title: Poor prognosis of rare sarcomeric gene variants in patients with dilated cardiomyopathy.
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.
authors.affiliation: Cardiovascular Institute and Adult Medical Genetics, University of Colorado, Aurora, Colorado, USA; Cardiovascular Department "Ospedali Riuniti,"and University of Trieste, Trieste, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Merlo
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Sinagra
authors.forename: Elisa
authors.initials: E
authors.lastname: Carniel
authors.forename: Dobromir
authors.initials: D
authors.lastname: Slavov
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhu
authors.forename: Giulia
authors.initials: G
authors.lastname: Barbati
authors.forename: Anita
authors.initials: A
authors.lastname: Spezzacatene
authors.forename: Federica
authors.initials: F
authors.lastname: Ramani
authors.forename: Ernesto
authors.initials: E
authors.lastname: Salcedo
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Lenarda
authors.forename: Luisa
authors.initials: L
authors.lastname: Mestroni
authors.forename: Matthew R G
authors.initials: MR
authors.lastname: Taylor
mesh_terms: D000328:Adult; D000367:Age Factors; D024722:Cardiac Myosins / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D002352:Carrier Proteins / Q000235:genetics; D003120:Colorado; D064211:Connectin / Q000235:genetics; D016757:Death, Sudden, Cardiac / Q000209:etiology; D018572:Disease-Free Survival; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006333:Heart Failure / Q000235:genetics / Q000401:mortality; D016027:Heart Transplantation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007558:Italy; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018995:Myosin Heavy Chains / Q000235:genetics; D010641:Phenotype; D016016:Proportional Hazards Models; D012042:Registries; D012189:Retrospective Studies; D012307:Risk Factors; D012518:Sarcomeres; D013997:Time Factors; D020107:Troponin T / Q000235:genetics; D014693:Ventricular Fibrillation / Q000235:genetics; D000099163:Myosin Binding Protein C
chemical_list: D024722:Cardiac Myosins; D002352:Carrier Proteins; D064211:Connectin; D018995:Myosin Heavy Chains; D020107:Troponin T; D000099163:Myosin Binding Protein C; C094239:MYH6 protein, human; C501641:MYH7 protein, human; C545568:TNNT2 protein, human; C577285:TTN protein, human
keywords: cardiomyopathy; genes; genetics; molecular genetics; phenotyping; prognosis