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Deletion in the cardiac troponin I gene in a family from Northern Sweden with hypertrophic cardiomyopathy
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
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2000 (English)In: Journal of Molecular and Cellular Cardiology, ISSN 0022-2828, E-ISSN 1095-8584, Vol. 32, no 3, 521-525 p.Article in journal (Refereed) Published
Abstract [en]

The cardiac troponin I gene has been described to be associated with hypertrophic cardiomyopathy. Until now, mutations in this gene have been found only in the Japanese population. We now present the first non-Japanese family, from northern Sweden, with a mutation in the cardiac troponin I gene. Clinical diagnose was based on echocardiography, with a maximum left ventricular wall thickness of >13 mm, or major electrocardiographic abnormalities, excluding subjects with other known causes of cardiac hypertrophy. Mutation screening was performed with a single-strand conformation polymorphism analysis and identification of mutation by direct DNA sequencing. We have identified a 33-bp deletion in exon 8 encompassing the stop codon. Nine individuals in three generations were tested, and four were carriers of this deletion. The mother was genetically affected and died of heart failure aged 90. Echocardiography at 71 years of age revealed no hypertrophy, but the electrocardiogram showed signs of left ventricular hypertrophy. Her two sons, also genetically affected, had left ventricular hypertrophy, with maximum wall thickness of 15 and 16 mm, respectively. One daughter and four grandchildren were clinically unaffected, but one of them, a 27-year-old woman with maximum wall thickness of 8 mm and normal electrocardiogram, was found to be genetically affected. In conclusion, we describe a non-Japanese family in which hypertrophic cardiomyopathy is due to a genetic defect in the cardiac troponin I gene. This mutation is a deletion of 33 bp in the last exon, whereas the previously described mutations in this gene are single nucleotide changes and a single codon deletion. The deletion of the C-terminal part of the cardiac troponin I protein, seems in this particular family to be associated with a mild phenotypic expression of familial hypertrophic cardiomyopathy.

Place, publisher, year, edition, pages
2000. Vol. 32, no 3, 521-525 p.
Keyword [en]
Cardiac troponin I, Familial hypertrophic cardiomyopathy, Genetics, Mutation
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:umu:diva-3982DOI: 10.1006/jmcc.1999.1099PubMedID: 10731450OAI: oai:DiVA.org:umu-3982DiVA: diva2:142909
Available from: 2004-05-10 Created: 2004-05-10 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Hypertrophic cardiomyopathy in Northern Sweden: with special emphasis on molecular genetics
Open this publication in new window or tab >>Hypertrophic cardiomyopathy in Northern Sweden: with special emphasis on molecular genetics
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hypertrophic cardiomyopathy (HCM) is a heterogeneous, often familial disease, characterized by cardiac hypertrophy, predominantly affecting the interventricular septum. To date, no study has systematically analysed the genetic and phenotypic aspects of the disease in a Swedish population. The aim of this thesis was to identify the genotypes causing HCM in northern Sweden, to characterize the disease phenotypes and correlate these findings.

Forty-six patients were recruited for the genetic studies (21 women), 11 familial and 35 sporadic cases. Eight sarcomeric protein genes were screened for mutations. A total of 11 different disease causing mutations were found in four genes. Six of the mutations were previously not described. A novel mutation (a 33 base pair deletion) in the troponin I gene was found in one HCM family. Despite the severe genetic defect, the associated phenotype displayed only mild cardiac hypertrophy and few symptoms. Most mutations (64%) were identified in the myosin binding protein C gene, a gene considered to have a low penetrance. Mutations were identified in 10 of 11 familial HCM cases, but only in three of the 35 sporadic cases.

It was found that cardiac amyloidosis can sometimes present itself as HCM. Three HCM patients (7%) carried the ATTR Val30Met mutation, also found in Swedish patients with familial amyloid polyneuropathy (FAP). The patients had no symptoms of polyneuropathy, but cardiac amyloidosis as the cause of hypertrophy was verified by myocardial biopsy in an index case. Amyloid heart disease should therefore be considered as a differential diagnosis in patients with HCM.

By studying heart rate variability (HRV), it was found that young patients with HCM had signs of autonomic dysfunction, expressed as a reduced HRV. Treatment with beta-blockade attenuated these effects. Abnormal autonomic function might be a substrate for lethal arrhythmias, most often encountered in younger patients with HCM. The results suggest a possible protective effect of beta-blockade, remaining to be studied further.

Ventricular function is frequently abnormal in HCM. In particular, diastolic dysfunction has been demonstrated. The recently described myocardial performance index allows the assessment of cardiac function by combining systolic and diastolic performance. We found that patients with hypertrophic cardiomyopathy had evidence of global and regional right ventricular dysfunction, besides left ventricular dysfunction. Hypertrophic cardiomyopathy is traditionally considered to be a disease of the left ventricle. The results show that hypertrophic cardiomyopathy should more be regarded as a biventricular disease.

In conclusion, the myosin binding protein C gene is the most common gene causing familial HCM in northern Sweden. This disease gene is considered to be associated with a mild, late-onset disease with ≈50% penetrance at 30 years of age. The low disease penetrance emphasizes the importance of adequate family screening when evaluating patients with HCM, since the familial nature of the disease might easily be overlooked. These particular disease features in northern Sweden contrast to most previous reports, which indicate another disease gene as the most frequent in HCM, associated with a much higher penetrance. Amyloid heart disease, requiring different treatment than HCM, should be kept in mind as a differential diagnosis in the management of patients with HCM.

Key words: Hypertrophic cardiomyopathy, genetics, autonomic nervous system, familial amyloid polyneuropathy, echocardiography.

Series
Umeå University medical dissertations, ISSN 0346-6612 ; 894
Keyword
Hypertrophic cardiomyopathy, genetics, autonomic nervous system, familial amyloid polyneuropathy, echocardiography
Research subject
Epidemiology
Identifiers
urn:nbn:se:umu:diva-274 (URN)91-7305-660-X (ISBN)
Public defence
2004-05-28, Sal E04, Byggnad 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Available from: 2004-05-10 Created: 2004-05-10 Last updated: 2010-08-10Bibliographically approved

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