TY - JOUR
T1 - Mortality Risk Associated With Truncating Founder Mutations in Titin
AU - Jansen, Mark
AU - Baas, Annette F
AU - van Spaendonck-Zwarts, Karin Y
AU - Ummels, Amber S
AU - van den Wijngaard, Arthur
AU - Jongbloed, Jan D H
AU - van Slegtenhorst, Marjon A
AU - Lekanne Deprez, Ronald H
AU - Wessels, Marja W
AU - Michels, Michelle
AU - Houweling, Arjan C
AU - Hoorntje, Edgar T
AU - Helderman-van den Enden, Paula J T M
AU - Barge-Schaapveld, Daniela Q C M
AU - Peter van Tintelen, J
AU - van den Berg, Maarten P
AU - Wilde, Arthur A M
AU - Ploos van Amstel, Hans K
AU - Hennekam, Eric A M
AU - Asselbergs, Folkert W
AU - Sijbrands, Eric J G
AU - Dooijes, Dennis
PY - 2019/5
Y1 - 2019/5
N2 - BACKGROUND: Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy, found inMETHODS: 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.
AB - BACKGROUND: Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy, found inMETHODS: 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.
KW - cardiomyopathy
KW - dilated
KW - mortality
KW - mutation
KW - natural history
KW - titin
KW - DILATED CARDIOMYOPATHY
KW - HEART-FAILURE
KW - VARIANTS
KW - GENETICS
KW - LONG
KW - FORM
U2 - 10.1161/CIRCGEN.118.002436
DO - 10.1161/CIRCGEN.118.002436
M3 - Article
C2 - 31112426
SN - 2574-8300
VL - 12
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
IS - 5
M1 - 002436
ER -