Posen B M, Moolman J C, Corfield V A, Brink P A
Department of Internal Medicine, University of Stellenbosch Medical School, Tygerberg, South Africa.
Br Heart J. 1995 Jul;74(1):40-6. doi: 10.1136/hrt.74.1.40.
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.
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.
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.
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.
家族性肥厚型心肌病是最常见的遗传性心脏疾病，心脏性猝死是该病患者最常见的死亡原因。部分家族性肥厚型心肌病病例由14号染色体上的β肌球蛋白重链（βMHC）基因错义突变引起，目前已发现至少17种此类突变。近期报告表明，特定的βMHC基因突变与家族性肥厚型心肌病的预后之间存在关联。这一前提目前正被用作向受累家庭提供咨询的依据。然而，这种突变与预后的关联尚未得到广泛评估。本研究对两个不同种族混血的南非家族进行了研究，这两个家族中不同的βMHC基因突变呈分离状态，旨在评估这种相关性。研究结果与先前发表的携带相同突变的欧洲家族报告进行了比较。
通过单链构象多态性分析和测序确定了两个受累家族中的βMHC基因错义突变（家系106：Arg403Trp；家系108：Arg249Gln）。使用聚合酶链反应扩增和基于限制性内切酶的突变检测技术对所有家庭成员进行了基因分型分析。对这两个家族中基因分型确诊的个体进行了临床、心电图和超声心动图研究。
家系106中鉴定出32例携带Arg403Trp突变的个体。家系108中有10例携带Arg249Gln突变。按照左心室最大壁厚≥13mm这一严格的超声心动图标准，家系106中成人（年龄≥16岁）的外显率为25%，家系108为33%。家系106中年龄≥16岁的基因分型阳性个体中，60%出现了符合家族性肥厚型心肌病的心电图和超声心动图异常；家系108中这一比例为80%。两个家族的预后均为良性。对于家系106，这与一个携带Arg403Trp突变的法国家族未发生早期心脏性猝死的报告相符。对于家系108，未出现此类死亡情况，这与一项对携带Arg249Gln突变的欧洲血统家族研究中24例基因分型确诊个体报告的4例死亡情况形成明显对比。
这项对南非一个大家族的研究证实了先前报告中所提示的Arg403Trp突变的良性性质。在将未发生家族性肥厚型心肌病相关死亡与一个欧洲家族中Arg249Gln突变报告的中等生存率进行比较时，必须考虑到第二个南非家族中受累个体的数量和相对年轻的年龄。本研究为目前将特定βMHC基因突变与预后相关联的证据提供了支持，这可作为向受累家庭提供咨询的依据。
