Mortality Risk Associated With Truncating Founder Mutations in Titin.

Area of Science:

• Cardiovascular Genetics
• Human Genetics
• Population Genetics

Background:

• Truncating titin variants (TTNtv) are the leading genetic cause of dilated cardiomyopathy, affecting up to 25% of familial cases and 0.5% of the general population.
• The long-term prognosis for asymptomatic TTNtv carriers is poorly understood due to highly variable clinical presentations.

Observation:

• This study analyzed standardized mortality ratios (SMR) in multigenerational pedigrees and relatives of dilated cardiomyopathy patients carrying TTNtv.
• Haplotype and genealogical analyses traced three recurrent TTNtv to 18th-century founder mutations.

Findings:

• Overall mortality was not significantly increased in 20,522 person-years of follow-up (SMR, 1.06).
• However, mortality was significantly elevated in individuals diagnosed after 1965 (SMR, 1.27) and those aged 60 years or older (SMR, 1.17).
• Reverse parent-offspring analysis revealed excess mortality (SMR, 1.26), primarily in individuals aged 60+.

Implications:

• The natural history of these TTNtv suggests a relatively mild disease course but with significant excess mortality in older patients.
• As life expectancy increases, TTNtv-associated morbidity and mortality are expected to become more prevalent, necessitating further research and clinical attention.