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[Clinical and molecular genetics of familial bundle branch block related to chromosome 19]
E Stephan1, R Chedid, J Loiselet
1Faculté de médecine de l'université Saint-Joseph, Beyrouth, Liban.
Insights
A hereditary conduction defect, inherited in an autosomal dominant pattern, was linked to a gene on chromosome 19q 13.3. This genetic mutation affects heart rhythm and can lead to serious cardiac issues, even in infants.
Area of Science:
- Cardiology
- Genetics
- Medical Research
Background:
- Hereditary conduction defects are a significant cause of cardiac arrhythmias.
- Previous studies have suggested a genetic basis for some conduction disorders, but specific genes remain unidentified.
Purpose of the Study:
- To describe the clinical, electrocardiographic, and prognostic features of a hereditary conduction defect.
- To identify the specific gene responsible for this condition through genetic mapping.
Main Methods:
- Longitudinal observation of four large Lebanese families over multiple generations.
- Electrocardiographic (ECG) analysis to categorize individuals into healthy, affected, and undetermined groups.
- Genetic linkage analysis using markers on chromosome 19q 13.3.
Main Results:
- An autosomal dominant mode of inheritance was confirmed, with reduced penetrance (70% in men, 50% in women).
- The culprit gene was localized to chromosome 19q 13.3, with linkage confirmed by haplotype analysis.
- Affected individuals presented with various conduction abnormalities, including right bundle branch block and complete atrioventricular block, with congenital onset observed.
Conclusions:
- A novel gene responsible for hereditary conduction defects has been identified at 19q 13.3.
- The condition exhibits variable penetrance and can progress to severe atrioventricular block.
- Genetic testing can identify carriers of this mutation, aiding in risk assessment and management.
Abstract:
Four large Lebanese families were observed for several years and over several generations which enabled the authors to describe the clinical electrocardiographic and prognostic features of a hereditary conduction defect and to locate the culprit gene at 19q 13.3. The ECG showed a healthy group and an affected group (mainly right bundle branch block, hemiblocks or complete AV block) and an undetermined group with minor QRS changes in the right precordial leads. The mode of transmission was autosomal dominant. The estimation of penetration in the observed pedigrees and in previously published pedigrees gave a value of 70% in men and 50% in women. There were, therefore, many healthy carriers of the mutation. The onset was congenital (8 babies aged 15 days to one year were affected). Healthy carriers followed up for 10 to 20 years remained normal. The clinical and ECG features progressed in 19% of subjects in the undetermined group. The changes progressed to complete AV block in 8% of affected subjects, both babies and adults. Several cases of sudden infant death were reported but were not documented. The detection of the culprit gene was made by genetic mapping. Markers situated at q 13.3 on chromosome 19 showed linkage. The haplotype related to the pathology was always present in the affected subjects. The genetic interval was 7 centiMorgans.