Mortality Risk Associated With Truncating Founder Mutations in Titin.
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.
['Jansen|Mark|M|', 'Baas|Annette F|AF|', 'van Spaendonck-Zwarts|Karin Y|KY|', 'Ummels|Amber S|AS|', 'van den Wijngaard|Arthur|A|', 'Jongbloed|Jan D H|JDH|', 'van Slegtenhorst|Marjon A|MA|', 'Lekanne Deprez|Ronald H|RH|', 'Wessels|Marja W|MW|', 'Michels|Michelle|M|', 'Houweling|Arjan C|AC|', 'Hoorntje|Edgar T|ET|', 'Helderman-van den Enden|Paula J T M|PJTM|', 'Barge-Schaapveld|Daniela Q C M|DQCM|', 'Peter van Tintelen|J|J|', 'van den Berg|Maarten P|MP|', 'Wilde|Arthur A M|AAM|', 'Ploos van Amstel|Hans K|HK|', 'Hennekam|Eric A M|EAM|', 'Asselbergs|Folkert W|FW|', 'Sijbrands|Eric J G|EJG|', 'Dooijes|Dennis|D|']
D000328:Adult D002311:Cardiomyopathy, Dilated D064211:Connectin D030541:Databases, Genetic D005260:Female D018703:Founder Effect D014644:Genetic Variation D049671:History, 18th Century D049672:History, 19th Century D049673:History, 20th Century D049674:History, 21st Century D006801:Humans D008297:Male D008875:Middle Aged D009154:Mutation D009426:Netherlands D010375:Pedigree D020641:Polymorphism, Single Nucleotide
mortality mutation titin natural history cardiomyopathy, dilated