Feb 18, 2012

Truncations of titin causing dilated cardiomyopathy

The New England Journal of Medicine
Daniel S HermanChristine E Seidman

Abstract

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. 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. 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 reg...Continue Reading

  • References39
  • Citations511
  • References39
  • Citations511

Citations

Mentioned in this Paper

Cardiomyopathy, Familial Idiopathic
Sarcomeres
Hypertrophic Cardiomyopathy
Genetic Screening Method
TTN gene
Myocardium
Cardiomyopathies
Adverse Event
Sequencing
Massively-Parallel Sequencing

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