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Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy
- Source :
- Circulation. 107(17)
- Publication Year :
- 2003
-
Abstract
- Background—Hypertrophic cardiomyopathy is an autosomal-dominant disorder in which 10 genes and numerous mutations have been reported. The aim of the present study was to perform a systematic screening of these genes in a large population, to evaluate the distribution of the disease genes, and to determine the best molecular strategy in clinical practice.Methods and Results—The entire coding sequences of 9 genes (MYH7,MYBPC3,TNNI3,TNNT2,MYL2,MYL3,TPM1,ACTC, andTNNC1) were analyzed in 197 unrelated index cases with familial or sporadic hypertrophic cardiomyopathy. Disease-causing mutations were identified in 124 index patients (≈63%), and 97 different mutations, including 60 novel ones, were identified. The cardiac myosin-binding protein C (MYBPC3) and β-myosin heavy chain (MYH7) genes accounted for 82% of families with identified mutations (42% and 40%, respectively). Distribution of the genes varied according to the prognosis (P=0.036). Moreover, a mutation was found in 15 of 25 index cases with “sporadic” hypertrophic cardiomyopathy (60%). Finally, 6 families had patients with more than one mutation, and phenotype analyses suggested a gene dose effect in these compound-heterozygous, double-heterozygous, or homozygous patients.Conclusion—These results might have implications for genetic diagnosis strategy and, subsequently, for genetic counseling. First, on the basis of this experience, the screening of already known mutations is not helpful. The analysis should start by testingMYBPC3andMYH7and then focus onTNNI3,TNNT2, andMYL2. Second, in particularly severe phenotypes, several mutations should be searched. Finally, sporadic cases can be successfully screened.
- Subjects :
- Genetics
Mutation
Genotype
Myosin Heavy Chains
TNNT2
Hypertrophic cardiomyopathy
Cardiomyopathy
TPM1
Biology
medicine.disease
medicine.disease_cause
Prognosis
Genetic determinism
Article
MYL3
Molecular Diagnostic Techniques
Physiology (medical)
medicine
Cardiomyopathy, Hypertrophic, Familial
Humans
MYH7
Genetic Predisposition to Disease
Cardiology and Cardiovascular Medicine
Carrier Proteins
Subjects
Details
- ISSN :
- 15244539
- Volume :
- 107
- Issue :
- 17
- Database :
- OpenAIRE
- Journal :
- Circulation
- Accession number :
- edsair.doi.dedup.....42c4af31b930f128c17878be2c0848c6