October 13, 2008Open Access
Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology
Key Result
A heterozygous missense mutation (I79N) in the cardiac troponin T (TNNT2) gene was identified in all 9 affected family members, causing variable expression of RCM, HCM, and DCM.
Study Design
Type
Observational (n=15)
Structured PICO
Can a single sarcomeric protein gene mutation cause variable cardiomyopathy phenotypes (RCM, HCM, DCM) within the same family?
P
Population
A family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM) (n=15; 9 affected, 6 unaffected).
I
Intervention
Genetic linkage analysis and sequencing of sarcomeric genes
C
Comparator
Unaffected family members
O
Outcome
Identification of the molecular defect triggering divergent remodeling pathwayssurrogate
A single TNNT2 mutation can cause diverse cardiomyopathy phenotypes including RCM, HCM, and DCM within the same family, highlighting the need for comprehensive screening.
Abstract
We identified a unique family with autosomal dominant heart disease variably expressed as restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM), and sought to identify the molecular defect that triggered divergent remodeling pathways. Polymorphic DNA markers for nine sarcomeric genes for DCM and/or HCM were tested for segregation with disease. Linkage to eight genes was excluded, but a cardiac troponin T (TNNT2) marker cosegregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution, inherited by all nine affected family members but by none of the six unaffected relatives. Mutation carriers were diagnosed with RCM (n = 2), non-obstructive HCM (n = 3), DCM (n = 2), mixed cardiomyopathy (n = 1), and mild concentric left ventricular hypertrophy (n = 1). Endomyocardial biopsy in the proband revealed non-specific fibrosis, myocyte hypertrophy, and no myofibrillar disarray. Restrictive Doppler filling patterns, atrial enlargement, and pulmonary hypertension were observed among family members regardless of cardiomyopathy subtype. Mutation of a sarcomeric protein gene can cause RCM, HCM, and DCM within the same family, underscoring the necessity of comprehensive morphological and physiological cardiac assessment in familial cardiomyopathy screening.