Back to Search
Start Over
Diagnostic disparity and identification of two TNNI3 gene mutations, one novel and one arising de novo, in South African patients with restrictive cardiomyopathy and focal ventricular hypertrophy
- Source :
- Cardiovascular Journal of Africa
- Publication Year :
- 2015
- Publisher :
- Clinics Cardive Publishing, 2015.
-
Abstract
- Summary Introduction The minimum criterion for the diagnosis of hypertrophic cardiomyopathy (HCM) is thickening of the left ventricular wall, typically in an asymmetrical or focal fashion, and it requires no functional deficit. Using this criterion, we identified a family with four affected individuals and a single unrelated individual essentially with restrictive cardiomyopathy (RCM). Mutations in genes coding for the thin filaments of cardiac muscle have been described in RCM and HCM with ‘restrictive features’. One such gene encodes for cardiac troponin I (TNNI3), a sub-unit of the troponin complex involved in the regulation of striated muscle contraction. We hypothesised that mutations in TNNI3 could underlie this particular phenotype, and we therefore screened TNNI3 for mutations in 115 HCM probands. Methods Clinical investigation involved examination, echocardiography, chest X-ray and an electrocardiogram of both the index cases and close relatives. The study cohort consisted of 113 South African HCM probands, with and without known founder HCM mutations, and 100 ethnically matched control individuals. Mutation screening of TNNI3 for disease-causing mutations were performed using high-resolution melt (HRM) analysis. Results HRM analyses identified three previously described HCM-causing mutations (p.Pro82Ser, p.Arg162Gln, p.Arg170Gln) and a novel exonic variant (p.Leu144His). A previous study involving the same amino acid identified a p.Leu144Gln mutation in a patient presenting with RCM, with clinical features of HCM. We observed the novel p.Leu144His mutation in three siblings with clinical RCM and varying degrees of ventricular hypertrophy. The isolated index case with the de novo p.Arg170Gln mutation presented with a similar phenotype. Both mutations were absent in a healthy control group. Conclusion We have identified a novel disease-causing p.Leu144His mutation and a de novo p.Arg170Gln mutation associated with RCM and focal ventricular hypertrophy, often below the typical diagnostic threshold for HCM. Our study provides information regarding TNNI3 mutations underlying RCM in contrast to other causes of a similar presentation, such as constrictive pericarditis or infiltration of cardiac muscle, all with marked right-sided cardiac manifestations. This study therefore highlights the need for extensive mutation screening of genes encoding for sarcomeric proteins, such as TNNI3 to identify the underlying cause of this particular phenotype.
- Subjects :
- Adult
Male
Risk
medicine.medical_specialty
Adolescent
restrictive cardiomyopathy
Ventricular Dysfunction, Right
DNA Mutational Analysis
Cardiomyopathy
TNNI3
South Africa
Fatal Outcome
Troponin complex
Ventricular hypertrophy
Internal medicine
Cardiomyopathy, Hypertrophic, Familial
medicine
Humans
echocardiography
Genetic Predisposition to Disease
disease-causing mutation
Cardiomyopathy, Restrictive
Polymorphism, Genetic
business.industry
Cardiovascular Topics
Troponin I
Restrictive cardiomyopathy
Hypertrophic cardiomyopathy
General Medicine
Striated muscle contraction
Middle Aged
hypertrophic cardiomyopathy
medicine.disease
Dissent and Disputes
Pedigree
3. Good health
Surgery
Mutation
cardiovascular system
Cardiology
TNNI3 Gene
Cardiology and Cardiovascular Medicine
business
Subjects
Details
- ISSN :
- 16800745 and 19951892
- Volume :
- 26
- Database :
- OpenAIRE
- Journal :
- Cardiovascular Journal Of Africa
- Accession number :
- edsair.doi.dedup.....f911b116795ed4494ac3514dfa331441