Mortality Risk Associated With Truncating Founder Mutations in Titin

Mark Jansen, Annette F. Baas, Karin Y. van Spaendonck-Zwarts, Amber S. Ummels, Arthur van den Wijngaard, Jan D. H. Jongbloed, Marjon A. van Slegtenhorst, Ronald H. Lekanne Deprez, Marja W. Wessels, Michelle Michels, Arjan C. Houweling, Edgar T. Hoorntje, Paula J. T. M. Helderman-van den Enden, Daniela Q. C. M. Barge-Schaapveld, J. Peter van Tintelen, Maarten P. van den Berg, Arthur A. M. Wilde, Hans K. Ploos van Amstel, Eric A. M. Hennekam, Folkert W. AsselbergsEric J. G. Sijbrands, Dennis Dooijes*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Background Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy, found in ≤25% of familial cases. Moreover, TTNtv associated with dilated cardiomyopathy are estimated to be present in 0.5% of the general population. The prognosis of asymptomatic carriers of TTNtv is poorly understood because TTNtv are associated with a highly variable phenotype. We aim to assess the natural history and clinical relevance of TTNtv by analyzing standardized mortality ratios (SMR) in multigenerational pedigrees and in close relatives of present-day patients. Methods Haplotype and genealogical analyses were performed on 3 recurrent TTNtv. Subsequently, the family tree mortality ratio method was used to compare all-cause mortality of subjects at an a priori 50% risk of carrying TTNtv to the general Dutch population. SMRs were stratified for sex, age, and calendar period. Subgroups were compared with Poisson regression. Similarly, SMRs were calculated in parents of 128 present-day dilated cardiomyopathy probands with TTNtv using the reverse parent-offspring method. Results The TTNtv were established as founder mutations and traced to 18th century ancestors. In 20 522 person-years, overall mortality was not significantly increased (SMR, 1.06; 95% CI, 0.95-1.18; P=0.162). However, mortality was significantly increased in subjects living after 1965 (SMR, 1.27; 95% CI, 1.04-1.53; P=0.009) and aged ≥60 years (SMR, 1.17; 95% CI, 1.01-1.35; P=0.02). The reverse parent-offspring analysis showed overall excess mortality (SMR, 1.26; 95% CI, 1.07-1.48; P=0.003), driven by subjects aged ≥60 years. Conclusions The natural history of the analyzed TTNtv shows a relatively mild disease course with significant excess mortality in elderly patients. With increasing life expectancy, TTNtv-associated morbidity and mortality will likely become more prevalent.

Original languageEnglish
Article numbere002436
Number of pages8
JournalCirculation: Genomic and Precision Medicine
Issue number5
Publication statusPublished - May 2019


  • cardiomyopathy
  • dilated
  • mortality
  • mutation
  • natural history
  • titin
  • LONG
  • FORM


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