Cardiovascular Journal of Africa: Vol 26 No 2 (March/April 2015)

17 / 67

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 26, No 2, March/April 2015 AFRICA 63
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
Jomien M Mouton, Adriano S Pellizzon, Althea Goosen, Craig J Kinnear, Philip G Herbst, Paul A Brink,
Johanna C Moolman-Smook
Abstract
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 cardiomyopa-
thy (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, echo-
cardiography, 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 muta-
tion screening of genes encoding for sarcomeric proteins, such
as TNNI3 to identify the underlying cause of this particular
phenotype.
Keywords: hypertrophic cardiomyopathy, restrictive cardiomyo-
pathy, troponin I, echocardiography, disease-causing mutation
Submitted 3/9/14, accepted 27/1/15
Cardiovasc J Afr 2015; 26: 63–69
DOI: 10.5830/CVJA-2015-019
Identifying disease and making sophisticated diagnoses at a
specialist level is dependent on opportunity. Effective and
accurate diagnosis starts with persons presenting to medical
concern, their subsequent funneling, levels of awareness and
expertise encountered, and available technology. In this article
we describe a young woman (index case) with classic features
of restrictive cardiomyopathy (RCM) who was referred to us
with hypertrophic cardiomyopathy (HCM). Cascade screening
identified the same disease in four relatives, in whom the
diagnosis for some has changed from tuberculosis (TB) as a cause
for pleural effusions, to cor pulmonale, constrictive pericarditis
(CP) and RCM as the cause of sarcoidosis or amyloidosis. At
the same time, an unrelated young boy presented with a disease
profile similar to our index case, but without a history of disease
in any other first-degree relative.
In view of the associated focal hypertrophy, we speculated
that it could be caused by a mutation in troponin I [I type 3
( TNNI3; Genbank accession no. X90780.1)], which has been
implicated in cases of unexplained RCM and/or HCM with
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 M Mouton, PhD,
Craig J Kinnear, PhD
Johanna C Moolman-Smook, PhD
Division of Cardiology, Department of Medicine, Faculty
of Medicine and Health Sciences, Tygerberg Academic
Hospital, Stellenbosch University, Cape Town, South Africa
Philip G Herbst, MB ChB, MRCP (UK), FCP (CMSA), Cert Cardiol
(CMSA)
Department of Medicine, Faculty of Medicine and Health
Sciences, Stellenbosch University, Cape Town South Africa
Adriano S Pellizzon, MB ChB (UCT), MMed (Int), FCP (SA)
Althea Goosen, RHN
Paul A Brink, MB ChB, MMed, BSc (Hons), PhD (SU)