title: Truncations of titin causing dilated cardiomyopathy.
abstract: BACKGROUND
  Dilated cardiomyopathy and hypertrophic cardiomyopathy arise from mutations in many genes. TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size.
  
  
  METHODS
  We analyzed TTN in 312 subjects with dilated cardiomyopathy, 231 subjects with hypertrophic cardiomyopathy, and 249 controls by using next-generation or dideoxy sequencing. We evaluated deleterious variants for cosegregation in families and assessed clinical characteristics.
  
  
  RESULTS
  We identified 72 unique mutations (25 nonsense, 23 frameshift, 23 splicing, and 1 large tandem insertion) that altered full-length titin. Among subjects studied by means of next-generation sequencing, the frequency of TTN mutations was significantly higher among subjects with dilated cardiomyopathy (54 of 203 [27%]) than among subjects with hypertrophic cardiomyopathy (3 of 231 [1%], P=3×10(-16)) or controls (7 of 249 [3%], P=9×10(-14)). TTN mutations cosegregated with dilated cardiomyopathy in families (combined lod score, 11.1) with high (>95%) observed penetrance after the age of 40 years. Mutations associated with dilated cardiomyopathy were overrepresented in the titin A-band but were absent from the Z-disk and M-band regions of titin (P≤0.01 for all comparisons). Overall, the rates of cardiac outcomes were similar in subjects with and those without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers (P=4×10(-5)).
  
  
  CONCLUSIONS
  TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases. Incorporation of sequencing approaches that detect TTN truncations into genetic testing for dilated cardiomyopathy should substantially increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy. Defining the functional effects of TTN truncating mutations should improve our understanding of the pathophysiology of dilated cardiomyopathy. (Funded by the Howard Hughes Medical Institute and others.).
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Herman
authors.forename: Lien
authors.initials: L
authors.lastname: Lam
authors.forename: Matthew R G
authors.initials: MR
authors.lastname: Taylor
authors.forename: Libin
authors.initials: L
authors.lastname: Wang
authors.forename: Polakit
authors.initials: P
authors.lastname: Teekakirikul
authors.forename: Danos
authors.initials: D
authors.lastname: Christodoulou
authors.forename: Lauren
authors.initials: L
authors.lastname: Conner
authors.forename: Steven R
authors.initials: SR
authors.lastname: DePalma
authors.forename: Barbara
authors.initials: B
authors.lastname: McDonough
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sparks
authors.forename: Debbie Lin
authors.initials: DL
authors.lastname: Teodorescu
authors.forename: Allison L
authors.initials: AL
authors.lastname: Cirino
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Banner
authors.forename: Dudley J
authors.initials: DJ
authors.lastname: Pennell
authors.forename: Sharon
authors.initials: S
authors.lastname: Graw
authors.forename: Marco
authors.initials: M
authors.lastname: Merlo
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Lenarda
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Sinagra
authors.forename: J Martijn
authors.initials: JM
authors.lastname: Bos
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Richard N
authors.initials: RN
authors.lastname: Mitchell
authors.forename: Charles E
authors.initials: CE
authors.lastname: Murry
authors.forename: Neal K
authors.initials: NK
authors.lastname: Lakdawala
authors.forename: Carolyn Y
authors.initials: CY
authors.lastname: Ho
authors.forename: Paul J R
authors.initials: PJ
authors.lastname: Barton
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
authors.forename: Luisa
authors.initials: L
authors.lastname: Mestroni
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
mesh_terms: D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D064211:Connectin; D005260:Female; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D017384:Sequence Deletion
chemical_list: D064211:Connectin; D009124:Muscle Proteins; C577285:TTN protein, human; D011494:Protein Kinases