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.
BACKGROUND
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 diseasecausing 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.


CONCLUSIONS
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.
SA MRC Centre for Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. jomien@sun.ac.za.
Jomien M
JM
Mouton
Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town South Africa.
Adriano S
AS
Pellizzon
Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town South Africa.
Althea
A
Goosen
SA MRC Centre for Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Craig J
CJ
Kinnear
Division of Cardiology, Department of Medicine, Faculty of Medicine and Health Sciences, Tygerberg Academic Hospital, Stellenbosch University, Cape Town, South Africa.
Philip G
PG
Herbst
Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town South Africa.
Paul A
PA
Brink
SA MRC Centre for Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Johanna C
JC
Moolman-Smook
D000293:Adolescent; D000328:Adult; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000175:diagnosis* / Q000235:genetics; D002313:Cardiomyopathy, Restrictive / Q000175:diagnosis* / Q000235:genetics; D004252:DNA Mutational Analysis; D034462:Dissent and Disputes; D017809:Fatal Outcome; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic; D012306:Risk; D013019:South Africa; D019210:Troponin I / Q000235:genetics*; D018497:Ventricular Dysfunction, Right / Q000175:diagnosis* / Q000235:genetics
D019210:Troponin I