Clinical Considerations for a Family with Dilated Cardiomyopathy, Sudden Cardiac Death, and a Novel TTN Frameshift Mutation

Emanuele Micaglio, Michelle M Monasky, Andrea Bernardini, Valerio Mecarocci, Valeria Borrelli, Giuseppe Ciconte, Emanuela T Locati, Marco Piccoli, Andrea Ghiroldi, Luigi Anastasia, Carlo Pappone

Research output: Contribution to journalArticlepeer-review


Dilated cardiomyopathy (DCM) is the leading indication for heart transplantation. TTN gene truncating mutations account for about 25% of familial DCM cases and for 18% of sporadic DCM cases. The clinical relevance of specific variants in TTN has been difficult to determine because of the sheer size of the protein for which TTN encodes, as well as existing extensive genetic variation. Clinicians should communicate novel clinically-relevant variants and genotype-phenotype associations, so that animal studies evaluating the molecular mechanisms are always conducted with a focus on clinical significance. In the present study, we report for the first time the novel truncating heterozygous variant NM_001256850.1:c.72777_72783del (p.Phe24259Leufs*51) in the TTN gene and its association with DCM in a family with sudden death. This variant occurs in the A-band region of the sarcomere, in a known mutational hotspot of the gene. Truncating titin variants that occur in this region are the most common cause of DCM and have been rarely reported in asymptomatic individuals, differently from other pathogenic TTN gene variants. Further studies are warranted to better understand this particular clinically-relevant variant.

Original languageEnglish
JournalInt J Mol Sci
Issue number2
Publication statusPublished - Jan 12 2021


  • Biomarkers
  • Cardiomyopathy, Dilated/complications
  • Connectin/genetics
  • DNA Mutational Analysis
  • Death, Sudden, Cardiac/etiology
  • Diagnostic Imaging
  • Electrocardiography
  • Female
  • Frameshift Mutation
  • Genetic Association Studies/methods
  • Genetic Predisposition to Disease
  • Heart Function Tests
  • Humans
  • Male
  • Middle Aged


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