Cardiomyopathy
Significance of Sarcomere Gene Mutations Analysis in the End-Stage Phase of Hypertrophic Cardiomyopathy

https://doi.org/10.1016/j.amjcard.2014.05.065Get rights and content

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.

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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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