title: Role of Titin Missense Variants in Dilated Cardiomyopathy.
abstract: BACKGROUND
  The titin gene (TTN) encodes the largest human protein, which plays a central role in sarcomere organization and passive myocyte stiffness. TTN truncating mutations cause dilated cardiomyopathy (DCM); however, the role of TTN missense variants in DCM has been difficult to elucidate because of the presence of background TTN variation.
  
  
  RESULTS
  A cohort of 147 DCM index subjects underwent DNA sequencing for 313 TTN exons covering the N2B and N2BA cardiac isoforms of TTN. Of the 348 missense variants, we identified 44 "severe" rare variants by using a bioinformatic filtering process in 37 probands. Of these, 5 probands were double heterozygotes (additional variant in another DCM gene) and 7 were compound heterozygotes (2 TTN "severe" variants). Segregation analysis allowed the classification of the "severe" variants into 5 "likely" (cosegregating), 5 "unlikely" (noncosegregating), and 34 "possibly" (where family structure precluded segregation analysis) disease-causing variants. Patients with DCM carrying "likely" or "possibly" pathogenic TTN "severe" variants did not show a different outcome compared with "unlikely" and noncarriers of a "severe" TTN variant. However, the "likely" and "possibly" disease-causing variants were overrepresented in the C-zone of the A-band region of the sarcomere.
  
  
  CONCLUSIONS
  TTN missense variants are common and present a challenge for bioinformatic classification, especially when informative families are not available. Although DCM patients carrying bioinformatically "severe" TTN variants do not appear to have a worse clinical course than noncarriers, the nonrandom distribution of "likely" and "possibly" disease-causing variants suggests a potential biological role for some TTN missense variants.
authors.affiliation: University of Colorado Denver CU-Cardiovascular Institute, Aurora, CO (R.L.B., S.G., D.S., L.M., M.T.).
authors.forename: Rene L
authors.initials: RL
authors.lastname: Begay
authors.affiliation: University of Colorado Denver CU-Cardiovascular Institute, Aurora, CO (R.L.B., S.G., D.S., L.M., M.T.).
authors.forename: Sharon
authors.initials: S
authors.lastname: Graw
authors.affiliation: Cardiovascular Department "Ospedali Riuniti" and Cardiovascular Center, ASS1-Trieste and University of Trieste, Trieste, Italy (G.S., M.M., G.B., A.S., F.B., A.D.L.).
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Sinagra
authors.affiliation: Cardiovascular Department "Ospedali Riuniti" and Cardiovascular Center, ASS1-Trieste and University of Trieste, Trieste, Italy (G.S., M.M., G.B., A.S., F.B., A.D.L.).
authors.forename: Marco
authors.initials: M
authors.lastname: Merlo
authors.affiliation: University of Colorado Denver CU-Cardiovascular Institute, Aurora, CO (R.L.B., S.G., D.S., L.M., M.T.).
authors.forename: Dobromir
authors.initials: D
authors.lastname: Slavov
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, CO (K.G., K.L.J.).
authors.forename: Katherine
authors.initials: K
authors.lastname: Gowan
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, CO (K.G., K.L.J.).
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Jones
authors.affiliation: Cardiovascular Department "Ospedali Riuniti" and Cardiovascular Center, ASS1-Trieste and University of Trieste, Trieste, Italy (G.S., M.M., G.B., A.S., F.B., A.D.L.).
authors.forename: Giulia
authors.initials: G
authors.lastname: Barbati
authors.affiliation: Cardiovascular Department "Ospedali Riuniti" and Cardiovascular Center, ASS1-Trieste and University of Trieste, Trieste, Italy (G.S., M.M., G.B., A.S., F.B., A.D.L.).
authors.forename: Anita
authors.initials: A
authors.lastname: Spezzacatene
authors.affiliation: Cardiovascular Department "Ospedali Riuniti" and Cardiovascular Center, ASS1-Trieste and University of Trieste, Trieste, Italy (G.S., M.M., G.B., A.S., F.B., A.D.L.).
authors.forename: Francesca
authors.initials: F
authors.lastname: Brun
authors.affiliation: Cardiovascular Department "Ospedali Riuniti" and Cardiovascular Center, ASS1-Trieste and University of Trieste, Trieste, Italy (G.S., M.M., G.B., A.S., F.B., A.D.L.).
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Lenarda
authors.affiliation: Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ (J.E.S., H.L.G.).
authors.forename: John E
authors.initials: JE
authors.lastname: Smith
authors.affiliation: Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ (J.E.S., H.L.G.).
authors.forename: Henk L
authors.initials: HL
authors.lastname: Granzier
authors.affiliation: University of Colorado Denver CU-Cardiovascular Institute, Aurora, CO (R.L.B., S.G., D.S., L.M., M.T.).
authors.forename: Luisa
authors.initials: L
authors.lastname: Mestroni
authors.affiliation: University of Colorado Denver CU-Cardiovascular Institute, Aurora, CO (R.L.B., S.G., D.S., L.M., M.T.).
authors.forename: Matthew
authors.initials: M
authors.lastname: Taylor
mesh_terms: D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D019295:Computational Biology; D064211:Connectin / Q000235:genetics*; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007558:Italy; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D012042:Registries; D012307:Risk Factors; D013997:Time Factors; D014481:United States
chemical_list: D064211:Connectin; C577285:TTN protein, human
keywords: cardiomyopathy; cardiovascular genetics; dilated cardiomyopathy; heart failure; missense variants