Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology

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.

Genotype-Positive Status in Patients With Hypertrophic Cardiomyopathy Is Associated With Higher Rates of Heart Failure Events

“…4 Studies evaluating specific correlations between genotype and clinical outcomes have reported conflicting findings. 1,2,[5][6][7][8][9][10][11] In a cohort of 203 patients, Olivotto et al 12 showed that adverse combined outcomes (cardiovascular death, nonfatal stroke, or progression to advanced heart failure symptoms) occurred more frequently in patients who tested positive for a pathogenic sarcomere mutation compared with those without pathogenic mutations. Although important, this study was limited by the small number of patients and the use of combined morbidity and mortality end points.…”

Fetal Cardiac Troponin Isoforms Rescue the Increased Ca2+ Sensitivity Produced by a Novel Double Deletion in Cardiac Troponin T Linked to Restrictive Cardiomyopathy

“…Differential effects of mutations on sarcomeric properties such as myofilament sliding, Ca 2ϩ sensitivity, or ATPase activity have emerged as a mechanism underlying those phenotypes (8,9). Recent studies have shown that RCM is part of the spectrum of sarcomeric gene mutations, including pediatric RCM (7,(35)(36)(37)(38)(39)(40). In the largest series of pediatric RCM reported to date, mutation screening of eight sarcomeric genes and desmin suggested a predominant role of mutations in TNNI3, TNNT2, and ACTC in disease pathogenesis (7).…”

Recurrent and founder mutations in the Netherlands: mutation p.K217del in troponin T2, causing dilated cardiomyopathy*

“…Mutations in TNNT2 can also cause HCM as well as restrictive cardiomyopathy (RCM) and non-compaction cardiomyopathy (NCCM). [28][29][30] Non-compaction cardiomyopathy caused by a TNNT2 mutation was only reported once in the literature and was also identified in person III-1 from family D ( figure 2). 30 Until recently, NCCM was believed to be a rare form of cardiomyopathy.…”