcomere genes.

Significance of sarcomere gene mutations analysis in the end-stage phase of hypertrophic cardiomyopathy / Biagini, Elena; Olivotto, Iacopo; Iascone, Maria; Parodi, Maria I.; Girolami, Francesca; Frisso, Giulia; Autore, Camillo; Limongelli, Giuseppe; Cecconi, Massimiliano; Maron, Barry J.; Maron, Martin S.; Rosmini, Stefania; Formisano, Francesco; Musumeci, Beatrice; Cecchi, Franco; Iacovoni, Attilio; Haas, Tammy S.; Bacchi Reggiani, Maria L.; Ferrazzi, Paolo; Salvatore, Francesco; Spirito, Paolo; Rapezzi, Claudio. - In: THE AMERICAN JOURNAL OF CARDIOLOGY. - ISSN 0002-9149. - STAMPA. - 114:5(2014), pp. 769-776. [10.1016/j.amjcard.2014.05.065]

Significance of sarcomere gene mutations analysis in the end-stage phase of hypertrophic cardiomyopathy

Biagini, Elena;Autore, Camillo;Musumeci, Beatrice;Cecchi, Franco;Salvatore, Francesco;
2014

Abstract

End-stage hypertrophic cardiomyopathy (ES-HC) has an ominous prognosis. Whether genotype can influence ES-HC occurrence is unresolved. We assessed the spectrum and clinical correlates of HC-associated mutations in a large multicenter cohort with end-stage ES-HC. Sequencing analysis of 8 sarcomere genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, and ACTC1) and 2 metabolic genes (PRKAG2 and LAMP2) was performed in 156 ES-HC patients with left ventricular (LV) ejection fraction (EF) <50%. A comparison among mutated and negative ES-HC patients and a reference cohort of 181 HC patients with preserved LVEF was performed. Overall, 131 mutations (36 novel) were identified in 104 ES-HC patients (67%) predominantly affecting MYH7 and MYBPC3 (80%). Complex genotypes with double or triple mutations were present in 13% compared with 5% of the reference cohort (p = 0.013). The distribution of mutations was otherwise indistinguishable in the 2 groups. Among ES-HC patients, those presenting at first evaluation before the age of 20 had a 30% prevalence of complex genotypes compared with 19% and 21% in the subgroups aged 20 to 59 and ≥60 years (p = 0.003). MYBPC3 mutation carriers with ES-HC were older than patients with MYH7, other single mutations, or multiple mutations (median 41 vs 16, 26, and 28 years, p ≤0.001). Outcome of ES-HC patients was severe irrespective of genotype. In conclusion, the ES phase of HC is associated with a variable genetic substrate, not distinguishable from that of patients with HC and preserved EF, except for a higher frequency of complex genotypes with double or triple mutations of sarcomere genes.
2014
Adult; Aged; Cardiomyopathy, Hypertrophic, Familial; Carrier Proteins; Cross-Sectional Studies; DNA; DNA Mutational Analysis; Echocardiography; Female; Follow-Up Studies; Genotype; Humans; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Myosin Heavy Chains; Pedigree; Prevalence; Retrospective Studies; Sarcomeres; Severity of Illness Index; Mutation; Cardiology and Cardiovascular Medicine
01 Pubblicazione su rivista::01a Articolo in rivista
Significance of sarcomere gene mutations analysis in the end-stage phase of hypertrophic cardiomyopathy / Biagini, Elena; Olivotto, Iacopo; Iascone, Maria; Parodi, Maria I.; Girolami, Francesca; Frisso, Giulia; Autore, Camillo; Limongelli, Giuseppe; Cecconi, Massimiliano; Maron, Barry J.; Maron, Martin S.; Rosmini, Stefania; Formisano, Francesco; Musumeci, Beatrice; Cecchi, Franco; Iacovoni, Attilio; Haas, Tammy S.; Bacchi Reggiani, Maria L.; Ferrazzi, Paolo; Salvatore, Francesco; Spirito, Paolo; Rapezzi, Claudio. - In: THE AMERICAN JOURNAL OF CARDIOLOGY. - ISSN 0002-9149. - STAMPA. - 114:5(2014), pp. 769-776. [10.1016/j.amjcard.2014.05.065]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/847365
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