Familial hypertrophic cardiomyopathy is an autosomal dominant genetically heterogeneous disease characterized by a partial penetrance and variable expressivity. Previous studies showed that the extent of hypertrophy is influenced by the angiotensin I converting enzyme insertion/deletion (I/D) polymorphism. Recently, molecular genetic analysis revealed the existence of healthy carriers and that as many as a quarter of genetically affected individuals do not express the disease. This data prompted us to re-investigate the role of the angiotensin I converting enzyme polymorphism on hypertrophy by assessing both clinically affected individuals and healthy carriers. For this, several families with mutations in the cardiac myosin binding protein C or the beta-myosin heavy chain genes were analysed. The mean maximal intraventricular septum thickness was compared as a function of angiotensin I converting enzyme genotypes in all genetically affected individuals (n = 114), and in subsets of subjects carrying either a splice acceptor site mutation in the cardiac myosin binding protein C gene (n = 33), or various missense mutations in the cardiac beta-myosin heavy chain gene (n = 81) or finally, mutation in the Arg403 codon of the beta-myosin heavy chain gene (n = 54). Significant association between the D allele and hypertrophy was observed only in the case of Arg403 codon mutations (mean septum thickness for subjects with the DD genotype: 19.3 +/- 2.7 mm: with the ID genotype: 13.4 +/- 1.3 mm and with the II genotype: 11.0 +/- 0.9 mm; P < 0.02). These results were confirmed by the chi 2 test showing an over-representation of DD genotype in patients carrying an Arg403 codon mutation associated with septal hypertrophy (P < 0.05). Our data confirms that the angiotensin I converting enzyme genotypes can influence the phenotypic expression of hypertrophy and shows that this influence depends on the mutation, raising the concept of multiple genetic modifiers in familial hypertrophic cardiomyopathy.

OBJECTIVES:This study was designed to verify initial observations of the clinical and prognostic features of hypertrophic cardiomyopathy caused by cardiac tropnin 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 counselling.

Background Progressive familial heart block type I (PF-HBI) is a dominantly inherited cardiac bundle-branch conduction disorder that has been traced through nine generations of a large South African kindred. Similar conduction disorders have been reported elsewhere; however, the cause of these diseases is unknown. The aim of the present study was to determine by linkage analysis the approximate chromosomal position of the gene causing PFHBI, thereby allowing family-based diagnosis and the development of positional cloning strategies to identify the causative gene.Methods and Results Eighty-six members of three pedigrees, 39 members of which were affected with PFHBI, were genotyped at four linked polymorphic marker loci mapped to chromosome 19, bands q13.2-q13.3 (chromosome 19q13.2-13.3). Maximum two-point logarithm of the odds scores (which represent the logarithm of the odds ratio of detecting linkage versus nonlinkage) generated were 6.49 (Theta=0) for the kallikrein locus, 5.72 (Theta=0.01) for the myotonic dystrophy locus, 3.44 (Theta=0) for the creatine kinase muscle-type locus and 4.51 (Theta=0.10) for the apolipoprotein C2 locus. The maximum multipoint logarithm of the odds score was 11.6, with the 90% support interval positioning the PFHBI locus within a 10 cM distance centering on the kallikrein 1 locus.Conclusions The gene for PFHBI maps to an area of approximately 10 cM on chromosome 19q13.2-13.3. There are several candidate genes in this interval; although a recombination event ruled out the myotonic dystrophy locus from direct involvement with PFHBI, the proximity of these two loci may be relevant to the observed cardiac abnormalities of myotonic dystrophy. The results provide a means of DNA-based diagnosis in the families studied and a foundation for cloning studies to identify the causative gene.

Human MutationVolume 6, Issue 2 p. 197-198 Mutation in Brief Identification of a novel Ala797Thr mutation in exon 21 of the β-myosin heavy chain gene in hypertrophic cardiomyopathy Johanna C. Moolman, Johanna C. Moolman Department of Medical Physiology and Biochemistry, University of Stellenbosch and South African Medical Research Council Center for Molecular and Cellular Biology, University of Stellenbosch Medical School, Tygerberg 7505, Republic of South AfricaSearch for more papers by this authorPaul A. Brink, Paul A. Brink Department of Internal Medicine, University of Stellenbosch Medical School and Tygerberg Hospital, Tygerberg 7505, Republic of South AfricaSearch for more papers by this authorValerie A. Corfield, Corresponding Author Valerie A. Corfield Department of Medical Physiology and Biochemistry, University of Stellenbosch and South African Medical Research Council Center for Molecular and Cellular Biology, University of Stellenbosch Medical School, Tygerberg 7505, Republic of South AfricaDepartment of Medical Physiology and Biochemistry, University of Stellenbosch and South African Medical Research Council Center for Molecular and Cellular Biology, University of Stellenbosch Medical School, Tygerberg 7505, Republic of South AfricaSearch for more papers by this author Johanna C. Moolman, Johanna C. Moolman Department of Medical Physiology and Biochemistry, University of Stellenbosch and South African Medical Research Council Center for Molecular and Cellular Biology, University of Stellenbosch Medical School, Tygerberg 7505, Republic of South AfricaSearch for more papers by this authorPaul A. Brink, Paul A. Brink Department of Internal Medicine, University of Stellenbosch Medical School and Tygerberg Hospital, Tygerberg 7505, Republic of South AfricaSearch for more papers by this authorValerie A. Corfield, Corresponding Author Valerie A. Corfield Department of Medical Physiology and Biochemistry, University of Stellenbosch and South African Medical Research Council Center for Molecular and Cellular Biology, University of Stellenbosch Medical School, Tygerberg 7505, Republic of South AfricaDepartment of Medical Physiology and Biochemistry, University of Stellenbosch and South African Medical Research Council Center for Molecular and Cellular Biology, University of Stellenbosch Medical School, Tygerberg 7505, Republic of South AfricaSearch for more papers by this author First published: 1995 https://doi.org/10.1002/humu.1380060219Citations: 12AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume6, Issue21995Pages 197-198 RelatedInformation

BACKGROUND--Familial hypertrophic cardiomyopathy is the most common inherited cardiac disorder, with sudden cardiac death at a young age the most frequent cause of death in affected individuals. Some cases of familial hypertrophic cardiomyopathy are caused by missense mutations of the beta myosin heavy chain (beta MHC) gene on chromosome 14 and at least 17 such mutations have been described. Recent reports suggest that a correlation exists between a specific beta MHC gene mutation and prognosis in familial hypertrophic cardiomyopathy. This premise is currently being used as a basis to provide counselling for affected families. This mutation/prognosis association, however, has not been widely assessed as yet. The clinical and prognostic features of two South African families of mixed racial descent, in which different beta MHC gene mutations were segregating, were studied to evaluate this correlation. The results were compared with those of previously published reports of European families carrying the same mutations. METHODS--The beta MHC gene missense mutations in two affected families were identified by single strand conformation polymorphism analysis and sequencing (pedigree 106: Arg403Trp; pedigree 108: Arg249Gln). All family members were subjected to genotypic analysis using polymerase chain reaction amplification and restriction enzyme based mutation detection techniques. Clinical, electrocardiographic, and echocardiographic studies were performed on genotypically affected individuals in these two kindreds. RESULTS--The number of individuals identified in pedigree 106 with the Arg403Trp mutation was 32.10 individuals bore the Arg249Gln mutation in pedigree 108. The penetrance rate in adults (equal to or greater than 16 years), using the strict echocardiographic criterion of maximum left ventricular wall thickness > or = 13 mm, was 25% for pedigree 106 and 33% for pedigree 108. Familial hypertrophic cardiomyopathy compatible electrocardiographic and echocardiographic abnormalities were seen in 60% of genotypically positive individuals aged > or = 16 years in pedigree 106 and 80% in pedigree 108. The prognosis was uniformly benign in the two families. For pedigree 106 this corresponded to a report of no early sudden cardiac deaths in a French family with the Arg403Trp mutation. For pedigree 108 the absence of such deaths was in apparent contrast to the four cases reported in 24 genotypically affected individuals in a study of a kindred of European ancestry bearing the Arg249Gln mutation. CONCLUSION--This study of a large South African kindred confirmed the benign nature of the Arg403Trp mutation suggested in a previous report. The number and the relatively young age of affected individuals in a second South African family must be considered when comparing the absence of familial hypertrophic cardiomyopathy associated deaths with the intermediate survival reported for the Arg249Gln mutation in a European family. This investigation lends support to current evidence relating specific beta MHC gene mutations to prognosis, which may be used as a basis to provide counselling for affected families.

Progressive familial heart block (PFHB) is an autosomal, dominantly inherited, progressive bundle branch disorder. In South Africa, PFHB may be a common reason for fitting a pacemaker and reports suggest that similar conduction diseases may prevail elsewhere under different names. ns the molecular basis is unknown for any of these diseases, identification and cloning of genes that may predispose individuals to the development of these disorders should provide fundamental insight into their pathophysiology. Consequently, in an attempt to define the locus of the causative gene, linkage analysis was performed on six pedigrees (107 living individuals, 43 of them affected) segregating for PFHB, using both classical and DNA genetic markers. Of 80 marker loci tested, 68 were excluded from linkage with the PFHB locus. Furthermore, substantial portions of chromosomes 1 (72%), 4 (70%) and 19 (55%) were excluded from linkage using multipoint mapping. Several excluded loci are candidate genes, namely, collagen genes COL1A1, COL1A2 and COL3A1, the HLA region, H-RAS, APOB, LDLR and the MNS bloodgroup (GPA and GPB genes). The loci excluded represent a total of 1 165 centimorgan (35%) of the genome.

The MN blood group antigens have traditionally been detected by serotyping; however, development of a DNA‐based method offers flexibility in the determination of this highly polymorphic system. Genotyping the MN blood group antigens was performed by polymerase chain reaction amplification of the specific alleles (PASA) in the human genome. In separate paired reactions, M or N allele‐specific oligonucleotide primers were amplified with a common distal primer. Only in the presence of the homologous template was a 781‐base pair polymerase chain reaction amplification product visible after agarose gel electrophoresis and ethidium bromide staining. This method of genotyping could be performed using either 1 μg of extracted DNA or 0.5 microL of whole blood, and the results showed 100‐percent correlation with those obtained by serotyping. PASA‐based genotyping of MN blood group antigens, which requires a small amount of starting material, has application in linkage and population studies and in forensic medicine.

Journal Article Identification of a new missense mutation at Arg403, a CpG mutation hotspot, in exon 13 of the β-myosin heavy chain gene in hypertrophic cardiomyopathy Get access Johanna C. Moolman, Johanna C. Moolman Search for other works by this author on: Oxford Academic PubMed Google Scholar Paul A. Brink, Paul A. Brink 1Department of Internal Medicine University of Stellenbosch Medical School and Tygerberg HospitalTygerberg 7505, South africa Search for other works by this author on: Oxford Academic PubMed Google Scholar Valerie A. Corfield Valerie A. Corfield * *To whom correspondence should be addressed at: US/MRC Centre for Molecular and Cellular Biology, PO Box 19063, Tygerberg 7505, South Africa Search for other works by this author on: Oxford Academic PubMed Google Scholar Human Molecular Genetics, Volume 2, Issue 10, October 1993, Pages 1731–1732, https://doi.org/10.1093/hmg/2.10.1731 Published: 01 October 1993 Article history Received: 08 July 1993 Revision received: 09 August 1993 Accepted: 09 August 1993 Published: 01 October 1993