CardiomyopathySignificance of Sarcomere Gene Mutations Analysis in the End-Stage Phase of Hypertrophic Cardiomyopathy
Section snippets
Methods
In this multicenter cross-sectional and longitudinal study, we retrospectively identified 156 patients diagnosed with ES-HC (130 index cases and 26 family members) from January 1981 to June 2010 and genetically screened between January 2007 and June 2010 at 6 referral centers in Italy and 2 in the United States. Five of these centers (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Alma Mater Studiorum, Università di Bologna, Italy; Dipartimento di Cardiologia, Seconda
Results
A total of 156 patients was identified with ES-HC (Table 1). Ninety-two patients (59%) had only mild or no symptoms (NYHA functional class I to II) at the time of ES diagnosis. Sequencing analysis identified a total of 131 mutations in 104 ES-HC patients (overall prevalence 67%) including 101 missense, 13 splicing, 11 frameshift, 4 nonsense, and 2 in-frame deletion mutations. Of these, 95 (73%) mutations have been previously reported as associated with HC phenotype, whereas 36 (27%) were novel
Discussion
The present study assessed the genetic and clinical profile of the largest cohort of ES-HC patients reported to date. In >150 HC patients with an LVEF <50%, a comprehensive sarcomere gene screening showed that (1) the rate and spectrum of mutations were similar to those of other patients with HC and preserved systolic function; (2) a higher frequency of multiple mutations was present compared with HC with preserved EF, particularly among younger patients; and (3) the clinical course and outcome
Disclosures
Dr. Rosmini was supported by a grant from “Fondazione del Monte di Bologna e Ravenna”, Italy. The “Galliera Genetic Bank” member of the Telethon Genetic Biobank Network (Project No. GTB12001), founded by Telethon Italy provided us with specimens.
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2020, Pharmacological ResearchCitation Excerpt :Despite these differences in outcome between patients carrying thick and thin filament mutations, recent studies on larger HCM populations confirmed that different mutations, even within the same gene, are associated with different disease severity, and confirmed that certain “high-risk” variants (e.g. mutations of the converter region of MYH7) are linked with a higher likelihood of SD [30,31]. Finally, patients carrying two or more different disease-causing variants in sarcomeric genes have a higher likelihood of lethal arrhythmias and adverse disease progression [32,33]. Genetic and non-genetic factors concur to drive the evolution of the pathogenesis of HCM.
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2020, Journal of the American College of CardiologyCitation Excerpt :In our selected group of 26 ES patients with genetic testing, we found mutations predominantly in the most common HCM genes (MYBPC3 and MYH7). Notably, these findings are consistent with several other studies demonstrating ES-HCM to be characterized by MYBPC3 and MYH7 mutations indistinguishable from that reported in patients with HCM and preserved EF (43,44,46,47). ES is an uncommon but high-risk phenotype associated with a significant increase in risk for HCM-related death, progressive and unrelenting heart failure, or sudden death events.
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