The long QT syndrome in South Africa

The long QT syndromes (LQTS) are Mendelian inherited conditions where syncope and sudden death are due to precipitous occurrence of polymorphic ventricular tachycardia. In South Africa a number of white, some coloured and some Asian individuals have been identified but, interestingly, not a single black person and neither has it been reported from Africa. With over 400 known causal-mutations, mostly in cardiac ion channel-genes, it is unlikely to be absent in African populations. LQTS is notorious for going undiagnosed or misdiagnosed, perhaps even more so in Africa. Amongst persons of Afrikaner descent the KCNQ1 A341V-mutation represents a founder effect. The availability of 170 living individuals sharing the same mutation has made it possible to study factors modifying risk. A blunted autonomic response has been shown to decrease risk of attacks

Identification of a novel Ala797Thr mutation in exon 21 of the β-myosin heavy chain gene in hypertrophic cardiomyopathy

[No abstract available]Articl

Identification of a new missense mutation in MyBP-C associated with hypertrophie cardiomyopathy

Hypertrophie cardiomyopathy is a primary cardiac disease, characterised by idiopathic myocardial hypertrophy, and is caused by defects in s arc orner ic protein encoding genes. One of these genes is cardiac myosin binding protein C (MyBP-C), in which a number of splice site and duplication mutations causing HCM have been described. During mutation screening of a South African HCM population by PCR-SSCP, a missense mutation, Arg654His, was detected in one proband. Although the mutation was present in his three adult children, only the proband himself was markedly affected. This is the first report of a disease associated missense mutation hi MyBP-C which does not affect the myosin or titin binding domains.Articl

Molecular genetics of cardiomyopathy: Changing times, shifting paradigms

Congestive heart failure is a major problem in developed and developing countries alike. Primary dysfunction of the heart muscle accounts for a significant proportion of patients with a non-ischaemic cause of heart failure. Application of genetic techniques has facilitated identification of some molecular causes of the inherited form of these diseases, dramatically increasing our understanding of the pathogenesis of these primary, previously termed 'idiopathic', cardiomyopathies over the last few decades. Knowledge of the different causes is beginning to coalesce into aetiological principles underlying the clinically distinguished cardiomyopathies. Hypertrophic cardiomyopathy (HCM) now appears to be a disease caused by a dysfunctional sarcomere, dilated cardiomyopathy (DCM), a disease of myocytic structural instability, and arrhythmogenic right ventricular cardiomyopathy, a disease of accelerated myocyte death. The aetiology of both HCM and DCM probably also involves cardiac energy imbalances, while additional factors modify the clinical expression in all cardiomyopathies. Even though our knowledge of the genetic aetiology of the cardiomyopathies is still incomplete, it already has relevant clinical significance. Elucidation of the full genetic contribution to the development and progression of the cardiomyopathies represents a new challenge in the study of these diseases, and will undoubtedly lead to new therapeutic approaches in the not-too-distant future.Revie

Molecular genetics of cardiomyopathy: Changing times, shifting paradigms

Congestive heart failure is a major problem in developed and developing countries alike. Primary dysfunction of the heart muscle accounts for a significant proportion of patients with a non-ischaemic cause of heart failure. Application of genetic techniques has facilitated identification of some molecular causes of the inherited form of these diseases, dramatically increasing our understanding of the pathogenesis of these primary, previously termed 'idiopathic', cardiomyopathies over the last few decades. Knowledge of the different causes is beginning to coalesce into aetiological principles underlying the clinically distinguished cardiomyopathies. Hypertrophic cardiomyopathy (HCM) now appears to be a disease caused by a dysfunctional sarcomere, dilated cardiomyopathy (DCM), a disease of myocytic structural instability, and arrhythmogenic right ventricular cardiomyopathy, a disease of accelerated myocyte death. The aetiology of both HCM and DCM probably also involves cardiac energy imbalances, while additional factors modify the clinical expression in all cardiomyopathies. Even though our knowledge of the genetic aetiology of the cardiomyopathies is still incomplete, it already has relevant clinical significance. Elucidation of the full genetic contribution to the development and progression of the cardiomyopathies represents a new challenge in the study of these diseases, and will undoubtedly lead to new therapeutic approaches in the not-too-distant future.Revie

Evidence of a long QT founder gene with varying phenotypic expression in South African families

We report five South African families of northern European descent (pedigrees 161, 162, 163, 164, and 166) in whom Romano-Ward long QT syndrome (LQT) segregates. The disease mapped to a group of linked markers on chromosome 11p15.5, with maximum combined two point lod scores, all generated at 0 = 0, of 15.43 for the D11S922, 10.51 for the D11S1318, and 14.29 for the tyrosine hydroxylase (TH) loci. Recent studies have shown that LQT is caused by an Ala212Val mutation in a potassium channel gene (KVLQT1) in pedigrees 161 to 164. We report that the same mutation is responsible for the disease in pedigree 166. Haplotype construction showed that all the families shared a common haplotype, suggesting a founder gene effect. DNA based identification of gene carriers allowed assessment of the clinical spectrum of LQT. The QTc interval was significantly shorter in both carriers and non-carriers in pedigree 161 (0.48 s and 0.39 s, respectively) than the same two groups in pedigree 161 (0.52 s and 0.042 s, respectively). The spectrum of clinical symptoms appeared more severe in pedigree 162. The possible influence of modulating genetic factors, such as HLA status and sex of family members, on the expression of an LQT founder gene is discussed.Articl

The origins of hypertrophic cardiomyopathy-causing mutations in two South African subpopulations: A unique profile of both independent and founder events

Hypertrophic cardiomyopathy (HCM) is an autosomal dominantly inherited disease of the cardiac sarcomere, caused by numerous mutations in genes encoding protein components of this structure. Mutation carriers are at risk of sudden cardiac death, mostly as adolescents or young adults. The reproductive disadvantage incurred may explain both the global occurrence of diverse independent HCM-associated mutations and the rare reports of founder effects within populations. We have investigated whether this holds true for two south African subpopulations, one of mixed ancestry and one of northern- European descent. Previously, we had detected three novel mutations - Ala797Thr in the β-myosin heavy-chain gene (βMHC), Arg92Trp in the cardiac troponin T gene (cTnT), and Arg645His in the myosin-binding protein C gene (MyBPC) - and two documented βMHC mutations (Arg403Trp and Arg249Gln). Here we report three additional novel mutations - Gln499Lys in βMHC and Va1896Met and Δc756 in MyBPC - and the documented βMHC Arg719Gln mutation. Seven of the nine HCM-causing mutations arose independently; no conclusions can be drawn for the remaining two. However, the βMHC Arg403Trp and Ala797Thr and cTnT Arg92Trp mutations were detected in another one, eight, and four probands, respectively, and haplotype analysis in families carrying these recurring mutations inferred their origin from three common ancestors. The milder phenotype of the βMHC mutations may account for the presence of these founder effects, whereas population dynamics alone may have overridden the reproductive disadvantage incurred by the more lethal, cTnT Arg92Trp mutation.Articl

Sudden death due to troponin T mutations

Objectives. This study was designed to verify initial observations of the clinical and prognostic features of hypertrophic cardiomyopathy caused by cardiac troponin T gene mutations. Background. The most common cause of sudden cardiac death in the young is hypertrophic cardiomyopathy, which is usually familial. Mutations causing familial hypertrophic cardiomyopathy have been identified in a number of contractile protein genes, raising the possibility of genetic screening for subjects at risk. A previous report suggested that mutations in the cardiac troponin T gene were notable because they were associated with a particularly poor prognosis but only mild hypertrophy. Given the variability of some genotype:phenotype correlations, further analysis of cardiac troponin T mutations has been a priority. Methods. Deoxyribonucleic acid from subjects with hypertrophic cardiomyopathy was screened for cardiac troponin T mutations using a ribonuclease protection assay. Polymerase chain reaction-based detection of a novel mutation was used to genotype members of two affected pedigrees. Gene carriers were examined by echocardiography and electrocardiology, and a family history was obtained. Results. A novel cardiac troponin T gene mutation, arginine 92 tryptophan, was identified in 19 of 48 members of two affected pedigrees. The clinical phenotype was characterized by minimal hypertrophy (mean [± SD] maximal ventricular wall thickness 11.3 ± 5.4 mm) and low disease penetrance by clinical criteria (40% by echocardiography) but a high incidence of sudden cardiac death (mean age 17 ± 9 years). Conclusions. These data support the observation that apparently diverse cardiac troponin T gene mutations produce a consistent disease phenotype. Because this is one of poor prognosis, despite deceptively mild or undetectable hypertrophy, genotyping at this locus may be particularly informative in patient management and counseling.Articl

Mutations of the light meromyosin domain of the β-myosin heavy chain rod in hypertrophic cardiomyopathy

Familial hypertrophic cardiomyopathy (HCM) is caused by mutations in 9 sarcomeric protein genes. The most commonly affected is β-myosin heavy chain (MYH7), where missense mutations cluster in the head and neck regions and directly affect motor function. Comparable mutations have not been described in the light meromyosin (LMM) region of the myosin rod, nor would these be expected to directly affect motor function. We studied 82 probands with HCM in whom no mutations had been found in MYH7 exons encoding the head and neck regions of myosin nor in the other frequently implicated disease genes. Primers were designed to amplify exons 24 to 40 of MYH7. These amplimers were subjected to temperature modulated heteroduplex analysis by denaturing high-performance liquid chromatography. An Ala1379Thr missense mutation in exon 30 segregated with disease in three families and was not present in 200 normal chromosomes. The mutation occurred on two haplotypes, indicating that it was not a polymorphism linked with another disease-causing mutation. The position of this residue within the LMM region of myosin suggests that it may be important for thick filament assembly or for accessory protein binding. A further missense mutation in exon 37, Ser1776Gly, segregated with disease in a single family and was absent from 400 population-matched control chromosomes. Because the Ser1776 residue occupies a core position in the myosin rod at which the substitution of glycine is extremely energetically unfavorable, it is likely to disrupt the coiled-coil structure. We conclude that mutation of the LMM can cause HCM and that such mutations may act through novel mechanisms of disease pathogenesis involving myosin filament assembly or interaction with thick filament binding proteins.Articl