Poor prognosis of rare sarcomeric gene variants in patients with dilated cardiomyopathy

Clin Transl Sci. 2013 Dec;6(6):424-8. doi: 10.1111/cts.12116. Epub 2013 Oct 3.

Abstract

Background: In dilated cardiomyopathy (DCM), the clinical and prognostic implications of rare variants in sarcomeric genes remain poorly understood. To address this question, we analyzed the outcome of rare sarcomeric gene variants in patients enrolled in our Familial Cardiomyopathy Registry.

Methods: DCM families harboring rare sarcomeric variants in MYH6, MYH7, MYBPC3, TNNT2, and TTN were identified. Genotype-phenotype association analysis was performed, and long-term survival-free from death or heart transplant was compared between carriers and noncarriers.

Results: We found 24 rare variants (3 in MYH6, 3 in MYH7, 3 in MYBPC3, 2 in TNNT2, and 13 in TTN) affecting 52 subjects in 25 families. The phenotypes of variant carriers were severe (3 sudden deaths, 6 heart failure deaths, 8 heart transplants, 2 ventricular fibrillations). There was no difference in the overall long-term survival between carriers and the 33 noncarriers (p = 0.322). However after 50 years of age, the combined endpoint of death or transplant was decreased in carriers as compared to noncarriers (p = 0.026).

Conclusions: Patients with DCM carrying rare variants in sarcomeric genes manifest a poorer prognosis as compared to noncarriers after the age of 50 years. These data further support the role of genetic testing in DCM for risk stratification.

Keywords: cardiomyopathy; genes; genetics; molecular genetics; phenotyping; prognosis.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Age Factors
  • Cardiac Myosins / genetics
  • Cardiomyopathy, Dilated / complications
  • Cardiomyopathy, Dilated / genetics*
  • Cardiomyopathy, Dilated / mortality
  • Cardiomyopathy, Dilated / surgery
  • Carrier Proteins / genetics
  • Colorado
  • Connectin / genetics
  • Death, Sudden, Cardiac / etiology
  • Disease-Free Survival
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Heart Failure / genetics
  • Heart Failure / mortality
  • Heart Transplantation
  • Heterozygote
  • Homozygote
  • Humans
  • Italy
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Myosin Heavy Chains / genetics
  • Phenotype
  • Proportional Hazards Models
  • Registries
  • Retrospective Studies
  • Risk Factors
  • Sarcomeres*
  • Time Factors
  • Troponin T / genetics
  • Ventricular Fibrillation / genetics

Substances

  • Carrier Proteins
  • Connectin
  • MYH6 protein, human
  • MYH7 protein, human
  • TNNT2 protein, human
  • TTN protein, human
  • Troponin T
  • myosin-binding protein C
  • Cardiac Myosins
  • Myosin Heavy Chains

Supplementary concepts

  • Familial dilated cardiomyopathy