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Biagini, Elena, MD, PhD; Olivotto, Iacopo, MD; Iascone, Maria, BSc, PhD; Parodi, Maria I., BSc; Girolami, Francesca, BSc; Frisso, Giulia, MD, PhD; Autore, Camillo, MD; Limongelli, Giuseppe, MD; Cecconi, Massimiliano, BSc; Maron, Barry J., MD; Maron, Martin S., MD; Rosmini, Stefania, MD; Formisano, Francesco, MD; Musumeci, Beatrice, MD; Cecchi, Franco, MD; Iacovoni, Attilio, MD; Haas, Tammy S., RN; Bacchi Reggiani, Maria L., MSc, MStat; Ferrazzi, Paolo, MD; Salvatore, Francesco, MD, PhD; Spirito, Paolo, MD; Rapezzi, Claudio, MD
The American journal of cardiology, 09/2014, Volume: 114, Issue: 5Journal Article
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.
