NEW YORK (Reuters Health) - The clinical expression of hypertrophic cardiomyopathy (HCM) due to mutations in the gene for cardiac troponin I (TNNI3) varies widely within and between families with no discernible mutation or gene-specific disease pattern.
These are the findings of a comprehensive analysis of the relation between genotype and clinical phenotype in 748 consecutive patients with HCM and their relatives.
“The aim was to examine the potential value of genetic diagnosis for management, counseling, and follow-up of HCM families with TNNI3 mutations, Dr. Jens Mogensen, from Skejby University Hospital in Aarhus, Denmark, and colleagues explain in the December 21st Journal of the American College of Cardiology.
The prevalence of TNNI3 mutations was 3.1% and disease penetrance was 48%. The investigators identified 13 distinct TNNI3 mutations (6 novel) in 23 probands and 77 family members. Mutations tended to cluster in exons 7 and 8.
The investigators observed a wide range of cardiac morphology in affected individuals, “from mild asymmetrical septal hypertrophy, apical and biventricular hypertrophy to ‘end-stage’ dilated HCM, and HCM with restrictive physiology.”
Electrocardiographic abnormalities and the prevalence of arrhythmias also varied widely, as did the age at diagnosis, which ranged from the second to the eighth decade of life.
Of note, two children of clinically unaffected mutation carriers were resuscitated from cardiac arrest and four other individuals died suddenly as their initial presentation, suggesting that genetic diagnosis is “important, particularly in unaffected offspring,” Dr. Mogensen and colleagues note.
Based on their findings, they conclude that “life-long follow-up of clinically unaffected mutation carriers is warranted to identify and treat those at risk of developing disease-related complications.”
It is also important to note that individuals without TNNI3 mutations have no risk of developing or passing the disease on to their offspring. “Thus, genetic diagnosis identifies relatives who require follow-up and enables termination of cardiac evaluation in individuals without the mutation, which is of great relief. This also facilitates cost-effective use of resources,” they note.
In a commentary, Drs. Calum A. MacRae and Patrick T. Ellinor from Massachusetts General Hospital in Boston say the authors should be commended for “the size and scope of this effort, the first systematic study of cardiac troponin I mutations in HCM.”
The findings suggest that, “at least for troponin I-associated disease, genotypic information allows one only to discriminate those who have inherited any risk (and then only in those in whom a mutation can be detected using current technology), but does not allow gradation of that risk,” they note.
Source: J Am Coll Cardiol 2004;44:2315-2328. [ Google search on this article ]
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