Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy

The aim of this study was to evaluate the potential utility of genetic diagnosis in clinical management of families with hypertrophic cardiomyopathy (HCM) caused by mutations in the gene for cardiac troponin I (TNNI3). Knowledge about the clinical disease expression of sarcomeric gene mutations in HCM has predominantly been obtained by investigations of single individuals (probands) or selected families. To establish the role of genetic diagnosis in HCM families, systematic investigations of probands and their relatives are needed. Cardiac troponin I was investigated by direct sequencing and fluorescent (F)-SSCP analysis in 748 consecutive HCM families. Relatives of HCM probands with TNNI3mutations were invited for cardiovascular and genetic assessment. The prevalence of TNNI3mutations was 3.1%. Mutations appeared to cluster in exons 7 and 8. A total of 100 mutation carriers were identified in 23 families with 13 different mutations (6 novel). Disease penetrance was 48%. Patients were diagnosed from the second to eighth decade of life. The morphologic spectrum observed represented a wide range of HCM. Two offspring of clinically unaffected mutation carriers were resuscitated from cardiac arrest, and an additional four individuals died suddenly as their initial presentation. Six individuals experienced other disease-related deaths. The clinical expression of TNNI3mutations was very heterogeneous and varied both within and between families with no apparent mutation- or gene-specific disease pattern. The data suggest that disease development may be monitored by regular assessment of cardiac symptoms and electrocardiographic abnormalities. Genetic diagnosis of TNNI3is valuable in identifying clinically unaffected mutation carriers at risk of disease development and facilitates accurate management and counseling.